United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(7508C)
EPA 738-R-99-
November 1999
vvEPA Registration
Eligibility Decision (RED)
3-Trifl uoro-Methy 1-4-N itro-Phenol
and Niclosamide
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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 All pesticides sold or distributed in the United States must be registered
Reregistration 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®).
Use Profile
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
History
Human Health
Assessment
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TFM was first registered as a pesticide in the U.S. in 1964 by the U.S.
Department of Agriculture (USD A), the Agency's predecessor for pesticide
regulation under FIFRA. Currently, two TFM products are registered with
EPA.
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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
indicate! by aLDjo"> 2000 mg/kg (Toxicity Category In). 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,
carcinogeniciry, mutagenicity or of increased tumor incidence.
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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 hi fish and water.
Tolerances have not have been established and are not required for TFM
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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
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exposure.
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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 ^Wle 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 (>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)
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 LC99 9 for sea lamprey while being substantially less
-------
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fit
than the LCjs for brown trout. This improves treatment effectiveness for sea
lampreys, yet ininimizes 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 qccur 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.
nil •
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
'^ , : ' " '' ii ' " " ' ' ' '""' '" ' ' ''' ' ' '' i, i ' " " • i ,"» II . ' ,':"', ' ' ": T M,"1!',1:11:,' :„
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.
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Product Labeling All TFM end-use products must comply with EPA's current pesticide
Changes Required product labeling requirements. Please see the attached labeling table for a
comprehensive list of labeling requirements from the TFM RED document.
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Regulatory The use of currently registered products containing TFM in accordance
Conclusion w^h 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 More 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
Reregistration 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 513-489-8695.
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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Table 14: Summary of Required Labeling Changes for TFM
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"Local, State, and Provincial Fish and Game Agencies must be contacted before product
Municipalities that use streams requiring treatment as potable water sources must be not
impending treatment at least 24 hours prior to application. Agricultural irrigators that us
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United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(75O8C)
EPA-738-F99-013
November, 1999
45-EPA R.E.D. FACTS
Niclosamide
Pesticide All pesticides sold or distributed in the United States must be registered
Reregistration 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',5'-dichloro-4'-nitro
salicylanilide (Niclosamide).
Use Profile
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
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Human Health
Assessment
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Niclosamide was first registered as a pesticide in the U.S. in 1964 by the
U.S. Department of Agriculture (USD A), 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°/o
granular formulation. The registrant has requested voluntary cancellation of
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the 5% granular product.
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Toxicity
Niclosamide has acute oral LD?0 values of > 1000 mg/kg (Toxicity
Category Hi). The acute dermal toxicity is minimal, as indicated by a LDSO >
2000 mg/kg (Toxicity Category iff). It produced slight skin irritation (toxicity
Category IV) and caused eye irritation (unclassified Toxicity Category based
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on short time interval of eye examination). It was a moderate skin sensitizer.
The acute inhalation data are not available.
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Niclosamide showed no evidence of causing developmental toxicity,
mutagenicity or carcinogenicity.
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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 wafer
from streams during treatment, and the rapicf 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.
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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
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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 nave ^ttle 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
• 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 (LD50 60 mg/kg)
• Avian subacute dietary- practically nontoxic (LC50 > 5,419 mg/kg diet()
• Mammalian acute- practically nontoxic (LDSO > 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 (EC50 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
-------
vl I
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
III ' ,'iSi" :"'Yi,"";», ' -. • / . • , ' ,: , ,:• . ,", ,". ' • J' ,v .'. V II / • • , , ' ,1 • , ,
of the stream. Thus, nontarget species that may have been affected in the treatment
ar,ea 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.
i,.
Risk Mitigation
iLiill i.
II if* n
Additional Data
'pu' "Required
L! • • '•-" •• •: , lif"' •.. . iii ". ,„ is1 I.1 !., :', I;,,*/ 'in1-; " " !.»,- f-,: •,
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.
, •• " : ,"", "v" .: ;,:,:,' >' :„ - ' ;.:; :" I • i, , ' ; 'V"'{h"8B .•: ,
1 .: , '"" •. ! .' •• i «',, "'Hi,, V |w •'"<•' -'I ,' , •: * • •; ,• ', - vj it :':' .
EPA is requiring the following additional generic studies for niclosamide to
regulatory assessments and conclusions:
Photpdegradation in Water Guideline # 835-2240 (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.
,j
Product Labeling All niclosamide end-use products must comply with EPA's current pesticide
Changes Required product labeling requirements. For a comprehensive list of labeling requirements,
please see attached labeling table from the Niclosamide RED document.
!::;'!' :, . 1i" I "' - ' • ' • •:•"• ^ ' , ,,„'; : !: '. ,',*: ;'f,i"'- 'i' |. ., • • '. ? !'$ •**
Regulatory 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.
-------
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-Methvl-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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Some materials that are chemical-resistant to this product are listed belo
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"Mixers, loaders, applicators and other handlers must wear:
Long sleeved shirt and long pants
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
CERTIFIED MAIL
NOV 17
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 reregistration. The
RED includes 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 yeurs,
' ri
Enclosures
/Lois A. Ro$si, Director/
Special Review and
Reregistration Division
-------
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SUMMARY OF INSTRUCTIONS FOR RESPONDING TO
THE REREGISTRATION ELIGIBILITY DECISK
1. DATA CALL-IN (DCR 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 justification. 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 Registration (EPA Form 8570-1). Use only an original application
form. Mark it "Application for Rcregistration." Send your Application for Reregistration (along with the
other forms listed in b-c 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 reretnstration) separately. You may, but are not required to, delete uses which
the RED says are ineligible tor 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 TCSF> 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
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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.
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EPA' form '$570^31 ..... for each product. ' ' " """„,"'" ...... ' " ......... "" ........ \[ ' ...... "' ...... '"'" ...... "'
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4, 'COMMENTS IN"'RESP6NSE TO FEDERAL REGISThER'NOTICE-Comrnents 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. \VHERE TO SEND PRODUCT SPECIFIC PCI RESPONSES f90-DAY) AND
: APPLTCATIONS V&k RERECTSTOATION (8-MONTH RESIPONSESJ" ..................
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Document ProcessingJDesk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C)
" EPA, 401 M St. S.W.
Washington, D.C. 20460-0001
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Room 266A, Crystal Mall 2
192 IJefferson Davis Hwy.
Arlington, VA 22202
: '' ' ' - •"' - ' '"j
6. EPA'S REVIEWS—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 reregjstration determination within 14 months after the RED has been issued
;;„ :,!,
-------
REREGISTRATION ELIGIBILITY DECISION
3-Trifluoro-Methyl-4-Nitro-Phenol
CASE 3082
and
Niclosamide
CASE 2455
-------
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-------
TABLE OF CONTENTS
EXECUTIVE SUMMARY v
I. INTRODUCTION 1
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 11
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... 7.". .. 21
F, Environmental Assessment for TFM 21
1. 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
-.'i;" i! 'i: ' •' • :,i (3) ' Insects .'. ........'..'".'........'.......". ". 22
c. Toxicity to Freshwater Aquatic Organism 22
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(1) Freshwater Fish, Acute and Chronic 22
"i;:; ,,',; •' •' ::(2) Freshwater Invertebrates, Acute and Chronic 23
(3) Toxicity to Estuarine/Marine Organisms 24
.'.. :,.:' ! d. ' Toxicity to plants ..........." '."".'.....".. I............ 24
2. TFM Environmental Fate and Transport 1. 24
a. TFM Degradation ". 25
b. TFM Metabolism .., .., . j. 26
; ' i! . ;i 'i' c. TFMMobility ............'...'.".". 27
d. TFM Accumulation 28
3. TFM Aquatic Exposure Assessment 28
G. Environmental Assessment for Niclosamide j. 28
1. Ecological Exposure and Risk Characterization for Niclosamide 28
*••; •„,"" „" „ ',„ a.'. ''' '""Summary 28
',,;";. ",::|j;; ^ ,' b.( „ ^ Toxicity to Terrestrial Animals .'...".. .'„",!.."...'".'..........".'."." 29
(1) Avian Acute Oral, Subacute Dietary and Chronic 29
(2) Mammals, Acute and Chronic '. 29
(3) Insects 29
cT 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. Niclosamide Bioaccumnlation 33
:: ": •
-------
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 Eligibility 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 Disrupter 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 REQL IRED 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
VI. 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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CITATIONS CONSIDERED TO BE PA^T OF THE
DATA BASE SUPPORTING TlJJEREREGISf RATION
DECISION (BIBLIOGRAPHY) 85
COMBINED GENERIC AND PRODUCT SPECIFIC
DATA CALL-IN I ...............
E.
1.
,2.
3.
4.
5.
Chemical Status Sheets ,. .„_..... .Y."... .i.,,.it,,.i. 5, •„• • •„•.•.-
Combined Generic and Product Specific DCI Response
Forms (Josert A) Plus Instructions''.* ?''.'.'"..'..""!.'; '".'..
Generic and Product Specific Requirements Status and
Registrants' Response Forms (Insert B) and Instructions
EPA's Batching of TFM and Niclosamide Products for
Meeting Acute Toxicity Data Requirements for
Reregistration
List of All Registrants Sent This Data Call-in Notice ...
LIST OF AVAILABLE RELATED DOCUMENTS AND
ETJlicTRONICALLY AVAILABLE FORMS
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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 Spate
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 forNiclosamide
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 defunct term for reference dose (RfD).
AE Acid Equivalent
a.i. Active ingredient
ARC Anticipated Residue Contribution
CAS . Chemical Abstracts Service
Cl Cation
CNS Central Nervous System
CSF Confidential Statement of Formula
DFR Dislodgeable Foliar Residue
DRES 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. Theestimatedpesticideconcentrationmanenvironmentsuch
as a terrestrial ecosystem.
EP End-Use Product
EPA U.S. Environmental Protection Agency
FAO/WHO Food and Agriculture Organization/World Health Organization
FDA Food and Drug Administration
F1FRA 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 Safe 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
LCSO 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/1, mg/kg or ppm.
LD50 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.
LD,0 Lethal Dose-low. Lowest Dose at which lethality occurs.
LEL Lowest Effect Level
LOG 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
hi drinking water under the Safe Drinking Water Act.
fig/g ' Micrograms Per Gram
,«g/L Micrograms per liter
mg/L Milligrams Per Liter
MOE Margin of Exposure
MP Manufacturina-Use Product
111
-------
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Maximum Permissible Intake
Master Record Identification (number). EPA's system of recording and tracking studies submitted.
Sot Applicable
l^o Observable Effect Concentration
National Pollutant Discharge Elimination System
No Observed Effect Level
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No Observed Adverse Effect Level
Organophosphate
Office of Pesticide Programs
pascal, the pressure exerted by a force of one newton acting on an area of one square meter.
Provisional Acceptable Daily Intake
Pesticide Assessment Guideline
Pesticide Analytical Method ,. ,
Pesticide Handler's Exposure Data
Preharvest Interval
Parts Per Billion '
Personal Protective Equipment
Parts Per Million
Pesticide Registration Notice
The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer Risk Model
Red Blood Cell
Reregistration Eligibility Decision
Restricted Entry Interval
Reference Dose
Registration Standard
Restricted Use Pesticide
Special Local Need (Registrations Under Section 24 © of FIFRA)
Toxic Concentration. The concentration at which a substance produces a toxic effect.
Toxic Dose. The dose at which a substance produces a toxic effect
Typical End-Use Product
Technical Grade Active Ingredient
Thin Layer Chromatography
Theoretical Maximum Residue Contribution
PI "III I >' ,!„! ;. .!',!!,! ,' . ''IP, ''l.n.1 i," i' , , 'IIP II /II "' ,' i I, l;ill.' ''I' ' .I illlllllli ,' ' Jill!"" II1 Pi il H'"'ll I ' ' " I
A unit of pressure needed to support a column of mercury 1 mm high under standard conditions.
WettablePowder ' ', , .' ' , '". '" ,' '„ , " , ."
Worker Protection Standard
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-------
EXECUTIVE SUMMARY
EPAhas completed its retegistration eligibility decisions for thepesticidestrifluoro-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 againstthe 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 proliibitive 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
-------
IX!' HI!,!,,.... ill1!
streams an,
-------
I.
INTRODUCTION
In 1988, the Federal Insecticide, Fungicide and Rodentici.de 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 reregislration 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)(2)(A) 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 Agency's decision regarding the reregistration eligibility of the
registered uses of TFM and niclosamide. The document consists of six sections. Section I is the
introduction. Section n describes TFM and niclosamide, their uses, data requirements, and regulatory
history. Section El 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 HI is a combined exposure and risk
characterization of the two chemicals. Section TV presents the reregistration decision for TFM and
niclosamide. Section V discusses the reregistration requirements for TFM and niclosamide. 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
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-Trifluoromethyl-4-nitrophenol (KJPAC)
a,a,a-trifluoro-4-nitro-m-cresol, sodium salt (CAS)
phenol
88-30-2
-------
ill
OPP Chemical Code: 036201
Empirical Formula: <
Basic Manufacturer: Clariant International (Germany)
H & S Chemical Company,
i
'£ , :<:,;•.;, :"',, ; i:1;,,, ,1 .,, ,«; „ •:, : isiiji| '"packed for USFWS (USA) and Fisheries and Oceans
:':.',,•',,;.' i,,-:"i:ii *,-/",„ ' ;"; '*.' Canada, Ottawa, Ontario (Canada).
. ,,„ ....... ,„,,„,„
; "I'l's ' ..... ' i •";
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s; ......
• Common Name: Bayluscide, niclosamide
• Chemical Name: 5-chloro-N-(2-chloro-4-nitrophenyl)-2-
"i.,:; .',>"'',, ........ ;,„, -f ...... ,• ..... ,;,•-«„ .•; -,;; ,r ....... r ::^ hydroxybenzamide (TUPAC)
'" ...... ;; ii ..... f*i !• « , "{••• ,, . ,I, *' ;;" ...... I;* ,;:,. ,-iv ',,.* • '"',; ''";'! ',. 2-am mo" ethanol salt of i^S'-dichloro-^-nitro "
f '"i if ....... ifi.il , ,{'.'1..;, J1*1 !!! ..... t: ••••:tf, 'ftii ..... Vj;!1 .''rtr •;! ..... •;• ' '" ;/ ', ISi,'!1, , ..... Ji'li1 ........ J.ilirr',;:', ,1,:";! ...... „:' ,u ..... . in . - ..... : ..... ;. ,: ........ :,
- ?:V . ......... \ ..... ...I '" , » j; . ...... .' ;; ..... . ... : , "'. ' »,. ,, , :i ....... ". -. ." ' : '?• ' ,.«, . ...... ; salicylanilide (CAS)
••"• Cnemicai Family: halogenatedmonomlr6ben2amide
„••• ........ ;;:, • ..... CAS Regjstc^ Number: _ ^ 1420-04-8 ....... '
"'""" ''': 07740,1 . ' "..'.'. ..... ............. '_ ." ...... ' ""' '
asic, Manufacturer:
. ..... ,,, «
,
Bayer, Specklty Products, Inc.
".. ...... packed for USFWS (USA) and Fisheries and Oceans
Canada/Ottawa, Ontario (Canada).
'lEi ....... Type of Pesticide:
Sites:
, ;,
:, >' : !"' . fj'i
* ,l|l|'i;"l , I11'.-'1'
M^\ if ....... ' ...... t(
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^"dl. ...... |Target Pests:
...... 1 ..... ''^iis^^
, ''ift ..... .w'1?^' ?FM:
' ..... i| '• ' i"1 -il!, ' • ,, ..... ..''I. Ifii i ,:
'i- ....... b •''«•' ...... Niclosamide
', ..... ill. .; '.'':.'. . ...... .1: ...... 11!1";
,
lampricides
tributaries to the Great Lakes, the Finger Lakes and Lake
...... Champlain ..........................
LWvai stage of the Sea Lamprey '(Peftromyzon marinus)
' ...... '"' '' ..... ' ""' .......... '' ''
. ..... ... , ...... , .. ,.., ....... ........ * .., ..... ,
Liquid concentrate (38%), Bar (solid)
si!;.; ..... I V, «•. ........... ..... ..;,; ...... i. : ..... , .„ ...... , > , . ..... ..... c/V ,/ , ,,> ,11 1 , / i ........ .,;i ...
70% Wettable Powder, Granular (3.2% and 5%)
'' •.: ^' ' •''<' '-
Niclosamide
" •
,, i. ...... nv ....... • ........
,1 "I!"1.,'I i'»,;»•' I!;,-,
Type of Pesticide:
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,
SclustbsQmiasJS in Puerto Rico
II I 111 II II
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Formulation Types:
70% Wettable Powder in FL, AR, and Puerto Rico
5% Granular in 3Vfl, 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, turbid waters. Specific application instructions and
formulas for application rates are included in die Manual for Application ofLampricides 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 are 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 \VP (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.
-------
lill
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 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
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.
Jhese 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).
TJfe wettable powder formulation of niclosamide is also labeled for use in ornamental fish ponds
m Fiprida 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 St 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 me 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 tqtal niumb.^0^jrfcutarjes) are treated on a 3 - 5 year cycle, hi a normal treatment yean 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
pounds active ingredient used
Superior
Michigan
Huron
Erie
Ontario
Total
6717
18150
40371
0
9438
74676
19991
3.1219
26953
9561
7026
94750
15997
25507
24065
414
10307
76290
1996
1997
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
0
7-4
(I
-
SI
53
25!
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 arc sufticien: 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 marinus) 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 life stage, the animal is not harmful to other fish and feeds by
-------
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fiteigng food fibom^stream water. Sea lampreys may lemain in lie larval stage from 3 to more than 17
years oelore transforming into the parasitic (predatory) stage. Parasitic stage lampreys feed by attaching
"; j^A "I'liiii ' ^,i! IIT > .Mm I j/ :,;.' ' ,111,11. MI , „ , ,,,i ,i BIV ^, ' r? • ' , v, »,"',, ,,i!,,',, • M," ,i ,„,,>, ' /*T, :
to fish and rasping deep wounds from which they suck blood, body fluids, and pieces of flesh. The
,.,'i-Iiiil'r t'iiiUi.' .•* ri. ,,.& i, , i , .,. i,. -t , , »,. si, .,'„,,' ,,AM, , , i, „• - „,-
lls of sjich a,ttacks are often fatal for;the-host fish.
' ''' ' " ''
Ill"
HI 'i'l
Sea lampreys were introduced to the Great Lakes when the Welland Canal around Niagara Falls
|y^ c^n|l||ctea in 1829; by the late 1940's, lampreys had severely impacted the commercial and sport
fisheiigs ujfhe|3rgat Lakes. Early attempts to control sea lampreys began in 1953 with the installation of
mecl&ical traps in spawning streams, but these measures were largely unsuccessful. No effective control
\vas accomplisThed" until the advent of a chemical control program with TFM (Lamprecid®) and
niclosamide (gayluscide) in the late 1950's. According to the USFWS "the successful chemical control of
S€a lampreys has allowed reestabHshment of a robust sport and commercial fishery in the Great Lakes."
These conipounds have been used since that time to manage the sea lamprey populations in the Great
Lakes, 'the"Pmger'tia£esTand™Lake Champlain^ The use of these chemicals is managedby 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.
In 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
maniifactunng-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 l
in? '.*:! ii .'« '"
niclosamid
id®) is an aquatic non-food outdoor use chemical. The lampricides (TFM and
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 ]?een 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 in fish are parent TFM and the TFM-glucuronide conjugate.
ll'l!M"l " ' '. .' '"'I .! ' M.I I ' l' ' , 'II 'II , ' ,1 .1 "' ',,' '. ' III' ' "111' I „!.' ,1 II
'I:
-------
III. SCIENCE ASSESSMENT
A. Physical Chemistry Assessment for TFM
TFM (Lamprecid®) is chemically a,a,a-trifluoro-4-nJtro-in-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 free 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
14.1 and 160 mg/kg for males and females, respectively (Toxicity Category n). The acute dermal toxicity
is minimal, as indicated by a LD50 > 2000 mg/kg (Toxicity Category ffl). It produced slight skin irritation'
(Toxicity Category IV) 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 are not available.
-------
i* in pill!1;, iniiip';'iii''"ii'!iniii inniin wiifi^viiDpii, 'nini:1:!:1!:"!!: n
:" fail i li'iiiR1::, jiiiiihSniii'iinii'i'iiiinininii"1 niinmis'ifii -t . :i n • \"»» i n: nil inu i«iiir
i" it
iiinnyiit iiiiiiiiniii.if'' m.ji'i'iii1;:, in: uuum1 IK „ jiini ^ anpii fiiii, HI in ui: 1;:;i i,«'i iFffii' <;;•„ i^ii HI nipgi unr
'»'"'!'., ', " ' » '" , \ • Jlili1"
i'+hf
Lit I "III I,
if 'i' :lii 'I i'ijl'
Table 3. Summary of the Results of Acute Toxicity Studies on Technical Grade TFM1
GUIDE-
Sl-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 sensitixaiion
MRID#
40999204
41898102
40999205
41898103
40999207
41898104
40999206
41898105
41898106
RESULTS
LD50 = 160mg/kg(M)
LD50=141mg/kg(F);
LD50>2000mg/kg;
Eye irritant (corneal opacity, conjunctival
redness, chemosis, & discharge; all clear by
day 7 after treatment)
Slight erythema seen on the treatment site.
Not a dermal sensitizer
TOXICITY
CATEGORY
II
111
Not available
in
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 Toxicity
I'!!1:,!1 " mi,'i
i-:!"; :' i',
SHI!: kl ,
'ill,.
The results did not show significant toxicity in two 90-day feeding studies in rats and in a 6-month
feeding study in dogs.
" ..... - 1' ' "
.'" ' 'I I !' , i'"
: established.
I. !""
I;,1':"
'Si*!!
; ui! i mi mi,
iiiiiip: "f
iiiil! ,:i«i||i'
Iiili,* /'E.i
'•at
Bit
'ini j i|i< ' .'I,, " ,i up" /" ,' ,i|n pic 'I'." , ii ,i, i " r,; in ' • ,i| ""i iiiiiP,,,1 i- ', »i '"',,' ', 'i,i 'mi""; ' " iiiii»
i', "j '' ,i" .i"!"*!" . iriiliill ' !'iiilili, "i!1'i 111 '"I'I 'ill'1,;,"',!! ,f' '",-" i,": .... ;' , I.'fi-ll''I1 ,ii i' ''"'''}" " 1'.' ', ,*:'- . "'„ "lil 'if "ii ,; i Si"! I, It i, ' ,.!' " ' 'It •" " ... i i1 ',:',!
,iij;:"';(i|:. In asecond90-da.y feeding study in rats (MRID 00112727), groups of weanling SD rats
(lO^ex^roup) were fed diets containing TFM (90%) at concentrations of 500, 900, 1620, 2916, or
'. "5248.|ym for 90id^._The_cpntrpl 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
i'i, f „," :" Dili!"'" i; Hi!1" '!lll:il ' .nif'i ,„;,',!, v. ,1 ..; , J er- r '_, ,^.:
, H i,,';,,, .i"1" !iii "ii,'' •'" .ill1" :;• Hi' ,' 'Sisriii, •• • i
* -ml
-------
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 hi 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'the diet at concentrations of 300,1250, or 5000 ppm for 6 months. The
controls (4/sex) received 2% corn 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 hi organ weight were seen hi 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
hi 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 in Bouin's fixative for
subsequent visceral examination and the remainder stained for skeletal examination.
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 toxiciry 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 toxiciry 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,
-------
Ill
E!
i ....... It ..... ,,
•' y 11
'„!.,,, I:
r iiJ:! {I! '
I
lesorptions/dam, fetal body weights, or fetal sex ratios. No statistically significant differences in the
incidence rates of any external, visceral, or skeletal rnalfonnations/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).
|', H " "IP' ^illllltilllli 'I I, ," 1, ' i"1, L ', „ , ' ' i'1,'I!" ' '.,,111. I" i ! ,„, - ' .| i.,1" il, . "" in1 I 111' i ,1,11, II'1 "I 'i, ' i11" i J||< . .l,li,,ll i."..'"7'. i".' '» , l,:f,i| , , ' , , '
to^ 5% of the cells died Under the conditionsipf this study, TFM
was negative for mutagenicity.
i
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 ^g/ml for 1725 hrs. in absence of the 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 Afg/ml Colcemid was added to the
washed ce|s. T|e cells were then incubated IH: 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 Mg/ml induced chromosomal aberrations, consisting
mainly of simple chromatid breaks. In the presence of S9 activation, 1150 and 1540 ^g/rnl of TFM
i',, .'I " , \ ' 14 i lii .'' •• -•,.', '"., ., .'•>' . ' ' '' •'•.;. •' ..- • 'ir' ", ;' ,'",;»'l"1' ,ii'
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-
LINE*
82-la
82-la
82-lb
83-3
84-2
STUDY TYPE
feeding studies
developmental
mutagenicity
MRID No.
00112726
rats
00112727
rats
00112725
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
ENDPOINT
NOAEL - 5249 ppm (525 mg/kg/day)
LOAEL not established
NOAEL = 1620 ppm (162 mg/kg/day)
LOAEL = 29 1 6 ppm (292 mg/kg/day)
NOAEL = 1250 ppm (31 mg/kg/day)
LOAEL = 5000 ppm (125 mg/kg/day)
NOAEL = 125 mg/kg/day
LOAEL = 250 mg/kg/day
NOAEL = 25Q 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
-------
'fill M; i-1'.,:,t
*;!* ..... ' .....
'll*"''; ..... : ............ :.V:.y .....
!>j,a >:!/.;*! v
"i/ ,' ••' "
. '
I,!1:;, iiili ..... ,
1,"' ...... ''"•
i: " "iir";1
i1 V'ifc
, .,,,
; iiBwi,11!1!11 vi
''
were evaluated, the endpoint has been applied to account for exposures to the general population
including both males and females.
11" „ • „ ,. i.. . , , .
Li Ill " ,i,,ii, ' Mi iillll ',• - ' I , I- ." ', ,' ..'", Mill1'-..),",:•" .:' 11, . ' > "i!"!,: M1 ".I.,- II |l. • ,.• ' i I, J, I' " A • • ' 1«"
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 chronic feeding study in hamsters, and the results do not indicate that
I "• , IL ,'^1 ni< • ,i«iiiiii!iiii,iii»i ,„ ,, »! a!" i, " ',„, i „ i," ' « e f hi,,1 ' " •! i'1,,"1 ii, '.I'"*, nil" niii'i" ::ii,," • ' ^ /vh t \\W'\,,: m\\\ > a\i • .'is1 «i •'.. iiiU'i,,, n. " , , ,:',""ii
TFM induced ail increase in any tumor incidence (MR1D 00081184). A chronic feeding study in rats was
||, also conducted m 1975 iQVD^'objp59"379),' but'the results are not' conclusive regarding whether TFM
induced an increase in any specific tumor incidence. It should benoted that the chronic toxicity studies
were conducted in the 1970's prior to implementation of the EPA Guidelines (1982) for toxicity testing.
I I :.,lll I I II I. ,,,6,,,,,". I ... ., r, ,'i, '! . , |. ;. :, il > ,„, ,1,1, ,,,i,i, „; ,', ,' V, ," , ' ,
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
11
TFM, has been classified as a low-volume and nonfood use chemical based on the quantity used,
the method o,f 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
. ; i ••,!;.- •:„ . .," ', ,,',,,,,,,, ,;,,,,|. „ ,.'.. ' lil »,... ...i . iji,.II ••; . „„ , , "
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 andniclosamide is
presented in the Manual for Application ofLampricides in the U.S. Fish arid Wildlife Service Sea
Lamprey Control Program including Standard Operating Procedures (1993). This manual focuses
on rninimizmg occupational and general public exposures by specifying the manner in which applications
are made (Le., techniques and equipment), the level of risk mitigation for those occupationally exposed,
and the 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.
I1", ,,,'lilll I.,, 'H|l
i i i! in
12
" I
-------
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 ori 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:
(la) mixmg/loading/appli cation of liquid TFM via direct metering pump from 6 gallon end-use product
drums (low chemical use treatment events);
(Ib) mixing/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/loader/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 has informed the Agency that
larger applications are actually made by a crew of 3-5 handlers over a period of 3-5 days.
13
-------
I'M
1111'
ii" "'"i'l'i'" '""ii' iiSr!"11"!
ji"1 ,',,!: .' Piiijiiii""";
„ :,,,:i ". .'"iii
";„• >• iAii.il rvsii
•i": ". ' '.ii'.riiiiThiiti11.: 'tiiiiiiit1.si!
'!': i 'Mi' 'Si!'11 K'SaSiilP1 Tilt;;11 ,!!'
,„ ;„; ,' „ i, I"1"
lisi;:
„•„:!, I;1'!:
fife
Ii: lii'I '
"I" },.
t"!" ;, j ';,,>"''" fcffl* I liill Ill;" "";""" V'.ii!" ,,I";•,, i, I , ?,!', ,„,,.'', " t")r. ' .1 ;„""!, .' ,,, ",;;,,':,,:„'"',,; L,. „•„:!, !S1! •',,: .:•;' „ "'"•.'"'" I1 ;V ••. r
MQEs 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-
illlllllllllli;.!! nm ju .UNI i"iiin ,,, , i|i n ln iiiihiiiijii! a • . ' ,„!",,, , .ii.jj,,, •,,,,•,„ •;»••", ij;;1, ilil,," iB,1'!:!,:",,111;, ..'Vfl,, I ,„« !h cr . , ,„ ,„, , , .,,£, •*; , "^ , , „
15,571 for 39 stream scenarios; the other two treatments resulted in MOEs of 73 and 75. Again, this
•i|i|^sMeJiO$s@e$ that the treatment amount was handled per day by one mkerAoader/appIicator and
,lii! ! Si11 '"ill '"lif, ! "'"Hi,, "'i P'!1'1! ,!'!! ,•',i niiillin ilij ,, 'JFI'IIHiili,,: I!,!1 ''I ,. i,l!"Wi'i ,;i: '„ »'"" '"' II' »4 111" Ii i ' f , ', : ! , :
-------
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 Category
Single dose 1 000 mg/kg; no mortality or clinical signs
LD50> 1000 mg/kg.
Toxicity Category in females 111 or higher; could not be
determined in males.
No mortality or clinical signs; LD50>2000 mg/kg.
Toxicity Category III for females; could not be determined for
males.
Evidence of eye irritation (iritis, corneal 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 with
unabraded skin.
Moderate dermal sensitizer.
: Submitted studies were not acceptable to fulfill guidelines, but provided some useful information for risk assessment.
b. Subchronic Toxicity
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 z 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 andhematology 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 s 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
-------
'L Ul'lll
fit*
! it
(ll'ii
Under, Jpe 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 :> 5000 ppm (500 mg/kg/day).
This subchronic toxicity (Guideline 82-la) study is classified as unacceptable and not
lijlilj"'. ! •.' "l1",: ~ IIC'I i'SIII1:"!' ''"•' ' !"*";"' ' SI", : • 1 '" .1 , " V ' ,,,'",l! • ,1(1 '," :, :!!!!, ,r I". . Til- ' i • ' „
upgradeable because the animals were not adequately dosed; the maximum dose was well below the limit
intake, pf 1000 mg/kg/day. Additionally, numerous parameters required by the Agency study guidelines
(e.g. comrjoimd analysis hi the diet, clinical chemistry) were not measured.
|I3 .r • ijij W, r:f;f - J !»;! f f.:.,iJ ']'< ""*,)- VI,;!'",' ,, ;''K'': ' . ' "fit. ' ' , • , '""'I' .' "f]" ; ,!,
Subchronic toxicity in dogs
I1111!1',;!'( T; ,-•",.' ;':,;l:l1!1 ISI!!1 • •':/ Ivi "" i,',;, , ,• "•''.-.'• "}••'•< ' ••,-.-•.. "'"'• : '; • iV ^'" ,. ^' 1 ,'•:,!: M '-J, •• . >' ' »• l-^ »:
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 Oj '62.5', 250, or 1000 ppm (0,1.56, 6.25, or 25 ing/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 the major
part of the study (weeks H-24 for males and H-20 for females). There were no treatment-related effects
on any clinical chemistry, hematology, or urinalysis parameters, and the rates of brpmsulfophthalein and
phenol-sulfbnephthalein 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 hi
•I'':!!!''.'.! 1 ,!, ,11! a Ill , '« ,„ „ M ,, ', :i. ' I,!!' ,, „>: !,:. "!, :; /'.'liiii ., ... " ,,||" I , T ', T,,:!!,^, .' • ,
controls vs. 1.0/1 for males and 2.0/1 for females), suggestive of lowered WBC production or elevated
eiyfhrocyte production, but neither possibility was substantiated by the hematology results.
i
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.
n i ill in i q
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. Ad^tionally, 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
, i', i ,, , •' ,r :» ,': „. '" r 'ii'« „' i, 'u; , n;,, (, . ',, , || ,
,n 'Hi, " .1, , i!1 ,,, '" . i ,ii, ,„' i ' ,, ,'" ri'i Tf!, , •, j, , ,i i : ' »'„ ;;i||i|i.
,:: Si! ,''
":»;'" ii, it' I" " ., ), I
-------
SubchronJc toxicity in hamsters
In a subchronic toxicity study (MRID 42552308), Bayer 73 (niclosatnide) (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 11.0%, 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 Toxichy/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. Osbome-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 («711 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
-------
not be considered conclusive in this sex. There was no evidence that clonitralid was carcinogenic to male
and female rats and female mice.
Developmental Toxicity
,1
irements.
Developmental toxichv in rabbits
i,, 11
,1 "• I,'1. i::
•Hill' ,
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 dbserved"at cesarean section (GD 29) resulting in only 10, 10, 10, and 7 animals used per group,
" ,: ..', [Jji11; ;•', .1 fH ''!••:;*• ,'';. ijil,;,1;!"!,,'1'!!'!"1"! Ill, "'A » • ./n/..•,• ,>, t, . , , -ft, •'." a: I'"' 'i,a' I,',; ,• ,. ii .,., • f ,,,; f'.r,,,
respectively. All fetuses were sexed, weighed, examined for external mahorrnations/variations, and X-
:ly. All fetuses were sexed, weighed, i
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.
I* 'll'l| I J, ,° C, ' ' i,, ',,!" "i, I ' -' , , ', , , , '."II ':::,':::" ,::"„:,' ,' ' :'•
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 rabbit. Therefore, the
decrease in fetal body weights is not 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 Utters in the 0, 20,60, and 180 mg/kg/day groups, respectively,
contained affected fetuses. The incidence rate is statistically significant (p z 0.05) rn 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.
Kill,,,, Phi! imp I1 Hi,.:. ..Hf 'MI 'lull "I'. " I:
, JFii:.* ,11,, „ IE ,, , '»:i In; '
iliPC'
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i
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an,1'
Several major deficiencies in the conduct of this study make it inadequate for the evaluation of the
J'":,1 potential developmental toxicity of Bayer 73 in me 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
f- , "I |,,!|1||'j'' ! J' iiii. ' 'I',, """'III!111' "II 111" i" IE1:1 ',,: '• lili'li "il'! I't" i||"l; T " ""i:,,ii Jill, „ :• r 5 I I, .:,"„>,! ," 5f\, " I, ' ,1 il. i.", '," ' " ,|," ,
Agency guideline requirements for a developmental toxicity study in rabbits. This study is inadequate for
'"',,, '\;;/-^
;;!! " ;»'"i \j|"^
: -;," ^'Vflei£jji>ed for jfeiWy weight ^a!a' .l16 use or> X:ray fik?8 i? ^adequate i^ feta! skeletal valuation, and
the dosing solutions were not analyzed for concentration, homogeneity, or stability.
!•'. ' I! fll I I'1 '" ' , ',1,1 I, I. II I'" i i ', , , ' "I '," " „ i „.'" ' " ' il'. W I..' , 'Ji'B,'', ' I"' 'i ' " 'I' ',"I"H , , „' ,, ,' .1
,'!»"' ,' g t" ,,j,;, '', """ Jlt Itjlj,,:!1,';:' : - ' '!, !:!*•( i,"||.":; "''": .>,:!" "I-, ' ' ,i ^ • t'f^ ;V;,i.: .&'. ';>'& •'!: "S'J~; ';i;; ' '"fl ^i .#?•>• •'}!:?,''"'*:•"'" :;i t;$ |i!|
Kill1'
lIBi
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•ir ii,a;,, •' v. •
,:;..,,,/ ;•'•'-. ' - "•••1'v. .'• K: 1 IS*; ,>ri /f ;>"•;#&!' :,:\:i>^
1111 *; '"
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18
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" iij S,
I
-------
e.
Mutagenicity
The 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 corn 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 FTFRA 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
-------
,j" !" ' ' " ',. '' ijgi||| '''I'll | ,11:' ' '''"" "'I,
ft • ', a-"1" I1'! :,,,:"lil: ,'£,,' ' :
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£. Dose Response Assessment
a.
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 dietary endpoints for niclosamide are not necessary and a reference dose
is not required.
ii i n ni
b. Short/Intermediate Term Occupational and Residential
n ni i n n n ii in I ni i
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
, ' ,'',,,I,11 ' , ,,;„ ii I '„ „, ,,,1,|i,i::l! i
Niclosamide is classified as a low-volume and nonfood use chemical based on the quantity used
the method of application, the L'SFWS 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
W niclosamide.
in i i in ii ii '"" ; •• ' „,"! •",-,• ' ,:,'" , , ,!'! , /.'.' , ,i :" „ '• " .;,• ,,|,'•'[t:','' • ' 'M;;!' '" ..'''' \. Vs.;
b. Occupational/Residential Exposure
It is anticipated tha: 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 conm>l program manual was used as a basis for the niclosamide and TFM
'NNNiiN^ « ', ii'i'i' m'f ,;,,'"''ii111 ri "' ,!!!!*5,1, n" ''';„!'!„ ::;; "";;: ; ", fc „;!!'' ;,'' : „;'"„,;, ";„": i;;;;;;,;,;;,;;;;1,; "', ' ' ,;; „: " ,;':;,',',;;;;;, ; ":,„;;;„;;:;, ';",„;;,,, ;, ,;,; ,„;;;:",';;,,;;,;: " : ",,n
exposure/risk assessmcm. TTic specifics of this manual and^ avaSable labeling should be the basis for any
,nj[clojs|^ldjian^TFM/ ux; f'osuipplication scenarios to swimmers, boaters and fisherman should result in
minimal exposure from the hmpricide 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.
20
-------
2. Risk Characterization
a. Dietary Risk including Drinking Water Risk
There is no reasonable expectation of humans being exposed to niclosamide residues in the diet
via water, fish, irrigated crops, and livestock for the Mowing reasons: 0) the low use volume (300 Ib
ai/yr); (ii) the infrequency of use (every 3-5 yr if a given stream harbors lamprey); (iii) the 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 the 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 niclosarnide-containing
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: (T) mixmg/loading/application 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
-------
11 „•„ «"„ ',!:.,!;;,.„ •, ,,T i,,i 11"1:
il'-II I :/!!!,,,,
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EH
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Stl ..''lillliulj1 '' I, "" tjif, ,., 'il Jliii* '!; : >i 'i'! ", "i '
aciite-nontoxic (>5, 000 ppm)
;>5,000 mg/kg)
'/";* -;.. ':|| !i:*;;Fis¥ to highly toxic ( 0.60 to 37 mg/L )
'•'"' " 'iQvertebrat^ (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 the toxicity of TFM. In 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.
,1 ' ' i,i, ill. Ull!1) ' '."I ', '« 1111 Illlillilllll ' ill " I1,'!" "M! '''I, "'' '. " " j, * ';<: ,„•', : "S,,: '!• "I!11,'1,;1' "i ', lit1 ' It'll,1','!,' i. ,;"," "I .:•> : 'If, '('i, S1!" i!''',;!'" •.' it ' •i!!i'"1!!i-' l^Htf
b. Toxicity to Terrestrial Animals
1 ;, , ' l"i| ' , '!' , ; 'i '. ' n, ilil" , ,i, ,; ' i,, I jl , "• ' "»i , ' ,1 •' „ ''I'iilL If ill' < < •: li'lil'l I'iiih, 'V , • 'In •, "'I'l', / '", „ T, ' „ :'„ « i.n, 'W'lkiiliiiliyil1' MUMi'i'ii '
* ' ' •' '" ' ' ' '•' "1L J •'"""'' 'i:"':;;i (1) Avian Acute OraC Subacute Dietary and Chronic
, Thg acute oral, toxiciry data suggest that TFM analytical and formulated grade material is
moderately to sughfly toxic (LD50 256-546 mg/kgj to avian species and practically non-toxic (LC50 >
5,000 ppm) on a subacute dietary basis (MRID 00022923; Ace # 160000). Avian chronic reproduction
studies are not required
•;il Mi!'I ;,,";,,i nil !,,> ill!!! ' , ' ;i' ,1, J1IIT ^'lilili..!!!.!!!!!;'!1''1!,! ,,'i! i iiPI'SH!'' .:ilh: „ ,'III! „, 'i;,, '" , ,1 li", l,li,Jj,i,i I, , ir . ,n, I,,;"!!", ,1 IIIIP ,1 lllilii;1!,, 'in, :',: Tl1'"" n, ' •!1''"iilim ill I'lii'l Fi''11 '','illil '"i''.'"!']!!;!.!!! r.ii1' i, Ill'i /I.'."''! llfti" I! ill'iii'Sl! ', 'fU!1'1!!
319 ^ • • •' • ' • •• "! •.:•*'»_'.• ""»":": ; "'* •; "" ' ;i"(2) Mammals, Acute and Chronic ' ' ; :'";:'" '
'"',;, all|y[_haj!iacutg^ipj^:l^^
,"' ;•' .'•„:'•;, i "• '',;:,,:i, ,;^,.;..;•• ;:!"::',",,,:= £-,» :"y;4; ; ; -.-':",:;•,;•:, ).;:..^:1'r;^.;;-
1 • "' • • • • • f •'• t1' n| • • i • '
IT ' i f^^ Tnc^pfc
' i ' \*^S JLU9w^»L9
III":'III "III, UnilJrlll! ,11 L , , "n| ,,l|i|l " lillil liilllll,, i, ,il lilli, I1 , '.IP' . nlX ,n „ ".iii|,i i, ,,/ , ' [i , ',,! ,i,,ii"il ,,""1 •'i::1'11!''11' .v : IfllllB., f," • (..'••|i1. c^j*."1*' Kif:C. i .,'.•.»»" :,ll BSTIiW'ft:,'
22
-------
In a study comparing the toxiciry of TFM to native species of lampreys with sea lampreys, the
toxicity of TFM to lamprey larvae was highest in the sea lamprey, intermediate in the northern brook
lamprey (Icthymyzonfossor), and lowest in the American brook lamprey (Lamptera appendix) (King
etal 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 the fish tested, channel catfish was
again the most sensitive species to TFM alone (LC50 = 0.75 mg/L) and to the combination of the two
chemicals (LC50 = 0.615 mg/L). In 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 are 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 andHoweU 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
Iampre3?s 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 the 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
-------
lit!' ,:!> ,,;;•'«,
ill,, 1!V 1)1
Miri; • -I !'• :,!'!
rll'lll ,„!,„» "'I1? ' IJT'1'
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Ill III
Ii . i,!,, • ft
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I'll IS,, , ,„['," -III,",
iillMl; IJKi '::,! ,
'i.'.il " ''. A ' f'.ili
i, ..... ".'»' ' ..... T »,, ..... :• n „ ' ,„, ...... J'1',,'; : : ^
;«i:,i",'";:":. „,: i a;fa 31 • t1. • •,-„s. , • yii;,,,::i":« :", •; i\,•; \ • • i :;;,, ,,;;; i• •, •..„„ „•, ?!,] ;, * ; /v 131 p;
dobsonflies. The most sensitive species were snails and aquatic earthworms. These data indicate that the
mixture of TFM and niclosamide enhanced the toxicity of TFM to some aquatic invertebrates.
/ii ....... f: iliiiir, ill "
, ' II ...... qilii: 'I ..»
, . , ,., .
,11'U ..... mil ........ I',;1 f ........ 1" ..... :,lf U!1 ' '""'"W
.,
1 „ ,f BiFI!; ,:ri, ""I'm iln'lyAlilli
There are no chronic toxicity data available for aquatic invertebrates. An aquatic invertebrate life
- ir—
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
!•;, I,' ,:-:"""!>, ...... f'tli," 'fell, ....... 'I 'I'1'"'!' ....... I f\'\' , ' ...I*,.' ,1,1 ..... ..... f '. ......... IT,.! I HI ........ ],, *?•«• ...... Vfll',, ...... . , ........... ,, :,,,
;• • ...... ;•;:' ::;„ : ....... •: ....... , .................. ........ • .............. .............. -• ..................... ' .......... i" ..... •
Because the use of TFM is unlikely to directly enter into estuarine/marine environments, toxicity
; ....... i '• : IIIJIFilllllillli" M:, ,,f ..... " ',J ......... ;B, "•'" :f!t ..... . ..... ..... , ' i"," -: ........... ..... r ..., • ,:« ...... , •• , t,- ...... •,:• ...... • ..... M •. - ..... " ....... i ....... ,:,, ' •• " ' • ,. , . i, i
testing for these species is not required.
f. .l^Yt'1 ..... ' -I, iri'iii ..... '.' „ "" '• ': ..... v .•' '.', *,""<• ~ ...... • ....... 3"'" '"Ii, ":;,': ..... i "V lf-"tm:\ M ..... '"Kili,,!' '," ....... i :•<"••
The herbicidal activity ^of various salts of TFM has been reported (Gilderhus and Johnson 1980).
TFM decreased the growth of Anacharis sp., Cabombasp., ss\
-------
.4.
photoproduct was 2,5-dflrydroxybenzoic 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 y€ry sable in the presence of sunlight thus indicating that photodecomposition is an unlikely
dissipator of TFM from trie Great Lakes environment This contradiction leads to some uncertainly as to
whether photolysis plays a role in the dissipation of TFM. Based on this uncertainty, an additional
aqueous pnotolysis study is required.
b.
TFM Metabolism
In a study designed to evaluate the degradation of TFM where aquatic sediments are not an
influentialfectpr, Thingyold (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 hi aqueous systems; however, toxicity decreases in sediment-water systems. In sediment-water
systems, irreversible sorption to sediments was reported It is likely that the bound residue was not TFM,
but the reduced form of TFM(^arninp-S-^trifluoromethy^phenol. Thingvold (1^75) found no evidence
that indicated that TFM.'"degrades in the presence or absence of auxffiary carbon sources, or under
aerobic or anaerobic conditions, in sediment-free aqueous systems. Carey, Fox and Schleen (1988)
report that with trie exception of reduction of the nitro group to an amino 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
completery ionized at the pH of most natural waters and does not partition strongly to sediment where
anaerobic conditions exis:. 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-TFN 1 may be re-oxidized to TFM (Carey and Fox, 1981).
" It)"! . ' : I.:" I, ' Illllll!)' 1II, J!!l I !i ;""..!• •',',! 1 • - ii" [ . 'l(/it ':.!".I1.' il v '"i','«; '• . -'I '. Wll'OHf "ii1 "4 i -J!''- I1'1!'"1 "!,' i'l"""!" .1. !<""/ '•''; (t !"!!,' * S'-l S"!1,;; ft..., . ' j>
In.an.acceptableanaerobic aquatic;metabolismguideunestody,Fathulla(1996,MRID
\ j- ;:::>'tT|:,;- •.,;" ,{* • 438876Q1 f found that,,uC-TrM applied to a loamy sand sediment/water system degraded rapidly in the
O^undeFam TfTie majordegraiiate was 4-amino-3-
(trifluoromethyl)phenol. reduced TFM (R-TFM), which comprised. 383% at approximately 4 hours, arid
increased to a maximum of l»4. 1% oif theapplied radioactivity on day 14 of anaerpbicity and then
decreased to 26.6% on day I ~,x and finally disappeared by day 273. 14CO2 was the only volatile
component found in the trapx reaching 7.7% of applied on day 273. Radioactivity recovered in the
water layer ranged from ^ 1 .T 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 (3^3) ^ 8.34 (day 273). Under a^l)iccbnditi^¥a1:yna(^^5;Mk&'437Sl80T)
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. 14CO2 was the only volatile component found in the traps,
reachmg 7J5% SI)to"8.83"(
-------
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 Kj, while increases in organic carbon result in increases in K^.
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 (K^ 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/silt/clay
64/32/4
84/14/2 •
96/2/2
44/46/10
organic
matter
9.0
5.0
0.9
2.5
OEC
meq/lOOg
132
4.6
1.1
6.2
K,,
pH6
11.7
6.65
l.ll
5.66
K,,
pHS
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 the 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.
27
-------
Avian acute- moderately toxic (LD50 60 mg/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. ha 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
(MRIDs 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 TGAT is not required for niclosamide because its use
(aquatic sites) will not result in honey bee exposure.
c. Toxicily 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,
Onchorhynchns mytiss (LC50 = 0.03 mg/L), sea lamprey, Petromyzon marinus, (LC50 = 0.049 mg/L)
and the bluegill sunfish, Lepomis marcrochirus, (LC50 = 0.049 mg/L). The freshwater fish acute toxicity
requirement has been fulfilled (MRID 43679302, 44206101).
29
-------
II IIP
111
11 I II
(I (II III
I
ll III1
ilf h,
Lllllili II rail
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 channel catfish was the most sensitive species to TFM (LCsq = 0.75 mgflL), niclosamide
(LCso = 0.0125 mg/L) and to the combination of these chemicals (LC50 = 0.615 rng/L). Based on the
results of this study the authors concluded that the mixture of THvfcniclosamide was at most additive
under; various test conditions (Bills and Marking 1976).
'ONo data were provided on the chronic toxicity of niclosamide to fish. Thus, tine 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
In acute toxicity tests, niclosamide was slightly to very highly toxic to aquatic invertebrates (EC50
range: 0.034 to > 50 ingTL). The acute freshwater invertebrate study requirement has Seen fulfilled
(MRJD 44174804). ' ' [ '
When TFM is used in combination with niclosamide (98:2 by weight), LCso values for lne 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
dobsonflies,The most sensitive species were turbellatians, 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.
\ ;'; ;' ~~ : . jr i ^ M .. f : ,; ; ji
(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
Miclosamide inhibited the growth of aquatic plants; diatoms suffered 50% growth inhibition at
|,| » „. ' ; ; ll'lJiin,, .' j!i,i!:i:illlf t1' :' ,< ^tClHVB '.I ...I" "Si1'1 ill. ' i' " ".' Til'''!!1 ,'B'lii' Mn 'i ' ' . " I I II I II I III ill II III III II I I I lill I II < I111''11:1 "'U1
concentrations less than 130 ppb. Green algae exhibited a considerable range in sensitivity to the effects
of niclosamide; EC5o 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.
DEI Ml HI! if'r \iiiil I
30
-------
2. Niclosamide Environmental Fate and Transport
The information in ibis 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 uncertainly associated with the 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 (MKED 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
-------
•ill liii : J I
' I!'11 lli'IiW'i ! HI""1 : Uiifiil!
if: !" l! I'll III11
1 1 HI 1 in i
In!) ill Hi)
lilifUil1 ill
!"' It"' '"ifill If
I III IIIIIIII I 111
II III I
llllllllllllll
111
II III I 1111
I
I
if ;|^rte4 and the output of the light source may pot 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 yv/yisible spectrum of niclpsamide (max. 330 ran), it does appear that
niclosamide is susceptible to photodegradation in water, and this will be a significant route of dissipation
only in clear and shallow water bodies.
i . i
b. Niclosamide Mobility
In an acceptable batch equilibrium study; (TJawson 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
h, ,'ft, „ ,,'Ui il llilllllllllllllllllii illiUllinilf ini'iini Ill'i',, i,!l, H'J TV: ' , 1 ,11'! ,"!!„'„ •'!"!,:" ' !!„,., ,! . '•' i < t IMI |.!'!l| ' "« ' ' Jlllli: 'I!'1'1 4" i, ,'• ,» IIIIIIUI fT» '\ilUi Hi 'iT , If ,, , ' I, ","!,., ""U>| .t " ',
solutions when the pH is less than 6.5.
Ilk "i"
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
25
9.0
pH6.5 pH7.0 pH&O pH9.0
average Kd
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,
liii | .. •IlilP'llflnllilR I J III III llll 111 III '..I.,; ..I" , r .' , :.,,
loamjand sandy loam sediments. In most aquatic environments, niclosamide will adsorb to suspended
solids and sediment
...... AJg^leroenM mobility1 study identified the major route of dissipation for niclpsamide from the
excluding dilution or dispersion, is adsorption to the sediment (MRlD 42552317).
illlllil, SllUiiiiSPH'iUlii'inni":!!, liiiiini': mill,,;, ...... Muni, ill,, >'«:.' »i < i« » ri:-,. ":,i'i JT ..... linn ..... i.'i< ...... >; ..... i""»i in ....... lir * ....... ................... n ................. ................ VL ..... AH, ............. . ............... ,„ ..... ....... vn.w ....... \ ii'nii ........ . • .......... -v",' ...... i< ........ ........ 'v .......
-, 1 4
•ii i
.j!!!!^''!!!!1'!]!!!!!11!'';!!'!, , , ,,, , ,, . « -,. , .'< ....... * , . ,„ ....... . . ,' < ..... ..... < <
Niclosamide concentrations decreased in the water column at a faster rate in beakers with lake water and
1 1|; !• , ;ii| WA^MB ...... : .; •••• ; ,wt vi; w D>- t* msi ans ; ..... •' J ....... \ ..... ». , , "n T,; "if mi"; iii;)' .- : > ••< i ..... ill ipic: ...... : ....... i«: -*;1'. ;ii IIHIII ..... n, ........... 'iif •«. ..... •; i r ..... • , ; - • ,i wv ......... twr • , 1 1 ..... ..... 5 ••> ••• '
1 1|; !• , ;ii| W . • , - ..... . , , , • . , •. , , ,
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 1 10% in dark beakers without sediment. In a test that
eliminated microbial and phptolytic processes, niclosamide cpncentations decreased raster in sterile dark
test tubes with sediment than in sterile dark test tubes without sediment. This study also found no
difiejjence in disappearance rates of mclpsamide among non-sterile light test tubes with sediment, sterile
light test tubes with sediment and sterile dark test tubes with sediment La the presence of sediment, the
half-life of niclosamide in the water column was less than 10 days.
32
'"•i.l I":,,:,!*': :»!*•
I'.:'.. .liSul Mill I "1 II ' .fl I
-------
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"9 mm Hg at 25°C and the
estimated Henry's Law constant is 6.5 x 10"10 atm-irf/mole.
No data have been provided concerning the mobility of niclosamide degradates. However,
previous information suggested that aminoniclosamide binds to sediment as well. Since aminoniclosamide
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 the 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 lank 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.
33
-------
III "'I ,|''' if IIM|! ii
I 1.1,1; l|| I i If l|i| .'.'I1
Niclosamide residues in fish muscle tissue were cpnsjst^t with water cx»ncentration 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 this 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)
u§ed.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); this range of treatment levels was used in the aquatic risk
assessment
H. Environmental Exposure and Risk Characterization for TFM and Niclosamide
a. Risk presumptions
ae 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
1111 II III Hill Illllll I II III I I I 111 III 'I II., "'„!!, , ' ,, , T, n KIIIN ',1,11 „ , .,r \Jlr1,, I, ^,:" ,: ,,'>•:,„ • ,,l li ,l:f
quotients (R-Q.) are calculated by dividing exposure estimates by acute and chronic ecotoxicity values.
' '
RQ=
."llllllld.li'll Ill1
' ' f',:,1 in iiui , 'ft,; '- us : i - ......... riir in „,, ni, irtiii ....... ,ii:iii;M ?, ?
l: is ,>!'!•' 7' fl,1 ,. ,i 'I1 J!ii'!i,!ii>; SIM''..!'!!,, slFlfcKTSjl '<,
llr, '; Jl' , "I1, i' ..... IP ..... Ill":; ....... "• iiili '"'Mil J
RQ values are then compared to OPP's levels of concern (LOCs). These LOCs are used by
OPP to analyze potential risk to npntarget 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 tor 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
"I'Sdyegely affected^ and (4) chronic risk- the potential for chronic riskis 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
ijjj'q. lilk I unit'I
i' !l • "lit1 '"'ffll".1
34
-------
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
EECVLC50 orLD50/sqft2 or LDSO/day3
EEC/LC50 or LD50/sqft or LDSO/day
(orLD50<50mg/kg)
EEC/LC50 or LD50/sqft or LDSO/day
EEC/NOAEC
0.5
0.2
0.1
1
LOG
EEC/LC50orEC50
EEC/LCSOorECSO
EEOLCSOorECSO
0.5
0.1
0.05
1 abbreviation for Estimated Environmental Concentration (ppm) on avian/mammalian food items
2 ( mg/ft2)/(LD50 x wt. of bird)
3 (mg of toxicant consumed/day)/ (LD50 x 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
EEC/EC05 or NOAEC
LOG
1
1
RQ
EEC2/EC50
EEC/EC05 or NOAEC
LOG
1
1
2 EEC = (ppb/ppm) in water
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 this 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
-------
i^iiiiiiin iiniin IK ijiih, I'lBiipiii mi!1 "i iiiiiii i', "ti
'l<.;ll|IIM!!|l,,V."ll'i nllllllliii ''illllli.1!'!' ,"»• "Bill I
Collected using pH range 12-1'.6, the predicted concentrations of TFM in the water, based on model
outputs, ranged from 0.7-2.2 ppm (personal communication, Dorrance Brege, U. S. Geological Survey
Biological Resource Division1999). 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 the use of niclosamide 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.
..'Mil
: •" in.
C.
Exposure and Risk to Non-target Terrestrial Organisms
Hill iji'i i Ir1' "' iij'""!'11"
Sill!' I1 J"!;' i ;;|
f<
TFM and niclosamide are only registered for use on aquatic sites; therefore, the typical terrestrial
analysis of risk, based on exposures developed by Hoerger and Kenega (1972) and as modified by
,11' 'Kj,,,, li^riNil: Illi;;"',, Plain., ,,i I ' " *, ' ,- ji.i , Tun, „ • '„ - nY it ' , IMIII,-,' ^' r ,ii/,», n,,n' • 'i „'," IH * I , .M 11 '-
Fletcher et al. (1994) is not applicable for establishing the risk of TFM to non-target terrestrial species.
However, because numerous ayian, i.e., waterfowl and shorebirds, and mammalian species (muskrats,
beayejs, raccoons and numerous other small mammals) typically utilize aquatic environments as nesting
and/oc feeding habitats and may be exposed to TFM and or niclosamide via contaminated water, it is
( ,| p • il! rliT*'1'MIW''. • I 'II* "" " ' ' 'i'1" '"""' I I
. r. . .,
appropriate to use the aquatic EECs for conducting the risk assessment to terrestrial species.
Cj|cu}ated aqijtf 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
"bhrarjle concerns are expected.
i i
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 6.7 ppm, acute high risk LOCs were exceeded for
of the species tested.
1 fiii-i'i-.jira '
,'' .III!.'' , ' ' „ II", IIII"1 ,h " , 'Ml! ""I,,!1 J
TFM RQ values for the various developmental stages offish 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 6.7 ppm and all of the developmental stages at a
treatment concentration of 22 ppm. Green eggs and eyed eggs were the most sensitive developmental
stages based on RQ.
iiii
11
if", i riy
•I'd ...... t. ,; 'i ...... ill!':-. ......... ill' . i
'';iiiii;iii!iur' ...... lit- "4 ..... .- ...... :iv,i
Jill! v u, !'' i 'JIK:1!1.'^''i*:!'1!1.1::''1"*^ ••i'':.1!!!!!'!:.*!!! f • "*.il:!y1*!'*
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
<';ii, [IK i
Jill;'.III! !!'"'i
I
36
-------
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
Bluegill sunfish
Sea lamprey .
Caip (Cyprinus carpio)
Green sunfish (Lepomis cyanellus)
me
(ppm)
0.025
0.025
0.025
0.025
0.025
96-hour
LCso (ppm)
0.03
0.094
0.049
0.120
0.170
RQ
0.83*
0.27"
0.5*
0.21"
0.15"
EEC
0.035
0.035
0.035
0.035
. 0.035
RQ
13*
0.37** '
0.71*
0.29"
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 the volume of water in the lakes, there is little
37
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I1!1 Ill1 ill,
concern about toxic levels in the Great Lakes themselves. However, due to the uncertainty regarding
penisteacenhere'may be chronic concerns for organisms downstream from the application site prior to
dilution in'the 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 aquatic inyertebrates at the predicted minimum concentration in
water pH 72 - 7.6. At the maximum predicted treatment concentration, acute restricted use and
endangered species LOCs are exceeded for 83% of the aquatic invertebrates tested.
I I 111 11 Pill | III i I II i «V. '(-.Siiii!,; ; . • < ' - J-i'lil!, ;"• •' I :V, .1 ' •,(': ill.: '":'•!": f * L 'I ;,!' If",, ; ,1.1,11",:111 '.-'' •,'! i 6
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.
111! '' """ '':":il ;"''Aquaticlnveltebrate ^
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. IM i ,
The TFM/niclosamide mixture results in higher toxicity to aquatic invertebrates; however, the
increase intixiclry is not proportional to thlt of me lamprey. Jn'oififiFwords, lampreys undergo a marked
increase inloxielty tollthe'lTl^lllniclolsarni(fe rompared 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 TEM/niclosamide mix is exploited to enhance mortality of sea
lamprey larvae while reducing effects on nontargets (persT comirl Terry Bills, Fishery Biologist, U.S.
Geological Survey 1999).
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 2.2 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
(IB Ili'i
, » if S'iVi i.-:i'I ;lii!\i[,,< ""i\< *-. iiv '• i&iiiir'i, i r.rif-" T,.i: I.•''''' " liS* •• ""iS"1::" ;: •ll||iil'l'»U"1''"""" if will!; '. ; Jl /.'I
llM ilill I'liii MQ iili iiii J!^^ I
-------
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, the 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 (Acipenserfulvescens), 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 the 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.
39
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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.
In 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 low 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. 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
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 al. 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. 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.
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
41
-------
in,, i '• ,'".,111; .I'"!''*! jiwi1 '...:; KiiiiiiiiiirTiiiii'iiiiiifT TIIIF i|; i:, ,'11, '"liiiiiiiniPH1"' Trill'1'1''1!,
'ih!',,l!i!fi|!":,!l i1 Willilliiilli'v1!!,:
$a?&W"i/am:,
":,,:;ll,1;"":;1", x: r*;.1
*: *>
viiiiii, ..... wit,.'" '-. : vv' .; ; jiiiii <3i&'fei.iv;l!h
I; .......... liiSffl! ....... I '^.ini1': „ ; ..... ''-,8: ..... i ..... • ..... 'I
-"
•*• .....
stream/river discharge rate, water temperature, pH and alkalinity and the proximity of sensitive nontarget
otfifiisrns: 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 that
"S " •aKWUBHIi ''PJW j i " /"'••• « B"-t;vv ''- ,•! '".
lead to increased mortalities and stream treatments with lampncides have resulted in a shift in sex ratios
"'"' ijjjjjjjjjjjjjj:jn|jjijjij,jjjijjjjjjjjjijjjjjjjjjjjjii:jjjjjjjjlijjjjijj I I ini'Mi;;;;;;;* <,,;;;•: ,i,, , 'HJJIJJIJMHIIJ !i!!i!!
TFM and niclosamide are only registered for use on aquatic sites. However, because numerous
111 lllllllli '"avian, (waterfowl and shorebirds) and mammalian species (musSats, 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.
i on the available toxicity data there is very little risk from either acute oral, acute dermal or
lllllllli:, :„ SIM I'l1 •lli.JillllJlllM ii ii Jliliiiillliiiillff^^ 'iiiii'niiiri"ii n 3 i mil i| T ' " llm « sr ™ u ' 11* mi1*, j .m ^ nil ii,
lietary exposure to mammals or birds. Acute RQs for both birds and mammals (< 0.01) show
^ '^'^jg^gf]^ SS^'ocfflS^niSati^onsTik^ly evoi at'a ^^JJJ^ iJ!.^^^1-1^;^^ • ^ •'•
addition, Aning the nearly forty yeareof TFM use to control the sea lamprey, there are no actual field
reports documenting any acute mortality to avian or mammalian species.
;i< Illlllli:1!!!1' .v'lllni' '
1 •IB; "' »l
lil,,":3ilil|
-------
TFM ranged in toxicity from 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 LC99.9 1.4
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 the 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 particulate 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
43
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1994 - 1998. Hie 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.
44
I
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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 bislineata
salamanders
red-spotted newt
Order Candata (salamanders)
Notrophthalmus viridescens
viridescens
Fishes
American brook lamprey
blackchin shiner
bluegill
bullheads
common shiner
emerald shiner
johnny darter
logperch
mimic shiner
Northern hog sucker
redhorses
silver lamprey
spottail shiner
suckers
tessellated darter
white sucker
Lampetra appendix
Notropis heterodon
Lepomis macrochims
Ameiurus spp
Lusilies cornutus
Notropis alherinoldes
Etheostoma nigrum
Percina caprodes
Notropis volucellus
Hypentelium nigricans
Moxostoma spp.
Ichthyomyzon unicuspis
Notropis hudsonius
Family Catastomidae
(suckers)
Etheostoma olmstedi
Catostomus commersoni
banded killiiish
blacknose dace
brown bullhead
common 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 nebulosus
Cyprinus carpio
Semotilus atromaculatus
Nocomis biguttatus
Mi'cropterus salmoides
Rhinichthys cataractae
Family Cyprinidae (carps and
minnows)
Family Percidae (perches)
Ambloplites repestris
Micropterus dolomieu
Noturus flavus
Noturus gyrinus
Percopsis omiscomaycus
Osteichthyes (boney 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.
45
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IV. RISK MANAGEMENT AND REREGISTRATION DECISION
A. Determination of Eligibility
Section 4(g)(2)(A) ofFlb'RA calls for the Agency to determine, after submission of relevant data
concerning an active ingredient, whether products containing the active ingredient are eligible for
reregistration. The Agency has previously identified and required the submission of the generic (Le. 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 the 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 this 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
reregistration, the current guidelines for conducting acceptable studies to generate such data, published
scientific literature, and the 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 the 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 that 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.
47
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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)
(2)
(3)
(4)
(5)
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 of Lampricides in the U.S. Fish and Wildlife Service Sea
Lamprey Control Program including Standard Operating Procedures (1993).
The USFWS administers a comprehensive medical monitoring program for their
employees engaged in any activities involving the use of TFM and niclosamide.
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)
The USFWS will maintain an incident reporting system.
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.
49
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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 the 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 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.
51
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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
lampricide applications, lampricide use has been reduced by 35% compared to levels used in the 1980's.
To further reduce chemical reliance while controlling the lamprey populations, the Commission has
recommended mat 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
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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
835-4300
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
-------
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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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 that registrants may distribute and
sell TFM and niclosamide products bearing old labels/labeling for 26 months from the 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 than registrants remain obligated to meet pre-existing
Agency imposed label changes and existing stocks requirements applicable to products they sell or distribute.
65
-------
VI. APPENDICES
67
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Appendix C. CITATIONS CONSIDERED TO BE PART OF THE DATA
BASE SUPPORTING THE REREGISTRATION DECISION
(BIBLIOGRAPHY)
GUIDE TO APPENDIX C
1. CONTENTS OF BIBLIOGRAPHY. This bibliography contains citations of all studies
considered relevant by EPA in arriving at the positions and conclusions stated elsewhere in the
Reregistration Eligibility Document Primary sources for studies in this bibliography have been
the body of data submitted to EPA and its predecessor agencies in support of past regulatory
decisions. Selections from other sources including the published literature, in those instances
where they have been considered, are included.
2. UNITS OF ENTRY. The unit of entry in this bibliography is called a "study". In the case of
published materials, this corresponds closely to an article. In the case of unpublished materials
submitted to the Agency, the Agency has sought to identify documents at a level parallel to the
published article from within the typically larger volumes in which they were submitted. The
resulting "studies" generally have a distinct title (or at least a single subject), can stand alone for
purposes of review and can be described with a conventional bibliographic citation. The
Agency has also attempted to unite basic documents and commentaries upon them, treating
them as a single study.
3. IDENTIFICATION OF ENTRIES. The entries in this bibliography are sorted numerically by
Master Record Identifier, or "MRID" number. This number is unique to the citation, and
should be used whenever a specific reference is required. It is not related to the six-digit
"Accession Number" which has been used to identify volumes of submitted studies (see
paragraph 4(d)(4) below for further explanation). In a few cases, entries added to the
bibliography late in the review may be preceded by a nine character temporary identifier.
These entries are listed after all MRID entries. This temporary identifying number is also to be
used whenever specific reference is needed.
4. FORM OF ENTRY. In addition to the Master Record Identifier (MRID), each entry consists
of a citation containing standard elements followed, in the case of material submitted to EPA,
by a description of the earliest known submission. Bibliographic conventions used reflect the
standard of the American National Standards Institute (ANSI), expanded to provide for
certain special needs.
a Author. Whenever the author could confidently be identified, the Agency has chosen to show
a personal author. When no individual was identified, the Agency has shown an identifiable
85
-------
BIBLIOGRAPHY
MRBD
CITATION
BIBLIOGRAPHY for TFM
Bills, T. D. and L. L. Marking. 1976. Toxicity of 3-trifluoromethyl-4-nitrophenol
(TFM), 2',5-Dichloro^'-nitrosalicylanide (Bayer 73), and 98.2 Mixture to Fingerlings
of Seven Fish Species and to Eggs and Fry of Coho Salmon. US Fish and Wildlife
Service, Investigations in Fish Control No.69 .pgs 1-9.
Carey, J. and Fox, M. Photodegradation of the Lampricide TFM- Pathway of the
Direct Photolysis in Solution. J. Great Lakes Res. 7(3):234-241, Internal Assoc.
Great Lakes Res. 1981. Ace. # 109279.
Dawson. V.K. Adsorption/Desorption of 14C-TFM by Bottom Sediments. U.S. Fish
and Wildlife Service. 1986. 158888/262165.
Dawson, V. K... D. A. Johnson, and J. L. Allen. 1986. Loss of lampricides by
adsorption on bottom sediments. Canadian Journal of Fisheries and Aquatic
Sciences. Yol 43. No. 8: pp 1515 - 1520.
Fletcher. J.S.. J.E Nellessen, andT.G. Pfleeger. 1994. Literature review and
evaluation of ihc EPA food-chain (Kenaga) nomogram, an instrument for estimating
pesticide residues on plants. Environ. Tox. Chem. 13:1383-1391.
Gilderhu,s. P. A. and Johnson, B.G.H. 1980. Effects of sea lamprey (Petromyzon
marinu>) control in the Great Lakes on aquatic plants, invertebrates and amphibians.
Can. J Fish Aquat. Sci. 37: 1895-1905.
Heath. R G.. J \V. Spann, E.F. Hill, and J Kreitzer. 1972. Comparative dietary
toxicities of Pesticides to birds. U.S. Fish and Wildlfie Service, Special Scientific
Report- Wildlife No. 152. 57.
HenrichJ.W, J.G. Weise and B.R. Smith. 1979. Changes in biological characteristics
of the sea lamprey (Petromyzon marinus) as related to lamprey abundance, prey
abundance, and sea lamprey control. Canadian Journal of Fisheries and Aquatic
Science 27: 1861-1871.
87
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i IKB wnw :iii<:s*i *i
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.. M., L. Treblay, G. J Van Der Kraak, K. R. Solomon,and M.. R. Servos.
1998. Identification of the lampricide 3-trifluoromethyl-4-nitrophenol as a agonist for
I'^E' =ine,rainbow trout estrogen receptor. Environmental Toxicology and Chemistry. Vol
L No. 3: pp 425-432.
x -1- ,
in the environment
ity. Academic Press, New York, I: 9-28.
Maid, A.W., Geissel, L. and Johnson, H.E. 1975. Toxicity of the lampricides 3-
tifluoromethyl-4-nitrophenol (TFM) to 10 species of algae. U.S. Fish and Wildlife
Serv., Invest, Fish Control 56:3-17.
, , " "I,,,,!! i "lull!"" nil™il"!'',,,'',' !"«Hil !i\,lL!''IiI!" r.i' I,'""!,' i,!!!!!!!"!™!!'1' "~r,° IilzJll' !"!' I' '""i,1,,,,"!,' ,,1111,11,,!' " ' ,11 '„,,'
11985. TFM and Bayer 73 in the Aquatic Environment Envir. Sec. Publ.
....................
rt 64. U. S. Fish and Wildlife Service, pp 3 - 8.
liiipiii ' ;• I'uinnii 'is ;«' ^iiiiiiiiiii/'iKiiiiiiiiiiiiiiiiiiiiiiiiiinii .jiiiiiii Bh'iEiiLiiiMiiiiiiiiiiiiir'iiiiiiiiiiiiiiii .iiiiiiiiiii. i « ...... inni . iiiiflii ..... : v . '\\\<
- ?Unpublished study
stitute, Inc., submitted
D:C;
1 00070314 Olso^L-E.; Marking, L.L. (1973) Toxicity_ of Four Toxicants to Green Eggs of
..... ervice^ ..... pi^-gQQ^fLgb^^^
....... 'Study;
=^^^^^^^^
i, A.W.; .Johnson, ..... H.E. (1977) Kinetics of Lampricide
-.™_™_ ™™_..«_._™-., ............
chigan State Univ., Dept of Fisheries
«,_,,,j,gg, _^,w^^ Service, Washington£>.C.;
i IB • > ., KFii.*':HK i
ii''in, 1 ill, iii1' an!1 I'llllliiilltiiftil'!!11" ',i'::'IBI!',!'!'1 ,i,,i!ki'i;,I1' i;!1,,HIM!!: HlnkjV'iLJsllliBHI,3':"'< !„>,!
-------
BIBLIOGRAPHY
MRID
CITATION
00081184 WARF Institute, Incorporated (1975) Two Year Chronic Feeding Study in Hamsters:
Contract No. 14-16-0008-620. Final rept. (For U.S. Dept. of the Interior, Bureau
of Sport Fisheries and Wildlife; unpublished study; CDL:097875-A; 097876;
097874; 097930)
00112725 Harris, D. (1973) TFM (85.6%): Chronic Study in Dog for Safety Evaluation:
Contract No. 14-16-0008-620. Final rept. (WARF Institute, Lac. for U.S. Fish and
Wildlife Service; unpublished study; CDL:097969-B)
00112726 Harris, D. (1971) TFM (82.4%) ...: 90 Day Rat Toxicity Feeding Study: Contract
No. 14-16-0008-620. Final rept. (WARF Institute, Inc. for U.S. Fish and Wildlife
Service; unpublished study; CDL:097969-C)
00112727 Harris, D. (1971) TFM (HB) ...: Rat 90 Day Toxicity Feeding Study: Contract
14-16-0008-620. Final rept. (WARF Institute, Inc. for U.S. Fish and Wildlife
Service; unpublished study; CDL: 097869-A)
00131201 MacKenzie, K.; Dickie, S. (1983) Teratology Study with TFM in Rats: Study No.
6115-102. Final rept. (Unpublished study received Oct 3,1983 under 6704-45;
prepared by Hazleton Raltech, Inc., submitted by U.S. Fish and Wildlife Service,
Washington, DC; CDL:071977-A)
40094602 Johnson, W. and Finley,M. 1980. Handbook of Acute Toxicity of Chemical to
Fish and Aquatic Invertebrates. USDI Publication 137, Washington, D.C.
40999201 Murli, H. (1988) Mutagenicity Test on a,a,a-Trifluoro-4-nitro-m-cresol in an in vitro
Cytogenetic Assay Measuring Chromosomal Aberration Frequencies in Chinese
Hamster Ovary (CHO) Cells: HLA Study No.: 10414- 0-437. Unpublished study
prepared by Hazleton Laboratories America, Inc. 27 p.
40999202 Cifone, M. (1988) Mutagenicity Test on a,a,a-Trifluoro-4-nitro-m-cresol in the Rat
Primary Hepatocyte Unscheduled DNA Synthesis Assay: HLA Study No.:
10414-0-447. Unpublished study prepared by Hazleton Laboratories America, Inc.
19 p.
89
-------
BIBLIOGRAPHY
MRID
CITATION
41898104
41898105
41898106
42187101
42551801
42551806
42551807
42551808
43677702
Glaza, S. (1990) Primary Eye Irritation Study of a,a,a-trifluoronitro-m-creosol (TFM)
Technical Grade in Rabbits: Final Report: Lab Project Number: HLA 00504439.
Unpublished study prepared by Hazleton Labs America, Inc. 33 p.
Glaza, S. (1990) Primary Dermal Irritation Study of a,a,a-trifluoro -nitro-m-creosol
(TFM) Technical Grade in Rabbits: Final Report: Lab Project Number: HLA
00504438. Unpublished study prepared by Hazleton Labs America, Inc. 22 p.
Glaza, S. (1990) Dermal Sensitization Study of a,a,a-trifluoro-nitro-m-creosol (TFM)
Technical Grade in Guinea Pigs-Closed Patch Technique: Final Report: Lab Project
Number: HLA 00504440. Unpublished study prepared by Hazleton Labs America,
Inc. 32 p.
Ivett, I (1989) Mutagenicity Test on a,a,a-Trifluro-4-nitro-m-creosol: In vivo Mouse
Micronucleus Assay: Final Report: Lab Project Number: HLA 10414-0-455.
Unpublished study prepared by Hazleton Labs America, Inc. 39 p.
Nitze, W. (1977) TFM: Ames Test: Lab Project Number: 7043135. Unpublished
study prepared by WARF Institute, Inc. 6 p.
Thingvold, D. Adsorption, Degradation and Persistence of 3-Trifluorometnyl-4-
nitrophenyl (TFM) in Aquatic Environments. Ph.D. Thesis, Univ. of Wisconsin, 1975.
Thingvold, D. and Lee, G. Persistence of TFM in Aquatic Environments.
Environmental Science and Technology, vol. 15, no. 11, p. 1335-1340. 1981.
Carey, J., Fox, M., and Schleen, L. Photodegradation of the Lampricide TFM- Field
Confirmation of Direct Photolysis and Persistence of Formulation Impurities in a
Stream during Treatment. J. Great Lakes Res. 14(3):33 8-346, Internat. Assoc.
Great Lakes Res. 1988.
Hudson, R, (1979) Toxicites of foe lampricides 3-trifluoromethyl-4-nitrophenol (TFM)
and the 2-aminoethanol salt of 2',5-dichloro-4'-nitrosalicylanilide (Bayer 73) to four
bird species. Investigations in Fish Control 89:1-5.
91
-------
Ill Illllllllllllll II 111 111
Ill III III II 111 III
Ml I III 111 111 III II ill
wi^^^^^^s^^L'.i "M" ,',' ..~I'.'.'i I, '."..2 i H. ~ " L" ,
, ...Si ....
in u i i in i iii in
I 33781801 Fathulla, R. (1995) Aerobic Aquatic Metabolism of (carbon 14) Labeled
"L:-i^.'~i**:'?i1!Tl!ii!:™™5*::s"5S'!.;^ 3-Tnf.liioromeTlryf^N^^ l^,_^™__ Final Report: Lab Project
Number. HWI-6293-133. Unpublished study prepared by Hazleton Wisconsin, Inc.
•n iiiiiiiiiiiiiimi'j :"':!iiiiiniiiiiiiiiii'iiii' n",i mum1": r ,' ninNi niiiiiiiiiiiiuiiiiiiii' MIL 111111111111, 'niiiiiiiini:,' iii iiiiiiiiiiii nnii i iiiiiiiiiiiiiiniiiiiii J. 10 U.
I IK:;1 i'i":"!!!iiiiiii'!iii I'iiiiiiiiiiiiiiiiiiii. iiRiLi::;!;! I'^iiiiiiiiiHij,,,!1 jimiEiii! 'iiiii^iiiNiiiiiaiiiiii1 "iiniiiiiiiiiiiiiini iiiiiiiiii f 'IIIM i IIP til
4||§7|p| Fathulla, R. (1996) Anaerobic Aquatic Metabolism of (carbon 14)-Labeled
' ..... ..... ''"ll
: HWl6293-135: EF-F-2L
~:~=i'==' , ,"] ' ~ •: ":ii!i2™-r-=- ..... !. " =s Wisconsin, Inc. 124 p.
((iiii ................................................. '
iL'ii^'iBi'iiiPiBii: iniiiiiiii"1! iiiBiiiii ii,;, njii»' & nniiiiiiMiiiihniiiiiiiii^nnnnnnnniiiiiii11':;,,;«'
"*441.869^1 Drottar, K.; Swigert, J. (1996) Mixture of TFM and Bayer 73: A 96-Hour
Acute Toxicity Test with the Bluegill (Lepomis macrochirus): Final
,-; i : intemationai"L'i3' 6*1 "p. "" ""' "'' ' '' ' " "
~^.~™~ ~'; ;, i^;,;;^',';;; '"."."II." _, r,' 1~ _!,,,' " 'i
^^^^ I
i, ..mm, "s,, ,t fmmj: mm:' rmm't "MiiSSSSHifSlfSMliS • _ ._ ™
' 'L -620-2 Drpttar, K.; Swigert, J. (1996) Mixture of TFM and Bayer 73: A 96-Hour
diynchus mykiss):
:: :;_::::i =:|':~:"i:.™r^i i; ^ Fjnal|i|Re|)ort: Lab Project Ninnb^ 433A-108. |Unpjiblished study^prepared by
6l""p~ I
Jill VI'£.!(( ,
|l llillllliliillllillIIIK'lill! 'lllllllliPli: :; |I IL : llllllliliilln'tLiiili; •••IIIIillll:IIWi!lilll'''>±
Reynolds, Joanne. Hydrolysis of [14C] TFM. Performed by XenoBiotic
Laboratories, Inc. Submitted by Great Lakes Fishery Commission, Ann Arbor,
!E?=^^^ !' = ;=•_=• L'lffi^E: Iii! Michigan. 1997.
Hubert, T. (1997) Uptake and Elimination of Lampricide TFM by Rainbow Trout:
[^ \ [ ' " [ J
!;«; f • iii"' |^^ : WtfJIJn^' JHt^^y prepared by Upper Mississippi Science Center. 677 p.
.S.'Dep^
...... ..... f tfoe' (fi?70 m
Formulations. Prepared by Hoechst Aktiengesellschaft. 5 p.
iiiiijaiM 'i:.,,,,,! < :< iliiiiii! p Nil ii.ir.i. i," ......... H " JjJiiiiiiPiPiiiiiiiiiiiiin.vi ijiiii'iiinniiii '' "iji ..... »ii;,|i|i «| iiBiiiiiii 1 1111 in 111 inn i i 1 1 nil 1 1 r ^ ,
n j , , ;. illiiin. | Illlliinu',,,, I, in ||i, "
"Mini u i; iniiiiNi'i v, ,'iipii? ,1111 jiiiinii" iiih'ii in niiiiii Jiiniiiiiiiiiiiiiiii,; r,,
iniii i nil n i nil i in pin nnii
inn i1 ilininn n I in inn in i mil1 in in n m iiiininn v inn i mini nun n n i n i nmi
hnick, R. (1991) U.S. Department of Interior, Fish and Wildlife Phase 3 Summary
^ Dietary LC50 Determination in Bobwhite Quail. Preparedby
'i ,iiiii;itli;:i !!'C/i;"!:!11! |!!''ii:ii fljljA IlillV iBI!''ii;' J::m ^MiXl "f iii H iir"*; 'iiJiiik 'iw^^ i :::i!!,ii>w^ fie ,:n' ,i i.i mir "iiiiii" i!1!.!' >"' iii ;:i!|iif • it; • i:"? \:its :PI<
-------
BIBLIOGRAPHY
MRID
CITATION
41616301
41616302
42552301
42552305
BIBLIOGRAPHY for NICLOSAMIDE
Bills, T. D. and L. L. Marking. 1976. Toxicity of 3-trffluorome%l-4-nitrophenol
(TFM), 2',5-Dichloro-4'-nitrosalicylanide (Bayer 73), and 98.2 Mixture to Fingerlings
of Seven Fish Species and to Eggs and Fry of Coho Salmon. US Fish and Wildlife
Service, Investigations in Fish Control No.69 .pgs 1-9.
Dawson, V. K., D. A. Johnson, and J. L. Allen. 1986. Loss of lampricides by
adsorption on bottom sediments. Canadian Journal of Fisheries and Aquatic
Sciences. Vol 43, No. 8: pp 1515 - 1520.
Fletcher, J.S., J.E. Nellessen, and T.G. Pfleeger. 1994. Literature review and
evaluation of the EPA food-chain (Kenaga) nomogram, an instrument for estimating -
pesticide residues on plants. Environ. Tox. Chem. 13:1383-1391.
Hoerger. F.D. and E.E. Kenaga. 1972. Pesticide residues on plants: correlation of
representative data as a basis for estimation of their magnitude in the environment
Environmental Quality. Academic Press, New York, I: 9-28.
Talbott, T. (1990) Product Chemistry of Bayluscide: Lab Project Number: C-33.1:
C-33.3: C-33.10. Unpublished study prepared by Mobay Corp. 16 p.
Talbott, T. (1990) Product Chemistry of Bayluscide [Chemical and Physical
Properties]: Lab Project Number: 99885: 98383: 98007. Unpublished study prepared
by Mobay Corp. 42 p.
Nelson, D.; Bauman, E. (1969) The Acute [Oral] Toxicity of Bayluscide (Bay 73)
70% Wettable Powder: Lab Project Number: 24859. Unpublished study prepared
by Chemagro Corp. 5 p.
Crawford, C.; Roney, D. (1971) The Skin and Eye Irritation Properties of Bayluscide
70% Wettable Powder to Rabbits: Lab Project Number: 30699. Unpublished study
prepared by Farbenfabriken Bayer A.G. 8 p.
93
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- I : '- • :- '
,,'l,lilllii|||lllllllillT, |l, ill I
'ii 1 iiiiiii iiii inr iiiiiiifi ii'iii iiiiM iiiiii^ igflOTiJiftBi!! ei'ii; i mrM«w*w?K;;MK>tiT i!ra^^^^^^^^ KK IK
IIIIIIII I IIIIIIIIIIIIII 111 II III 1111 I III I IIIIIII I 11 III III I I IIIIIIIIIIIIII I II III lll|l|l I III IllllllllPl.'llllllll.i.llliiiilllllllllllllllllilll'i.i'r'irilllilllS, I IIIIIii'1''1! !'' "'!;. "',"' '•m,,,'".!! ..W;""! | ' 'rup,!! jfi'l!, I Ul 1 |i"i'!!"»; '< .'K IIII'LiI:^!; ll<\;;'<>lKlllli;illlli:;:iiT||i|illl|!l||l|j||Iil|||lll||l|i "Si /"Mull i. , i "J {M. •»*,, ,,M ,1 1J. , Sl, - II, niL™ MM 1, „,. , J, :
ii in iiiiiiii iiii i iiiiii I, i 11 n 11111, i iiiiH Number: 14:16r0008.dp2Q. Unpublished study prepared by WARP Institute, toe.
in iiniiiii" i iiiiii i"*"Hi iiii'iiiiniiiiiiiiliiiiiiiii iiiiiiiiiiiiiiiini 1168 p.
11 , M' i ' 'i
42552308 Harris, D. (1974) Bayer 73: 90 Day Subacute Feeding Study-Hamster: Lab Project
Number: i4^16-6d08-62"6. y^^jigj^ ^^ pj-gp^g^ £y ^^p j^gm^e, Inc.
142^.
42552309 Procter, B.; Dussault, P.; Rona, G.; et al. (1974) A Study of the Chronic Toxicity of
Bayer 73 in Dog: Lab Project Number: 6425. Unpublished study prepared by
Bio-Research Labs Ltd. 87 p.
42552310 Dyd^;ChapiieI,"C:
iiiilll"!!' n lllllli
\mm "i i " 1,1 in
lliill ill IliliillliiFil I ('ill i lllllil
HI"! (•• m II'IIIH '73 in Rabbit: Lab Project Number: 3. Ur
lill I IIIIIIIII, I •111' I ii D « I « ' !f • *;TI " I!IL" ' ' • • - '"' •':
Illlll1 lllllli "lll'l i ilii'lll'll'iii illllll1 Labs Ltd, 45 p.
42552313 SchidS D.; Harrnan, P. (1978) Hydrplyas ar^^hotolysis of_the Lainpricide Bayer
73: Lab Project Number: 85, Unpublished study prepared by US Fish and Wildlife
Service. 8 p.
iiiiiiiiiii iiiiiiiiiiiiii
42552315 Dawson. \'.: Johnson, D.; Allen, J. (1986) Loss of Lampricides by Adsorption on
II III I IIIIIIIIIIIIII III Illlll Illlll III IIIIIIIIIIIIII Ml I I «E n 't" i „, MB Jl 1 1 , IJIIMIIIIII I pi J ijBini ii i i ii i ii mill i
Bottom Sediments. Canadian Journal of Fish. Aquat. Science 43:1515-1520.
42552316 DawsoiT v" (1986) Adsorption-Desorption of [carbon 14]-Bayer 73 by Bottom
Sediments^ y^p^^gj^^^p^^g^^^^ Hitih^'Wildlife Service. 110 p.
I 111 III III I|1|| 111 I 111 111 . HI lill Illlilllllll IIIIIIIII IIIIIIIIIIIIII III IIIIIIIIIIIIII III II11 III 111 I II I 1 I IIIIIIIIIIIIII I IIIIIII II I Illlll I . Illlll I Mil 111 IIIIIIIIIIIIII III IIIIIIIII II 111IIII IIII IIIIIIIII IIIIIIII
42552317 Ho, K.; Gloss, S. (1987) Distribution and Persistence of the Lampricide Bayer 73
Ilirill II Ill I "IIII Ill II 'foUbwfiga Control Application. Can. J.'Fish. Aquat Sci. 44:112-119.
niiH^^^^ it-'::
""""'
M^^^^^^^^^^^^^^^^ l,i IlHiill IIIIH^^^^^^^^^^^^ !1K^^^
|82) SR 73: Chronic Toxicological Study with
-------
BIBLIOGRAPHY
MRID
CITATION
Lab Project Nos.: 10989; 82382. Unpublished study prepared by Bayer AG, Dept.
of Toxicology. 504 p.
43044901
43667101
43667102
43667103
43677701
43677702
43677901
43677902
Williams, M.; Heim, L. (1993) Dissociation Constant (for Niclosamide): Lab Project
Number: 41223: FIFRA-D-63-10. Unpublished study prepared by ABC Labs, Inc.
31 p.
Riekena, C. (1995) Product Identity and Composition of 3.2% Bayluscide Granular:
Lab Project Number FIS/0594/C142. Unpublished study prepared by Bell Labs, Inc
64 p.
Riekena, C. (1995) Analysis and Certification of Product Ingredients of 3.2%
Bayluscide Granular: Lab Project Number: FIS/0594/C142. Unpublished study
prepared by Bell Labs, Inc.34 p.
Riekena, C. (1995) Physical and Chemical Characteristics of 3.2% Bayluscide
Granular: Lab Project Number: FIS/0594/C142. Unpublished study prepared by Bell
Labs, Inc. 15 p.
Schafer, E.; Bowles, W.; Hurlbut, J. (1983) The acute oral toxicity, repellency, and
hazard potential of 998 chemicals to one or more species of wild and domestic birds.
Arch. Environmental Contam. Toxicol. 12:355-382.
Hudson, R. (1979) Toxicites of the lampricides 3-trifluoromethyl-4-nitrophenol (TFM)
and the 2-aminoethanol salt of 2',5-dicMoro-4-mtrosah\^lanilide (Bayer 73) to four
bird species. Investigations in Fish Control 89:1-5.
Cifone, M. (1995) Mutagenicity Test on Niclosamide in the L5178Y TK+/Mouse
Lymphoma Forward Mutation Assay: Final Report: Lab Project Number:
16403-0-431:20989:431. Unpublished study prepared by Corning Hazleton Inc. 71
P-
Murli, H. (1995) Mutagenicity Test on Niclosamide
(2l,5-Dichloro-4'-Nitrosalicylanilide) Measuring Chromosomal Aberrations in vivo in
95
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BIBLIOGRAPHY
MRID
CITATION
44206101 Drottar, K.; Swigert, J. (1997) Niclosamide Ethanolamine Salt TGAI (Bayer 73
Technical): A 96-Hour Flow-Through Acute Toxiciry Test with the Bluegjll (Lepomis
macrochirus): Amended Final Report: Lab Project Number 433A-104. Unpublished
study prepared by Wildlife International Ltd. 51 p.
97
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Appendix D. COMBINED GENERIC AND PRODUCT SPECIFIC DATA
CALL-IN
99
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
GENERIC AND PRODUCT SPECIFIC
DATA CALL-IN NOTICE
CERTIFIED MAIL
Dear Sir or Madam:
This Notice requires you and other registrants of pesticide products containing the
active ingredient identified in Attachment A of this Notice, Hie Data Call-in Chemical Status
Sheet to submit certain data as noted herein to the U.S. Environmental Protection Agency
(EPA, the Agency). These data are necessary to maintain the continued registration of your
produces) containing this active ingredient Within 90 days after you receive this Notice you
must respond as set forth in Section HI below. Your response must state:
1.
2.
3.
How you will comply with the requirements set forth in this Notice and its Attachments 1
through 6; or
Why you believe you are exempt from the requirements listed in this Notice and in
Attachment 3 (for both generic and product specific data), the Requirements Status and
Registrant's Response Form, (see section ffl-B); or
Why you believe EPA should not require your submission of data in the manner
specified by this Notice (see section ffl-D).
If you do not respond to this Notice, or if you do not satisfy EPA that you will comply with its
requirements or should be exempt or excused from doing so, then the registration of your
produces) subject to this Notice will be subject to suspension. We have provided a list of
all of your products subject to this Notice in Attachment 2. All products are listed on both the
101
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j and product specific Data Call-in Response Forms. Also included is a list of all
iiilpgistranti who were sent this Notice ^i^chliient ^
athority for this Notice is section 3(c)(2)03) of the Federal Insecticide,
By CoflecfiarToF
roval No. 2070-0107
ilit, in nini!,!!|!i"lllUllli'illlHILilllllili'j liil'H'iji'lJiniiii '"Sill ' rii"innP!lii"i!lill. IIIJI" TlilllllilllllliiT 'liijnnilllll. i'!,1;1!! !i: ;;!lll I
I WIBl!^MOphisJ^|otice is divided into) six sections and^sjx^Attachments. T^N^ceJteelfcpnfams
iS tewtdibixnaiiaa and instructions applicable to all Data Call-In Notices. The Attachments contain specific
! 'i '"'*] I " ', ,: 'n , 1 I! , ' 'I ' i"i! 'I ' ' !' ' ; '' " • ''' •
y!'ftti^H iil-cnemical information and instructions. The six sections of the Notice are:
, i
Why You are Receiving this Notice
Dati^Required by this Notice
;Cfti^limce"wi5rit^^
Consequences of Failure to Comply with this Notice
,,.^y~^_, __^g^ _ g^^j; possjgje Unreas ona|jjg A^vexse Effects
Inquiries and Responses to this Notice
!!H^^^^ IIH^^^^^^^^^^
1 illl:, ,.i!Tii i 'PUni lllllihiill'niiiilll,' • IlillliilPi'llliElllillllllllllllllllPI'iill iirilijllillllllllllllllllllimilli:! lilli ''[Ilirilirilllliililillliti illlili111!11' < illlhlljIiiilliiiiSiiL "H \ .'iPllliii IIIUIIIIII111 ii,, < I" I, " i|:i|,!lilli" £ f i! mm m, :
»;:> ,i. i !• 1 « t :
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SECTION I.
WHY YOU ARE RECEIVING THIS NOTICE
The Agency has reviewed existing data for this active ingredient(s) and reevaluated the data
needed to support continued registration of the subject active ingredients). This reevaluation identified
additional data necessary to assess the health and safety of the continued use of products containing this
active ingredient(s). You have been sent this Notice because you have produces) containing the subject
active ingredients).
SECTION n. DATA REQUIRED BY THIS NOTICE
II-A. DATA REQUIRED
The data required by this Notice are specified in the Requirements Status and Registrant's
Response Forms (Insert B) (for both generic and product specific data requirements). Depending on
the results of the studies required in this Notice, additional studies/testing may be required.
II-B. SCHEDULE FOR SUBMISSION OF DATA
You are required to submit the data or otherwise satisfy the date requirements specified in the
Requirements Status and Registrant's Response Forms (Insert B) within the time frames provided.
II-C. TESTING PROTOCOL
All studies required under this Notice must be conducted in accordance with test standards
outlined in the Pesticide Assessment Guidelines for those studies for which guidelines have been
established.
These EPA Guidelines are available from the National Technical Information Service (NTIS),
Attn: Order Desk, 5285 Port Royal Road, Springfield, VA 22161 (Telephone number.
703-605-6000).
Protocols approved by the Organization for Economic Cooperation and Development (OECD)
are also acceptable if the OECD recommended test standards conform to those specified in the
Pesticide Data Requirements regulation (40 CFR § 158.70). When using the OECD protocols, they
should be modified as appropriate so that the data generated by the study will satisfy the requirements
of 40 CFR § 158. Normally, the Agency will not extend deadlines for complying with data
requirements when the studies were not conducted in accordance with acceptable standards. The
OECD protocols are available from OECD, 2001 L Street, N.W., Washington, D.C. 20036
(Telephone number 202-785-6323; Fax telephone number 202-785-0350).
103
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J Ji1^^ I
• •iiiiiiiiiH^^^^ ,io,'i"i ,,„ iiiiiiii .UK! ,,1,1 ii'Tiiiiiiin i niiiiiiii"'
iiiiiiii;::,; n , f "sm ; i
11! iifW^
nnini"
IHI'ILIn
i.:.! "i1 i,v t1/ •*., ri 'w i-, t! I»WL!,"«•
:iT'! ,i I/.!: a: ....... i:- " '..SKI)* • ..... i ..... jiiii"]' ii; iiiAit
HLit'a ..... 'I (•'.! fiftf^ ..... ;l"'l ..... '
yili,1,,"1!!'!1,,, v L li'lin, lOgUiliii! ,
illP'lt UP1' JBIIIPilliJEl:
i "ii '.•"•«»• .......... ; : 'MM* "i: : ...... , yur lUM^
All new studies and proposed protocols submitted in response to this Data Call-in Notice must
be irt accordance with Good Laboratory Practices [40 CFR Part 160].
H-D. REGISTRANTS RECEIVING PREVIOUS SECTION 3(c)(2}(E') NOTICES
ISSUED BY THE AGENCY
iiiiinin niiii i n n i in i inn i in inn i in in n • n n i iiiniini i in i n i i in linn i i n
lillllll I 111
Unless otherwise noted herein, this Data Call-in does not in any way supersede or change the
requirements of any previous Data Call-In(s). or any other agreements entered into with the Agency
pertaining to such prior Notice, j^ggjg^.^^ roast comply wiS the requirements of all Notices to avoid
issuance of a Notice of Intent toSuspend their affected products.
SECTION HI. COMPLIANCE WITH REQUIREMENTS OF THIS NOTICE
I iliiiiiiiiiii iiliiii i iiiiiiii
You must use the correct forms and instructions when completing your response to this Notice.
pe of Data Call-in you must comply with (Generic or Product Specific) is specified in item
iber 3 on the four Data Call-In forms (Attachments 2 and 3).
DI-A. SCHEDULE FOR RESPONDING TO THE AGENCY
The appropriate responses initially required by this Notice for generic and product specific data
11W i! rriust be submitted to the Agency within 90 days after your receigt of this Notice. Failure to adequately
respond to this Notice within 90 days of your receipt will be a basis for issuing a f^gge oFintent to
Suspend (NOIS) affecting your products. This and other bases for issuance of NOIS due to failure to
comply with this Notice are presented in Section IV-A and IV-B.
I"
i i i
m-B. OPTIONS FOR RESPONDING TO THE AGENCY
IIIIIIP !• Illllil llillll llillll
I i 111I Hi
ic Data Requirements
in iiiiiiii i ii iiiiiiii'jii iiiiVi'iii iiiiiiii IIH ii in iiiiiiii
iiiiiiin Hi < i iiiiiiii
I'll i iiiiiiii iii11 ii ii I'liiiiiiiiii1 iiiiiiiiiiiii'i1 iiiiiN, i i iii1 in iii i iii1
The options for responding to this Notice for generic data requirements are: (a) voluntary
cancellation, (b) delete use(s), (cj claim generic data exemption^ (d) agree to satisfy the generic data
requirements imposed by this Notice or (e) request a data waiver(s).
A discussion of how to respond if you choose the Voluntary Cancellation option, the Delete
; A'dls'cusslbn'bf tEe various
ins aV^abTelbr satisfying lie generic data requirements of this Notice is contained in Section
. A discussion of options relating to requests for data waivers is contained in Section Ht-D.
II ill 111 II 111 I III III III 11
• .HI ''Two forms apply to generic data requirejnoits, one or both of which must be used in responding
::: ^=f!o the Agency, depending upon your response. These two forms are the Date-^Jafi-Jn Response Form
!' :" lllllllllllllll!l!l11 <<<<<»<»<<<<<'»<<"<<<<<»"<»'SiMllllMli!'1-1«...' |||||;;||;;yin illlllllllllllllllililnjillllillillllliiqilllllliii:!:!!!!!!!^ ijllllllnlllllllllllll .'Lillilll;, illllllll'iHiiillllllllllllllillllllllilJllllllllllllllin'lliilltdlilPli, 'Illllnlllill j|||||lll«lllllllllllllillllllll lilllllillli|.||lli'Illliillil/lilgiliU"!'!IPlliliillllllllllilllllllllillllliiilllllilllll'IIIIE'ifll'ITIIIIilPil'IIIIIIIIIIFillEillllPi raiiliBllil«
-------
The Data Call-in Response Forms (Insert A) must be submitted as part of every response to this
Notice. The Requirements Status and Registrant's Response Forms (Insert B) also must be submitted if
you do not qualify for a Generic Data Exemption or are not requesting voluntary cancellation of your
registrations). Please note that the company's authorized representative is required to sign the first
page of both Data Call-in Response Forms (Insert A) and the Requirements Status and Registrant's
Response Forms (Insert B) and initial any subsequent pages. The forms contain separate detailed
instructions on the response options. Do not alter the printed material. If you have questions or need
assistance in preparing your response, call or write the contact person(s) identified in Attachment 1.
a.
Voluntary Cancellation -
You may avoid the requirements of this Notice by requesting voluntary cancellation of your
produces) containing the active ingredient that is the subject of this Notice. If you wish to voluntarily
cancel your product, you must submit completed Generic and Product Specific Data Call-in Response
Forms (Insert A), indicating your election of this option. Voluntary cancellation is item number 5 on
both Data Call-In Response Formfs). If you choose this option, these are the only forms that you are
required to complete.
If you chose to voluntarily cancel your product, further sale and distribution of your product after
the effective date of cancellation must be in accordance with the Existing Stocks provisions of this
Notice, which are contained in Section IV-C.
b. Use Deletion -
You may avoid the requirements of this Notice by eliminating the uses of your product to which
the requirements apply. If you uish to amend your registration to delete uses, you must submit the
Requirements Status and Registrant's Response Form (Insert B), a completed application for
amendment, a copy of your proposed amended labeling, and all other information required for
processing the applicauoa Use deletion is option number 7 under item 9 in the instructions for the
Requirements Status and Registrant's Response Forms (Insert B). You must also complete a Data
Call-in Response Form (Insert A) by signing the certification, item number 8. Application forms for
amending registrations ma> be obtained from the Registration Support Branch, Registration Division,
Office of Pesticide Program^,. EPA, by calling (703) 308-8358.
If you choose to delete the use(s) subject to this Notice or uses subject to specific data
requirements, further sale, distribution, or use of your product after one year from the due date of your
90 day response, is allowed only if the product bears an amended label.
c. Generic Data Exemption -
Under section 3(c)(2)(D) of FIFRA, an applicant for registration of a product is exempt from
the requirement to submit or cite generic data concerning an active ingredient if the active ingredient in
105
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f-i!'?ii»w,^iiL'!wift;;!i ^Miifijs; li&t'^i^iifs^f'iiii
•;!sjniiiiiiii;iiFnAilliiijlSiililiSiii^ iiiiiiiiiiii!;,•'!:''''ill' •''" 'i''Is!1 iiiiiiiliiiiiiii'iiiiiiiiiiiiiill'ii1' •,I'*'* iri'is*!!! ini1!, i^lMJliiiiiii'!''iii*!"11:',,I• liiiiiisiiiSP'1>'f1'1',;ii1 ^i'!1" -iij'riiiliflii illSiH1 'd^iiilkiii'''^1!1!!1!!' si ill'''i'BF ,jijf: i,•'''m KLi''"!ii'!!':,; il;?* it
-------
e. Request for Generic Data Waivers.
Waivers for generic data are discussed in Section ni-D.l. of this Notice and are covered by
options 8 and 9 of item 9 in the instructions for the Requirements Status and Registrant's Response
Form (Insert B). If you choose one of these options, you must submit both forms as well as any other
information/data pertaining to the option chosen to address the data requirement.
2.
Product Specific Data Requirements
The options for responding to this Notice for product specific data are: (a) voluntary
cancellation, (b) agree to satisfy the product specific data requirements imposed by this Notice or (c)
request a data waiver(s).
A discussion of how to respond if you choose the Voluntary Cancellation option is presented
below. A discussion of the various options available for satisfying the product specific data
requirements of this Notice is contained in Section ffl-C.2. A discussion of options relating to requests
for data waivers is contained in Section ffl-D.2.
Two forms apply to the product specific data requirements one or both of which must be used in
responding to the Agency, depending upon your response. These forms are the Data-Call-in
Response Form (Insert A), and the Requirements Status and Registrant's Response Form (Insert B),
for product specific data. The Data Call-in Response Form (Insert A) must be submitted as part of
every response to this Notice. In addition, one copy of the Requirements Status and Registrant's
Response Form (Insert B) also must be submitted for each product listed on the Data Call-In Response
Form (Insert A) unless the voluntary cancellation option is selected. Please note that the company's
authorized representative is required to sign the first page of the Data Call-in Response Form (Insert A)
and Requirements Status and Registrant's Response Form (Insert B) (if this form is required) and initial
any subsequent pages. The forms contain separate detailed instructions on the response options. Do
not alter the printed material. If you have questions or need assistance in preparing your response, call
or write the contact person(s) identified in Attachment 1.
a. Voluntary Cancellation
You may avoid the requirements of this Notice by requesting voluntary cancellation of your
produces) containing the active ingredient that is the subject of this Notice. If you wish to voluntarily
cancel your product, you must submit a completed Data Call-in Response Form (Insert A), indicating
your election of this option. Voluntary cancellation is item number 5 on both the Generic and Product
Specific Data Call-in Response Forms (Insert B). If you choose this option, you must complete both
Data Call-in response forms. These are the only forms that you are required to complete.
107
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Illllllllll II Illllllll Illllllll I III III I1I11I|||11B^ Illllllll Illllllll^ Illllllll llllllllllllllllll|llll
Ill
If you choose to voluntarily cancel your product, further sale and distribution of your product
ive date of cancellation must be in accordance with the Existing Stocks provisions of this
Section fy-C.
''ill ..... ..... 1H^^^^^^^^^ ..... SB
......... . [[[
Satisfying flie Product Specific Data Requirements of this Notice.
MSA, IKW&'Z
'ire"vinc^"c)plibns ..... ^jg"1^ ...... ^^fyfte proict specific 'd^^ ..... of this .................................
nis 'iie"d1scusse3 in Section titl-C. of this Notice and comprise options 1 through 6
j™^!ir3~!~™t^ ...... !j5Fj5eiH'$ ..... STlEe 53staic^onT^^^p^bduct"ispeaific Requirements Status and Registrant's Response
' ' ......... J&HDlQnsert B) and item numbers 7a and 7b (agree to satisfy the product 'specific date, requirements
*for an MjJP ...... OTEJJP as ..... applicable) on the product specific Data c^jyfo Response Form (Insert A).
" avai!ab]e"for addressing pr53u^f specific data requirements differ slightly from
_ tions for i&lilping generic data requirements'. D*ele5on of a use(s) and the low volume7minor use
d^q|frj3puon are not vaJKToptibns for fulfilling procbct specific data requirements, ft is important to ensure that
you are isuig ffie coErect"fo^ns iEdlnsEucEanswfien~con9leting your response to the Reregistration
11 i i Eligibility Decision document
I c" Request for Product Specific Data Waivers.
"I ""fj"!:"1™"1':"' - '"' if I
iWaivers for product specific data are discussed in Section iII-D.2. of this Notice and are
of item 9 in the instructions for the Requirements Status and Registrant's Response
(Insert B). If you choose this option, you must submit the Data Call-in Response Form (Insert
A) and t|e Requirements Status and Registrant's Response Fjorm (Insert B) as well as any other
. pertaining
?i ..... ailtemnutnberl'.'
ffl-C SATISFYING THE DATA REQUIREMENTS OF THIS NOTICE
, .jenenc.Data
satisfy the generic data requirements (i.e. you select item number Go), then you must select one of the
six options on the Generic Requirements Status and Registrant's Response Form (Insert B) related to
^^B^^^^^ e?S^ d§%*e
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(3) I have made offers to cost-share (Offers to Cost Share)
(4) I am submitting an existing study that has not been submitted previously to the Agency
by anyone (Submitting an Existing Study)
(5) I am submitting or citing data to upgrade a study classified by EPA as partially
acceptable and ungradable (Upgrading a Study)
(6) I am citing an existing study that EPA has classified as acceptable or an existing study
that has been submitted but not reviewed by the Agency (Citing an Existing Study)
Option 1. Developing Data
If you choose to develop the required data it must be in conformance with Agency guidelines
and with other Agency requirements as referenced herein and in the attachments. All data generated
and submitted must comply with the Good Laboratory Practice (GLP) rule (40 CFR Part 160), be
conducted according to the Pesticide Assessment Guidelines (PAG) and be in conformance with the
requirements of PR Notice 86-5. In addition, certain studies require Agency approval of test protocols
in advance of study initiation. Those studies for which a protocol must be submitted have been identified
in the Requirements Status and Registrant's Response Form (Insert B) and/or footnotes to the form. If
you wish to use a protocol which differs from the options discussed in Section H-C of this Notice, you
must submit a detailed description of the proposed protocol and your reason for wishing to use it The
Agency may choose to reject a protocol not specified in Section II-C. If the Agency rejects your
protocol you will be notified in writing, however, you should be aware that rejection of a proposed
protocol will not be a basis for extending the deadline for submission of data.
A progress report must be submitted for each study within 90 days from the date you are
required to commit to generate or undertake some other means to address that study requirement, such
as making an offer to cost share or agreeing to share in the cost of developing that study. This 90-day
progress report must include the date the study was or will be initiated and, for studies to be started
within 12 months of commitment, the name and address of the laboratory(ies) or individuals who are or
will be conducting the study.
In addition, if the time frame for submission of a final report is more than 1 year, interim reports
must be submitted at 12 month intervals from the date you are required to commit to generate or
otherwise address the requirement for the study. In addition to the other information specified in the
preceding paragraph, at a minimum, a brief description of current activity on and the status of the study
must be included as well as a full description of any problems encountered since the last progress
report.
The time frames in the Requirements Status and Registrant's Response Form (Insert B) are the
time frames that the Agency is allowing for the submission of completed study reports or protocols. The
noted deadlines run from the date of the receipt of this Notice by the registrant If the data are not
submitted by the deadline, each registrant is subject to receipt of a Notice of Intent to Suspend the
affected registrations).
109
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submitting a Data Call-In Response Form (Insert A) and a Requirements Status and Registrant's
Response Form (Insert B) committing to develop and submit the data required by this Notice.
In order for you to avoid suspension under this option, you may not withdraw your offer to share
in the burden of developing the data. In addition, the other registrant must fulfill its commitment to
develop and submit the data as required by this Notice. If the other registrant fails to develop the data
or for some other reason is subject to suspension, your registration as well as that of the other registrant
normally will be subject to initiation of suspension proceedings, unless you commit to submit, and do
submit, the required data in the specified time fiame. In such cases, the Agency generally will not grant
a time extension for submitting the data.
Option 4. Submitting an Existing Study
If you choose to submit an existing study in response to this Notice, you must determine that the
study satisfies the requirements imposed by this Notice. You may only submit a study that has not been
previously submitted to the Agency or previously cited by anyone. Existing studies are studies which
predate issuance of this Notice. Do not use this option if you are submitting data to upgrade a study.
(See Option 5).
You should be aware that if the Agency determines that the study is not acceptable, the Agency
will require you to comply with this Notice, normally without an extension of the required date of
submission. The Agency may determine at any time that a study is not valid and needs to be repeated.
To meet the requirements of the DCI Notice for submitting an existing study, all of the following
three criteria must be clearly met:
a.
You must certify at the time that the existing study is submitted that the raw data and
specimens from the study are available for audit and review and you must identify where
they are available. This must be done in accordance with the requirements of the Good
Laboratory Practice (GLP) regulation, 40 CFR Part 160. As stated in 40 CFR 160.3,
Raw data means any laboratory worksheets, records, memoranda, notes, or exact
copies thereof, that are the result of original observations and activities of a study and
are necessary for the reconstruction and evaluation of the report of that study. In the
event that exact transcripts of raw data have been prepared (e.g., tapes which have
been transcribed verbatim, dated, and verified accurate by signature), the exact copy or
exact transcript may be substituted for the original source as raw data. *Raw data' may
include photographs, microfilm or microfiche copies, computer printouts, magnetic
media, including dictated observations, and recorded data from automated instruments."
The term "specimens", according to 40 CFR 160.3, means "any material derived from a
test system for examination or analysis."
Ill
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b. Health.and safety studies completed after May 1984 must also contain all GLP-required
^^^^^^^^^•^^.^^^^^^jy-^^^ information pursuant to the requirements of 40
• , iiiiii" jK^HKJttiiniJbiMHfrmCFR Part 160. Registrants also must certify at the time of submission of the existing
'that such GI^ information' is available for post May 1984 studies by including an
appropriate statement on or attached to the study signed by an authorized official or
"» : == ;.• - ••'i T •; : .• .: ' .•. . representative of the registrant.
;;;;;,„;—;;;; "";„==;,;„""::;';—;|, iiiiiiiiiiiiii;;,;;; „;;;;:,„;; ,,,1;;=:=;;;; r;i::^^ =;, : |
c. You must certify that each study fulfills the acceptance criteria for the Guideline relevant
i;*?;!":-™' ':^«! ~ie™™™? ^™ i to the study provided in the FIFRA Accelerated Reregistration Phase 3 Technical
Iffi^iiiijiji ^N'£ii£fli ' • f m • S , , ,g, • i, „ . i •
; IIH^ iiiiH iiiGuidelines (PAG) or meets the purpose of the PAG (both documents available from
NTIS). A study not conducted according to the PAG may be submitted to the Agency
|^;;^~,~; ;™;~ ~^il '„ ™ ^ !^L.'r|^^,S£^^^^^ J^^nifi^^1311* bslieves th^ the "study clearly meets the purpose of the
iSSiHiH^^^ jiSii^bPAG. The registrant is referred to 40 CFR 158.70 which states the Agency's policy
llljp||||p 'i:^ that the purposes of the PAG are met by the stiiidy, clearly articulate the
|T!IIirZ ,; !.M £l«"t F'™' rationale why you believe the study meets the purpose of the PAG, including copies of
l||llt I IflllllllH llllllllll|ill 111 ll|lilllll III 111 1111^ J J ' r turn • tit •*•
! • • ! " ;i;l!; ':i " ' any supporting information or date It has been the Agency's experience that studies
•11 • 11| mi HI 11 • • m || mil || | i.jRjjijljIiP'j1:.! jhjjjjjjiljjjlijjjjjjljllllljjjjjjjljjjij1 ilillilr"^'.^!!!!!!!!!!! II Illllll I 1 II III Illllll I II I I ifci1 ' n I " < ., < aliii i«i M' ' iiiiii '
-------
upgraded, call or write the contact person listed in Attachment 1. If you submit data to upgrade an
existing study you must satisfy or supply information to correct Ml deficiencies in the study identified by
EPA. You must provide a clearly articulated rationale of how the deficiencies have been remedied or
corrected and why the study should be rated as acceptable to EPA. Your submission must also specify
the MRID number(s) of the study which you are attempting to upgrade and must be in conformance
with PR Notice 86-5 entitled "Standard Format for Data Submitted under FIFRA."
Do not submit additional data for the purpose of upgrading a study classified as unacceptable
and determined by the Agency as not capable of being upgraded.
This option also should be used to cite data that has been previously submitted to upgrade a
study, but has not yet been reviewed by the Agency. You must provide the MRID number of the data
submission as well as the MRID number of the study being upgraded.
The criteria for submitting an existing study, as specified in Option 4 above, apply to all data
submissions intended to upgrade studies. Additionally, your submission of data intended to upgrade
studies must be accompanied by a certification that you comply with each of those criteria, as well as a
certification regarding protocol compliance with Agency requirements.
Option 6. Citing Existing Studies
If you choose to cite a study that has been previously submitted to EPA, that study must have
been previously classified by EPA as acceptable, or it must be a study which has not yet been reviewed
by the Agency. Acceptable toxicology studies generally will have been classified as "core-guideline" or
"rare-minimum." For ecological effects studies, the classification generally would be a rating of "core."
For all other disciplines the classification would be "acceptable." With respect to any studies for which
you wish to select this option, you must provide the MRID number of the study you are citing and, if the
study has been reviewed by the Agency, you must provide the Agency's classification of the study.
If you are citing a study of which you are not the original data submitter, you must submit a
completed copy of EPA Form No. 8570-34, Certification with Respect to Citations of Data.
2. Product Specific Data
If you acknowledge on the product specific Data Call-in Response Form (Insert A) that you
agree to satisfy the product specific data requirements (i.e. you select option 7a or 7b), then you must
select one of the six options on the Requirements Status and Registrant's Response Form (Insert B)
related to data production for each data requirement. Your option selection should be entered under
item number 9, "Registrant Response." The six options related to data production are the first six
options discussed under item 9 in the instructions for completing the Requirements Status and
Registrant's Response Form (Insert B). These six options are listed immediately below with information
in parentheses to guide registrants to additional instructions provided in this Section. The options are:
113
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Vc ........ Jiiiiii!giiiEii!!!!!iiiiii!ii:i::iii!ii:irf!;£ ..... ''
^^^ ..... l!!?!:::!!!!!!!!!::!!!!!!]!:;:!:;;;!::1^ ...... ISM'
...... '
i:,!!!!:!,,!!!!!!!!!!!'!1!];!!:!!!!:!!:::!!!!!! ..... I'iiiiiiiRi'iiiiii:!! ...... L\wi;a«r.*f:<,
.................... !l ................
"^^
., [[[
;! .....
III!1!,: ; 'Jllliiilijiini!!.!!')1 • !lll!!'i| -SI' 'il'H'l!;!' :il"L.i ""lll'il!" Illiiillll:' llllJlR I'.!!1!'t; / n'llllllni'illll! II "lllP'PIIIIICiUlllllllillin11 ,i.i< "l[,
Ii I
i'1 P'lllllLii'JII! I'll 'IIIIIIIIIIICilllllllllilllllT1,;,1"!!,, '> !!!!''Ill"1* fl11'!'' iill!"lllhlllllllllilinilllll|lljlllH!!! .iillllllHlllllliiiHiljlii ,ll! I
.attain y anyone (Submitting an Existing Study)
....... •* ..................... • .................. ! ...... '. ..... " - ......... • ..... ~ ........... i .............. " ............. . ....... ' ......................... :• ............... (5) I am submitting or citing data to upgrade a study classified by EPA as partially
•|^»';|||S^|^^^5:^^PS6€ ..... an¥upgradeable (Upgrading a Study)
'" | am citing an existing study that EPA has classified as acceptable or an existing study
.....
. ..... :;:„ ........ . .................. • ..... ::: ................................... ; ...... : ........................ • ................... , ........ ...... ; ..... :::;;;;: ...... • ...... , ............... ::,:: ......... :::;, ............. . ..... , ........... ,:::„ ............. •;,. ............... , .......... . .................. , ..... ;:,:::: ........... ::;: ..... • ....... -,-,: ...... ;: ................ , ................. • .............. • ........................ ,::;::: ................ : ........ : ......... • ........ • ............... :;;;: ............................ , ......... ,-..- ....... ,:::::: ..... ,„:„::::::, ....... . ..... • ........ ; ........ ........ :r :,:::::,:::,::
Option 1. Developing Data — The requirements for developing product specific data are the same as
those described for generic data (see Section HI.C.1, Option 1) except that normally no protocols or
........... . [[[ ................... = ..... ! ....... ........ ....... i ...................... • • ................. S ...... ............................... a ................. ...... a ............................. « ...................... '• ................ ........... ' [[[ ............................... •• .............. - ....................................... ' .......... - ....... ........... .................. ' ........ = ................................ '• ............. ' ................................ ....................................... & ................ ......... S .................................. ...... ............... , ..................... :-::,
i are required.
— If you enter into an agreement to cost share, the
data as to generic data (see Section M.C.1, Option 2)
option for acute toxieity data and certain efficacy data and
"
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m-D. REQUESTS FOR DATA WAIVERS
1. Generic Data
There are two types of data waiver responses to this Notice. The first is a request for a low
volume/minor use waiver and the second is a waiver request based on your belief that the data
requirements) are not appropriate for your product.
a.
Low Volume/Minor Use Waiver
Option 8 under item 9 on the Requirements Status and Registrant's Response Form
(Insert B). Section 3(c)(2)(A) of FIFRA requires EPA to consider the appropriateness of
requiring data for low volume/minor use pesticides. In implementing this provision, EPA
considers low volume pesticides to be only those active ingredients whose total production
volume for all pesticide registrants is small. In determining whether to grant a low volume, minor
use waiver, the Agency will consider the extent, pattern and volume of use, the economic
incentive to conduct the testing, the importance of the pesticide, and the exposure and risk from
use of the pesticide. If an active ingredient is used for both high volume and low volume uses, a
low volume exemption will not be approved. If all uses of an active ingredient are low volume
and the combined volumes for all uses are also low, then an exemption may be granted,
depending on review of other information outlined below. An exemption will not be granted if
any registrant of the active ingredient elects to conduct the testing. Any registrant receiving a low
volume/minor use waiver must remain within the sales figures in their forecast supporting the
waiver request in order to remain qualified for such waiver. If granted a waiver, a registrant will
be required, as a condition of the waiver, to submit annual sales reports. The Agency will
respond to requests for waivers in writing.
To apply for a low volume/minor use waiver, you must submit the following information, as
applicable to your produces), as part of your 90-day response to this Notice:
(i). Total company sales (pounds and dollars) of all registered produces) containing the
active ingredient If applicable to the active ingredient, include foreign sales for those products
that are not registered in this country but are applied to sugar (cane or beet), coffee, bananas,
cocoa, and other such crops. Present the above information by year for each of the past five
years.
(ii) Provide an estimate of the sales (pounds and dollars) of the active ingredient for
each major use site. Present the above information by year for each of the past five years.
(iii) Total direct production cost of produces) containing the active ingredient by year
for the past five years. Include information on raw material cost, direct labor cost, advertising,
sales and marketing, and any other significant costs listed separately.
115
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mi" ,,'",31 nnijiiiiK'in i iin
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ill',, „ fit, 1*1' '1 ''In ,;• ] 'l. 1 !!fl!Di| I1"! \ M\SV >'< i • Jui , , '* i », W '•' ....... I''1 :'J V i • '<' * ' I'M: I!' il
- ..... ^^ ' —
' ilillNIi! ...... Blllllliilll1!1"!1.!'!1 lilililllllJIIBIiiiillllllil
"i i!"!!1':1' ii| IK;'!!!':! iiii'::" iiiiiiiLi • i Mntsiif n:1: ; iiiiiii na ijiiiiii; n Tiff KiRM1?! IIIIH^^^ Hi" fiiti! 11; li'iiia!1 iiiiiii'i: n w, FI ! MI, ':: I'U't r: iiniiiii i
"Ii'iii : (Kilii::: •sil III : ;«! "IS WIWUWB itnHhlftttM'VMi IKM|HMII&:!?!rlir.''>piBril'eWl iUillW ' 11!!^^ 9111
(iy) Total indirect production cost (e.g. plant overhead, amortized plant and equipment)
^Sarged" to produces) containing the actjyemgraneirtbyye' affoTtfieTp^st'rive years. Exclude all
nonHcecurring costs that were directly related to the active ingredient, such as costs of initial
asiranon
!^llll^l-0j™^11^ seeinTwaiveV. Ecli
r sought and the estimated cost to you (J|sfed separately
:>>' • '(i ? ..... tibiB
of
a requirement and
^^&iaLTKparexr^i an3 a^ociaied test) of
conducting flbe testing needed to fulfill each of these data requirements.
ili;'ia".(;i.!sa=lQidoUss) of the active ingredient, direct production costs of produces) containing the active
i'lii;;;;! fw ^^^^^^^^^^^^^ jSjjrttagredient (following the parameters in item 2 above), indirect production costs of produces)
1 !!"!"' "l|ll""l!"l! ' ' ' it!lli:" 8 '""" "9 ' ^^ingreSiient ^Qii^^g'igQp^^gig^1 j^ jte"m 3 above), and costs of data
lining to the active ingredient
;- -=;, • ^=^j=^:=jr|^=. ;-= i^viii)i A description of the importance and unique benefits of the active ingredient to
."rI^^ss the use patterns and the efiectiveness of the active ingredient relative to registered
l 'and non-chemical control strategies. Focus ..... onTb^neBts uiiiqiiie to lie active
ingiSent, providing information that is as quantitative as possible, ff you do not have
""" ' ........................... ........ ' ...... q^B^ve^ala^ponliHbhlbn^alse"your 'estimates, then present 'the reasoning used to derive
your estimates. To assist the Agency in determining the degree of importance of the active
I r
=Es?i^=:ingtedient in terms of its benefits, you should provide information on any of the following factors,
^^=;K;KTj.asL^)plicable to your product(s): (a) documentation of the usefulness of the active ingredient in
:,;f H f|^B^jf^:fipa^^i:Ee^'BKn^al^ei^D^'(b) description of the beneficial impacts on the environment of use
!'",! ,1,1, ! ! * li,!!!,!!,!' 6f ^e^ac^nngl^en^ as ppposecTto its' registered alternatives, (c) information on the
..ii.' K?^'.'^ ^=Ej.gu——^^e QtfjyQ ingredient after use and on its persistence in the environment, and (d)
::::; ;; ^^fri'zBe^ip^abf its usefulness against a pest(s) °f public health significance.
I
I, j
Failure to submit sufficient information for the Agency to make a determination regarding
^win ^™^^ ,_^g^^—^—: a waiver.
ip:-b«n^ •illll!!!!^ ("I lililll IlitdlliB^^^^^^^^^^^
mm:wf, iiK^^^^^^^^^^^^^^^ 1! i in i1' mi ,i n: Kwsrowi H«;; ii; K,^ fiiiis 'JWWIHEW
||I| |;i"|l|| ililliriilllllllillllllllllllllllillllliiliiiaillllll II I 11 ^Illimiili ulillii'lllllllilil'"!'!"!!!!! IKiiny, n< » 'III1' IxilliJLu'' illlii llllliiLlllhillilllii'il InllimillllilllillUIHIBilll. ' 111,1
•J^'^'flilH^^
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estforWai
: of Data
i lii'l* i 'il't 1: Si Ifil'K^ :ni il!: "!£ I' ''TItiH I liliiniHl1 «!1M^^^ I
fO, !! i!W li«^
ifiviiiuK i' jiiniiiir 1,,,,'ii!1 mil'-1 'iiiiiiiB'iHiiiini1! "i, iiiii'iiiiH'ini1 ii'ili'i1 1': jiniiijii: it; iiiiiini'ii'iiiiiiin'ii 11111 inn illinium niiiiiliiiiiiiiiiiiiiiiiiiiniii IIIHIIIII
"i« arf
Option 9, underlem 9, on the Requirements Status and Registrant's Response Form.
~ ?^^^ ft?010- believe that a particular data requirement should not apply
; iiii i mm:, is mm because "the requirement is inappropriate.' You must submit a rationale explaining why you
sji;j£.»'i,»«»'.believe the data requirements should not apply. You also must submit the current label(s) ofyour
»l;;i "IIHI ]"" 1 ,»„ ill" lll'i; '!'< .UdlllWIII!:! 41' ill IHk'"
^^^^^^ illl! li:ii , i I' IIKII '• 1IIMIII!"1 illll
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-------
product(s) and, if a current copy of your Confidential Statement of Formula is not already on file
you must submit a current copy.
You will be informed of the Agency's decision in writing. If the Agency determines that
the data requirements of this Notice are not appropriate to your produces), you will not be
required to supply the data pursuant to section 3(c)(2)(B). If EPA determines that the data are
required for vour produces! you must choose a method of meeting the requirements of this
Notice within the time frame provided by this Notice. Within 30 days of your receipt of the
Agency's written decision, you must submit a revised Requirements Status and Registrant's
Response Form indicating the option chosen.
2.
Product Specific Data
If you request a waiver for product specific data because you believe it is inappropriate,
you must attach a complete justification for the request including technical reasons, data and
references to relevant EPA regulations, guidelines or policies. (Note: any supplemental data must
be submitted in the format required by PR Notice 86-5). This will be the only opportunity to
state the reasons or provide information in support of your request. If the Agency approves your
waiver request, you will not be required to supply the data pursuant to section 3(c)(2)(B) of
EEFRA. If the Agency denies your waiver request, you must choose an option for meeting the
data requirements of this Notice within 30 days of the receipt of the Agency's decision. You
must indicate and submit the option chosen on the product specific Requirements Status and
Registrant's Response Form (Insert B). Product specific data requirements for product
chemistry, acute toxicity and efficacy (where appropriate) are required for all products and the
Agency would grant a waiver only under extraordinary circumstances. You should also be
aware that submitting a waiver request will not automatically extend the due date for the study in
question. Waiver requests submitted without adequate supporting rationale will be denied and
the original due date will remain in force.
SECTION IV. CONSEQUENCES OF FAILURE TO COMPLY WITH THIS NOTICE
IV-A. NOTICE OF INTENT TO SUSPEND
The Agency may issue a Notice of Intent to Suspend products subject to this Notice due to
feilure by a registrant to comply with the requirements of this Data Call-in Notice, pursuant to FIFRA
section 3(c)(2)(B). Events which may be the basis for issuance of a Notice of Intent to Suspend
include, but are not limited to, the following:
1. Failure to respond as required by this Notice within 90 days of your receipt of this
Notice.
117
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IV-B. BASIS FOR DETERMINATION THAT SUBMITTED STUDY IS
UNACCEPTABLE
The Agency may determine that a study (even if submitted within the required time) is
unacceptable and constitutes a basis for issuance of a Notice of Intent to Suspend, The grounds for
suspension include, but are not limited to, failure to meet any of the following:
1) EPA requirements specified in the Data Call-In Notice or other documents incorporated
by reference (including, as applicable, EPA Pesticide Assessment Guidelines, Data Reporting
Guidelines, and GeneTox Health Effects Test Guidelines) regarding the design, conduct, and
reporting of required studies. Such requirements include, but are not limited to, those relating to
test material, test procedures, selection of species, number of animals, sex and distribution of
animals, dose and effect levels to be tested or attained, duration of test, and, as applicable,
Good Laboratory Practices.
2) EPA requirements regarding the submission of protocols, including the incorporation of
any changes required by the Agency following review.
3) EPA requirements regarding the reporting of data, including the manner of reporting, the
completeness of results, and the adequacy of any required supporting (or raw) data, including,
but not limited to, requirements referenced or included in this Notice or contained in PR 86-5.
All studies must be submitted in the form of a final neport; a preliminary report will not be
considered to fulfill the submission requirement.
IV-C. EXISTING STOCKS OF SUSPENDED OR CANCELLED PRODUCTS
EPA has statutory authority to permit continued sale, distribution and use of existing stocks of a
pesticide product which has been suspended or cancelled if doing so would be consistent with the
purposes of the Act.
The Agency has determined that such disposition by registrants of existing stocks for a
suspended registration when a section 3(c)(2)(B) data request is outstanding generally would not be
consistent with the Act's purposes. Accordingly, the Agency anticipates granting registrants permission
to sell, distribute, or use existing stocks of suspended produces) only in exceptional circumstances. If
you believe such disposition of existing stocks of your produces) which may be suspended for failure to
comply with this Notice should be permitted, you have the burden of clearly demonstrating to EPA that
granting such permission would be consistent with the Act You also must explain why an "existing
stocks" provision is necessary, including a statement of the quantity of existing stocks and your estimate
of the time required for their sale, distribution, and use. Unless you meet this burden, the Agency will
not consider any request pertaining to the continued sale, distribution, or use of your existing stocks
after suspension.
119
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in iiiiliK isi ;;ir •iiiiir';vbc:1 in m:a i* •;',;![ a;;/ s :ii»W,&iireiM"WtiraR«aii>i t.aeimi I
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: : :: :..= " ; r If JOU reqUCSt 3. VOl
i
product is in full compliance with all Agency requirements, you will have, under most circumstances,
-. — -— — ~- is due, to sel^ gjstrlbute,' or use existing
stocks. l4ormally, the Agency will allow persons other than the registrant such as independent
distributors, retailers and end users to sell, distribute or use such existing stocks until the stocks are
<£Eaustea Any sale, distribution or use of stocks of voluntarily cancelled products containing an active
ingredient for which the Agency has particular risk concerns will be determined on a case-by-case
IIP
i ,,
, ,11 ill ! n^^^^^^^^^^^^^^ i^^^ i IE if!!! i! I
jiiH^^^^^ am IIIK: iH^^^^ !UM^^ 11
Requests for voluntary cancellation received afiej the 90 day response period required by this
^J" ==-nSlotiee will not .result in the agency granting any additional time to sell, distribute, or use existing stocks
ijeyond a year from the date the 90'day response was due, unless you demonstrate to the Agency that
you are in full compliance with all Agency requirements, including the requirements of this Notice. For
Te, If you fo^fe 10 voluntarily cancel your registration six months before a 3-year study is
ie submitted, all progress reports and other information necessary to establish that you
have been conducting the study in an acceptable and good faith manner must have been submitted to
the Agency, before EPA will consider granting an existing stocks provision.
im^ iiin^^ i in i n i iii i nil iiiiiiiiiiiiii n i iii i n i in iii i 11
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TO REPORT POSSIBLE
UNREASONABLE ADVERSE EFFECTS
Registrants are reminded that FIFRA section 6(a)(2) states that if at any time after a pesticide is
j^jg^^™1™^!^^ regarding unreasonable adverse effects on the
gijjgjimggtjjy' the pesticide, the registrant shall submit the information to the Agency. Registrants must
IMpy the Agency of any factual information they have, from whatever source, including but not limited
-=^^^^ ^HSlanriit^'pleliminarv- results of studies, regaKj^ ^jj^or^ig adverse effects on man or the
•m
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in
continues as long as the products are registered by the Agency.
liiii IE y
1 ;
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' ...1W^^^^^ !! <:3 IliB !!n^^^^ ' till
If you have any questions regardjng the requirements and procedures established by this Notice,
liifl!SI (£e conta3perspn(sj listed in .
I
•IH^ liliiililH^^^^ lH!1:!!Ili^^^^^^^^^^^^^ a*
ses to this Notice must include completed Data Call-in Response Forms (Insert A)
raaad'ctt^Iete^'R^quJrernents State and Registrant's Response Forms (gJseJJ gj^ fOT fJotE (generic and"
" ""^^^^ sgecific data) and any pthe£ d^KJ^uments required by this iNotice, and should be ^submitted to the
s^££^^tpersoii(s) identified in Attachment 1. If the voluntary cancellation or generic data exemption
neecl
Call-in Resonse Forms
>| M120
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The Office of Compliance (OC) of the Office of Enforcement and Compliance Assurance
(OECA), EPA, will be monitoring the data being generated in response to this Notice.
si, Director
Special ReView and
Reregistration Division
Attachments
The Attachments to this Notice are:
1- Data Call-in Chemical Status Sheet
2- Generic Data Call-in and Product Specific Data Call-in Response Forms with
Instructions
3- Generic Data Call-in and Product Specific Data Call-in Requirements Status and
Registrant's Response Forms with Instructions
4- EPA Batching of End-Use Products for Meeting Acute Toxicology Data
for Reregistration
5 - List of Registrants Receiving This Notice
Jirements
121
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1. Chemical Status Sheets
123
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TFM AND NICLOSAMIDE DATA CALL-IN CHEMICAL STATUS SHEET
INTRODUCTION
Youhave been sent this Generic Data Call-in Notice because you have produces) containing TFM
orNiclosamide.
This Generic Data Call-in Chemical Status Sheet contains an overview of data required by this
notice, and point of contact for inquiries pertaining to the reregistration of TFM and Niclosamide. This
attachment is to be used in conjunction with (1) the Generic Data Call-in Notice, (2) the Generic Data
Call-In Response Form (Attachment 2), (3) the Requirements Status and Registrant's Form (Attachment
3), and (4) a list of registrants receiving this DCI (Attachment 5). Instructions and guidance accompany
each form.
DATA REQUIRED BY THIS NOTICE
The additional data requirements needed to complete the generic database for TFM and
Niclosamide are contained in the Requirements Status and Registrant's Response. Attachment 3. The
Agency has concluded that additional product chemistry data on TFM and Niclosamide are needed. These
data are needed to fully complete the reregistration of all eligible TFM and Niclosamide products. •
INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding the generic data requirements and procedures established by
this Notice, please contact Laura Parsons at (703) 305-5776.
All responses to this Notice for the generic data requirements should be submitted to:
Laura Parsons, Chemical Review Manager
Special Review Branch
Special Review and Registration Division (H7508C)
Office of Pesticide Programs
U.S. Environmental Protection Agency
Washington, D.C. 20460
RE: TFM and Niclosamide
125
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2. Combined Generic and Product Specific DCI Response Forms (Insert A)
Plus Instructions
127
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] ' I ilratoctitjjns1"-«« «-|etingThe""' 'Itata CauUIn IRe^omeTo'rinV''For xhe'Generic And Proiluct
,„„„ , iwJti liSgecific Data Call-In
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part of
. Ifyou
are an erfi-use product registrant only and Cave Been sent this DO letter as part of a RED document
ave been sent just the product specific "Data Call-in Response Forms." (Insert A) Only
i5JJiijJJ2£g?s5anLls! resjransible for generic 3ata have been sent ihe generic data response form. The type of
• or prodlutspecl&c} g"gj'j||—j-g gj j——--—g—^. _?Fg— .^-j xypebif
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Althqugh fie form is the same for both generic arid product specific dateC instructions for completing
™ :g= fljeje, fojrns are different Pleas^yeadjh^ carefully before filling out the forms.
:^; *;;;;;;"EpAhas developed these forms individually for each registrant, and has preprinted these forms with a
Items 1 tfcjrpugh 4 have been preprinted on the form. Items 5 through 7 must be completed by the
registrant as appropriate. Items 8 through 11 must be completed by the registrant before submitting a
I'l'llgpo-ggg-lo the Agency.
=j=^: ;:i=i5^=;=npfc'"r^lic"repbrting ^^^^ g^ ^^ collection of information is estimated to average 15 minutes per
--:: ' ; :''"!:': •••' -i ~"iigjpTBSs^S8;ni3ing tirne for reviewing instructions, searching existing data sources, \
1 • ;; :: i i fn^intetning the date needed, and cxmapletins and reviewing the collection of information.
* ,,,,,, \,,'_ i I,,,;; ,ii||! ;,, CJ, i ,i _ _ „ , ,
ing the burdeni estimate or any other aspect of this collection of information, including
Li "—~~ -™
Environmental Protection Agency, 401 M St., S.W., Washington, D.C. 20460; and to the Office of
h: •• | Management and Budget, Paperwork Reduction Project 2070-0107, Washingtb^ D.C. 20503.
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INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
(INSERT A)
Generic and Product Specific Data Call-In
Item 1. ON BOTH FORMS: This item identifies your company name, number and address.
Item 2. ON BOTH FORMS: This item identifies the case number, case name, EPA chemical
number and chemical name.
ItemS. ON BOTH FORMS: This item identifies the type of Data Call-in. The date of
issuance is date stamped.
Item 4. ON BOTH FORMS: This item identifies the EPA product registrations relevant to the
data call-in. Please note that you are also responsible for informing the Agency of your
response regarding any product that you believe may be covered by this Data Call-in
but that is not listed by the Agency in Item 4. You must bring any such apparent
omission to the Agency's attention within the period required for submission of this
response form.
ItemS. ON BOTH FORMS: Check this item for each product registration you wish to cancel
voluntarily. If a registration number is listed for a product for which you previously
requested voluntary cancellation, indicate in Item 5 the date of that request. Since this
Data Call-In requires both generic and product specific data, you must complete item 5
on both Data Call-In response forms. You do not need to complete any item on the
Requirements Status and Registrant's Response Forms (Insert B)
Item 6a. ON THE GENERIC DATA FORM: Check this Item if the Data Call-in is for
generic data as indicated in Item 3 and you are eligible for a Generic Data Exemption for
the chemical listed in Item 2 and used in the subject product By electing this exemption,
you agree to the terms and conditions of a Generic Data Exemption as explained in the
Data Call-in Notice.
If you are eligible for or claim a Generic Data Exemption, enter the EPA registration
Number of each registered source of that active ingredient that you use in your product.
Typically, if you purchase an EPA-registered product from one or more other producers
(who, with respect to the incorporated product, are in compliance with this and any
other outstanding Data Call-in Notice), and incorporate that product into all your
products, you may complete this item for all products listed on this form. If, however,
you produce the active ingredient yourself, or use any unregistered product (regardless
of the fact that some of your sources are registered), you may not claim a Generic Data
Exemption and you may not select this item.
129
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ItemS. ON BOTH FORMS: This certification statement must be signed by an authorized
representative of your company and the person signing must include his/her title.
Additional pages used in your response must be initialed and dated in the space
provided for the certification.
Item 9. ON BOTH FORMS: Enter the date of signature.
Item 10. ON BOTH FORMS: Enter the name of the person EPA should contact with
questions regarding your response.
Item 11. ON BOTH FORMS: Enter the phone number of your company contact
Note: You may provide additional information that does not fit on this form in a signed letter
that accompanies your response. For example, you may wish to report that your
product has already been transferred to another company or that you have already
voluntarily canceled this product For these cases, please supply all relevant details so
that EPA can ensure that its records are correct
131
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Instructions For Completing The "Requirements Status and Registrant's Response Forms"
(Insert B) For The Generic and Product Specific Data Call-In
INTRODUCTION
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and Rodenticide Act If you are an end-use product registrant only and have been sent this DCI letter
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Registrant? s Response Forms." Only registrants responsible for generic data have been sent the generic
data response forms. The type of Data Call-in (generic or product specific) is indicated in item
number 3 ("Date and Type of DCI") on each form.
form is the same for both product specific and generic data, instructions for
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Please read these instructions carefully before filling out the forms.
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I I^^:^^l~^:^^^iiIII^i EPA liai iggVg|op"SF tKese JSrns'indmdua]05'''ES: g^^gg^-g^ g^j ^as preprinted these forms
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1; ::::• : • :;; r :_• ;:: .'ingredient.
Items I inrough 8 nave b^eTT preprinted on the form. Item 9 must be completed by the registrant
l—-^:^1 '.-^T^TEI '!^=i|§rqpnate.' Items 10 through 13 must be completed by the registrant before submitting a response
I • to the Agency.'
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maintaining the data needed^ an3 completing'aiiiid reviewing flie collection of information. Send
:, • ."jjjg-j-jg™ g__ ^|2gggio^i^[y'QJjjgj. ggpg^ 5f this collection of information, inckiding
ions for reducing this burden, to Chief, Information Policy Branch, Mail Code 2137, U.S.
|&VTOrra^M.Prote^tion Agency, 401 M St., S.W., Washington, D.C. 20460; and to the Office of
Paperwork Reduction Project 2070-0107, Washington, D.C. 20503.
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INSTRUCTIONS FOR COMPLETING THE "REQUIREMENTS STATUS AND
REGISTRANT'S RESPONSE FORMS" (Insert B)
Generic and Product Specific Data Call-In
Item 1. ON BOTH FORMS: This item identifies your company name, number and address.
Item 2. ON THE GENERIC DATA FORM: This item identifies the case number, case
name, EPA chemical number and chemical name.
ON THE PRODUCT SPECIFIC DATA FORM: This item identifies the case
number, case name, and the EPA Registration Number of the product for which the
Agency is requesting product specific data.
Item 3. ON THE GENERIC DATA FORM: This item identifies the type of Data Call-in.
The date of issuance is date stamped.
ON THE PRODUCT SPECIFIC DATA FORM: This item identifies the type of
Data Call-in. The date of issuance is also date stamped. Note the unique identifier
number (ED#) assigned by the Agency. This ID number must be used in the transmittal
document for any data submissions in response to this Data Call-in Notice.
Item 4. ON BOTH FORMS: This item identifies the guideline reference number of studies
required. These guidelines, in addition to the requirements specified in the Data Call-In
Notice, govern the conduct of the required studies. Note that series 61 and 62 in
product chemistry are now listed under 40 CFR 158.155 through 158.180, Subpart c.
ItemS. ON BOTH FORMS: This item identifies the study title associated with the guideline
reference number and whether protocols and 1,2, or 3-year progress reports are
required to be submitted in connection with the study. As noted in Section HI of the
Data Call-in Notice, 90-day progress reports are required for all studies.
If an asterisk appears in Item 5, EPA has attached information relevant to this guideline
reference number to the Requirements Status and Registrant's Response Form (Insert
B).
139
-------
AH
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Item 6.
ON BOTH FORMS: This item identifies the code associated with the use pattern of
ticide. In the case of efficacy data (product specific
J^requiiernent), the required study only pertains to products which have the use sites
j-liHHMMK^IIid^orP68*8 indicated. A brief description of each code follows:
••i •i HI itH^^^^ tfiifa ran iiH Km
Teirestrjal.fpod
Terrestrial feed
:
sir c
!JD
JiS
Aquatic food
Aquatic non-food outdoor
Aquatic non-food industrial
Aquatic non-food residential
* Greenhouse foocl
Greenhouse non-foi
Fprestry
Residential
Indoor food
Indoor non-food
EEoQr medical
Indoor residential
- ; I '
Oi»| BOTH FORMS: This item identifies the cpde assigned to the substance that must
be used for testing. A brief description of each code follows:
,~!± I
"i,::::;::::
EUP End-Use Product
Manufacturing-Use Product
Manufacturing-Use Product and Technical Grade Active Ingredient
s^^t ;^S",;' '"'i^^^SSS^'iSSryS?^ i Pure Active Ingredient
^^PAI/M! Pure Active Ingredient and Metabolites
^^PAl/PAIRA! Pure Active Lndredient or Pute Active Ingredient Radiolabelled
~ ~ Pure Active Ingredient Radiolabelied
Pure Active Ingredient Radiolabelled and Metabolites
Pure Active Ingredient Radipkbelled and Plant Metabolites
Typical End-Use Product
Typical End-Use Product, Percent Active Ingredient Specified
Typical End-Use Product and Metabolites
Typical End-Use Product or Pure Active Ingredient and Metabolites
Technical Grade Active Ingredient
Technical Gjad£ Actiy^Jn^edient or Pure Active Ingredient
MP/TGAI
PAIRA/M
PAIRA/PM
TEP
TEP: %
111 Wffi '
.,,...,,i : .,,... : , :i::;4 TjEP/PAI/M
TGAI/PAIRA Technical Grade Active Ingredient or Pure Active Ingredient
!^ Radiolabelled
'GAI/TEP Technical Grade Active Ingredient or Typical End-Use Product
I|||r^ Metabolites
^JM£ _ Impurities
"'BiGR Degradates
See: guideline comment
140
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•'•
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-------
Item 8. This item completed by the Agency identifies the time frame allowed for submission of
the study or protocol identified in item 5.
ON THE GENERIC DATA FORM: The time frame runs from the date of your
receipt of the Data Call-In notice.
ON THE PRODUCT SPECIFIC DATA FORM: The due date for submission of
product specific studies begins from the date stamped on the letter transmitting the
Reregistration Eligibility Decision document, and not from the date of receipt. However,
your response to the Data Call-in itself is due 90 days from the date of receipt.
Item 9. ON BOTH FORMS: Enter the appropriate Response Code or Codes to show how
you intend to comply with each data requirement. Brief descriptions of each code
follow. The Data Call-in Notice contains a fuller description of each of these options.
Option 1. ON BOTH FORMS: (Developing Data) I will conduct a new study and
submit it within the time frames specified in item 8 above. By indicating that I
have chosen this option, I certify that I will comply with all the requirements
pertaining to the conditions for submittal of this study as outlined in the Data
Call-in Notice and that I will provide the protocols and progress reports
required in item 5 above.
Option 2. ON BOTH FORMS: (Agreement to Cost Share) I have entered into an
agreement with one or more registrants to develop data jointly. By indicating that
I have chosen this option, I certify that I will comply with all the requirements
pertaining to sharing in the cost of developing data as outlined in the Data Call-In
Notice.
However, for Product Specific Data, I understand that this option is available
for acute toxicity or certain efficacy data ONLY if the Agency indicates in an
attachment to this notice that my product is similar enough to another product to qualify
for this option. I certify that another party in the agreement is committing to submit or
provide the required data; if the required study is not submitted on time, my product
may be subject to suspension.
Options. ON BOTH FORMS: (Offer to Cost Shared I have made an offer to enter into
an agreement with one or more registrants to develop data jointly. I am also
submitting a completed "Certification of offer to Cost Share in the Development
of Data" form. I am submitting evidence that I have made an offer to another
registrant (who has an obligation to submit data) to share in the cost of that data.
I am including a copy of my offer and proof of the other registrant's receipt of
that offer. I am identifying the party which is committing to submit or provide the
required data; if the required study is not submitted on time, my product may be
subject to suspension. I understand that other terms under Option 3 in the Data
Call-in Notice apply as well.
141
-------
However, for Product Specific Data, I understand that this option is available
only for acute toxicity or certain efficacy data and only if the Agency indicates in an
SaMcbment to this Data Call-in Notice that my product is similar enough to another
"iiiiriiiiBiiJiMiiiiihiiiiiiiiiiii. i1" :niiiiiiiii!i!i'i
ON BOTH FORMS: YSubrnitting Existing Data) I will submit an existing
i11^^0i §tudy""ii>y the specified due date that has never before been submitted to EPA.
By indicating that I have chosen this option, I certify that this study meets all the
•*?»»]£quirements pertaining to the conditions for submittal of existing data outlined in
if" ™ • '= the Data Call-in Notice and I have attached tip ..needed supporting im^brmatipn
ilqng with this response.
I
Option 6.
date, or will cite data to upgrade a study that EPA has classified as parti aly
.^^^^^Q an3 poterfiaUy upgradeabie. By indicating that I have chosen this
option, 1 certify that I have met all the requirements pertaining to the conditions
for submitting or citing existing data to upgrade a study described in the Data
Call-in Notice. I am indicating on attached correspondence the Master Record
Identification Number (MRID) that EPA has assigned to the data that I am citing
as well as the MRID of the study I am attempting to upgrade.
11 ........ , .................. I
ON BOTH FORMS: (Citing a Study) I am citing an existing study that has
been previously classified by EPA as acceptable, core, core minimum, or a
's classafication of &e
til i i
understand that this option is available ONLY for acute toxicity or certain efficacy data
and ONLY if the cited study was conducted on my product, an identical product or a
product which the Agency has "grouped" with one or more other products for purposes
of depending on the same data. I may also choose this option if I am citing my own
dataj Ea .ejther .case, I will provide the MRID or Accession number (s). If I cite another
registrant's data, I will submit a completed "Certification With Respect To Data
Compensation Requirements" form.
aijili^ !:|!||
in^^^^^^^ 142
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-------
FOR THE GENERIC DATA FORM ONLY: The following three options (Numbers 7,
8, and 9) are responses that apply only to the "Requirements Status and Registrant's
Response Form" (Insert B) for generic data.
Option 7. (Deleting Uses) I am attaching an application for amendment to my registration
deleting the uses for which the data are required.
Option 8. (Low Volume/Minor Use Waiver Request) I have read the statements
concerning low volume-minor use data waivers in the Data Call-in Notice and I
request a low-volume minor use waiver of the data requirement. I am attaching a
detailed justification to support this waiver request including, among other things,
all information required to support the request. I understand that, unless modified
by the Agency in writing, the data requirement as stated in the Notice governs.
Option 9. (Request for Waiver of Data) I have read the statements concerning data
waivers other than lowvolume minor-use data waivers in the Data Call-in Notice
and I request a waiver of the data requirement I am attaching a rationale
explaining why I believe the data requirements do not apply. I am also submitting
a copy of my current labels. (You must also submit a copy of your Confidential
Statement of Formula if not already on file with EPA). I understand that, unless
modified by the Agency in writing, the data requirement as stated in the Notice
governs.
FOR PRODUCT SPECIFIC DATA: The following option (number 7) is a response that
applies to the "Requirements Status and Registrant's Response Form" (Insert B) for
product specific data.
Option 7. (Waiver Request) I request a waiver for this study because it is inappropriate
for my product. I am attaching a complete justification for this request, including
technical reasons, data and references to relevant EPA regulations, guidelines or
policies. [Note: any supplemental data must be submitted in the format required
by P.R, Notice 86-5]. I understand that this is my only opportunity to state the
reasons or provide information in support of my request. If the Agency approves
my waiver request, I will not be required to supply the data pursuant to Section
3(c) (2) (B) of FBFRA. If the Agency denies my waiver request, I must choose a
method of meeting the data requirements of this Notice by the due date stated
by this Notice. In this case, I must, within 30 days-of my receipt of the Agency's
written decision, submit a revised "Requirements Status" form specifying the
option chosen. I also understand that the deadline for submission of data as
specified by the original Data Call-in notice will not change.
143
-------
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Item 10.
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ON BOTH FORMS: This item must be signed by an authorized representative of your
company. The person signing must include his/her title, and must initial and date all other
of this form.
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«' "- !! Item 11. ON BOTH FORMS: Enterthedate of signature.
" | '" ' " '!,!; "" i "; '" I ' "
iii'lA^
: Enter the phone number of your company contact.
^^^•NQTE: You may provide additional information that does not fit on this form in a signed letter
;^al&at.accpjapanies mis your response. For example, you may wish to report that your
ct" Bas already Seen tia^ferred to another company or that you have already
^T^Ll^^I^! 'fuft^tJteAgency can ensure mat its records are correct.
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4.
EPA's Batching of TFM and Niclosamide Products for Meeting Acute
Toxicity Data Requirements for Reregistration
In an effort to reduce the time, resources and number of animals needed to fulfill the acute
toxicity data requirements for reregistration of products containing TFM or Niclosamide as the active
ingredient, the Agency has batched products which can be considered similar for purposes of acute
toxicity. Factors considered in the sorting process include each product's active and inert ingredients
(identity, percent composition and biological activity), type of formulation (e.g., emulsifiable
concentrate, aerosol, wettable powder, granular, etc.), and labeling (e.g., signal word, use classification,
precautionary labeling, etc.). Note that the Agency is not describing batched products as "substantially
similar" since some products within a batch may not be considered chemically similar or have identical
use patterns.
Using available information, batching has been accomplished by the process described in the
preceding paragraph. Notwithstanding the batching process, the Agency reserves the right to require, at
any time, acute toxicity data for an individual product should the need arise.
Registrants of products within a batch may choose to cooperatively generate, submit or cite a
single battery of six acute toxicological studies to represent all the products within that batch. It is the
registrants' option to participate in the process with all other registrants, only some of the other
registrants, or only their own products within a batch, or to generate all the required acute toxicological
studies for each of their own products. If a registrant chooses to generate the data for a batch, he/she
must use one of the products within the batch as the test material. If a registrant chooses to rely upon
previously submitted acute toxicity data, he/she may do so provided that the data base is complete and
valid by today's standards (see acceptance criteria attached), the formulation tested is considered by
EPA to be similar for acute toxicity, and the formulation has not been significantly altered since
submission and acceptance of the acute toxicity data. Regardless of whether new data is generated or
existing data is referenced, registrants must clearly identify the test material by EPA Registration
Number. If more than one confidential statement of formula (CSF) exists for a product, the registrant
must indicate the formulation actually tested by identifying the corresponding CSF.
In deciding how to meet the product specific data requirements, registrants must follow the
directions given in the Data Call-in Notice and its attachments appended to the RED. The DCI Notice
contains two response forms which are to be completed and submitted to the Agency within 90 days of
receipt. The first form, "Data Call-in Response," asks whether the registrant will meet the data
requirements for each product. The second form, "Requirements Status and Registrant's Response,"
lists the product specific data required for each product, including the standard six acute toxicity tests.
A registrant who wishes to participate in a batch must decide whether he/she will provide the data or
depend on someone else to do so. If a registrant supplies the data to support a batch of products,
he/she must select one of the following options: Developing Data (Option 1), Submitting an Existing
Study (Option 4), Upgrading an Existing Study (Option 5) or Citing an Existing Study (Option 6). If a
155
-------
in n11 linn iwiinilniiiiiilliiilin iniiinn in inn ninliilni
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registrant depends on another's data, he/she must choose among: Cost Sharing (Option 2), Offers to
Cost Share (Option 3) or Citing an Existing Study (Option 6). If a registrant does not want to
participate in a batch, the choices are Options 1, 4, 5 or 6. However, a registrant should know that
choosing not to participate in a batch does not preclude other registrants in the batch from citing his/her
studies and offering to cost share (Option 3) those studies.
Two products were found which contain TFM as the active ingredient These products have
been placed into two batches. Five products were found to contain Niclosamide as the active
ingredient and these products have been placed in three batches in accordance with the active and inert
ingredients and type of formulation.
I' , - • , ,,. . , • , , • :, i
NOTE: The technical acute toxicity values included in this document are for informational purposes
s current acceptance criteria.
i!K^^^^^^^^^
TING ACUTE TOXICITY
~- BAIffNG OF TEM PROmCTS FOR
[^^^ty d^ requirements for leregistration of products containing TFM as the active ingredient, the
^^lar^itpjsition and biological activity), type of formulation (e.g., emulsifiable concentrate, aerosol,
Wettable powder, granular, etc.), and labeling (e.g., signal word, use classification, precautionary
ii'tlllElIlLl
some products within a batch may not be considered chemically similar or have identical use patterns.
^^i^ilMng available information, batching has been accomplished by the process described in the
preceding paragraph. Notwithstanding the batching process, the Agency reserves the right to require,
at any time, acute toxicity data for an individual product should the need arise.
Registrants of products within a batch may choose to cooperatively generate, submit, or cite a
single• batteryof six acute toxicological studies to represent all the products within that batch. It is the
*S5S*-J i-> ogtion togarticigate in foegrocess with all olhCT registrants, only some of the other
, or to generatesal! the required acute toxicological
. If a restrant chooses to generate the data for a batch, heie
, ..,
daa he/he ma do sprovKted that the data tee is conlete and
ignfficanuy t gj^^
^sjtom^m and acceptance of the iac^iitoxicity_ data. |Regardless p£ whsjte new date is generated or
•• js referenced, registrants must cleariy identify lie test material by ElPA Registration
i iii »ii«: inri";, wiiyjit' «iii!b i m,"' FK, t 11:111
llrliil1! ill!!'!
l ,,,
^^^^ !i»^
-------
Number. If more than one Confidential Statement of Formula (CSF) exists for a product, the registrant
must indicate the formulation actually tested by identifying the corresponding CSF.
In deciding how to meet the product specific data requirements, registrants must follow the
directions given in the Data Call-in (DCI) Notice and its attachments appended to the RED. The DCI
Notice contains two response forms which are to be completed and submitted to the Agency within 90
days of receipt. The first form, "Data Call-in Response," asks whether the registrant will meet the data
requirements for each product. The second form, "Requirements Status and Registrant's Response,"
lists the product specific data required for each product, including the standard six acute toxiciry tests.
A registrant who wishes to participate in a batch must decide whether he/she will provide the data or
depend on someone else to do so. If a registrant supplies the data to support a batch of products,
he/she must select one of the following options: Developing Data (Option 1); Submitting an Existing
Study (Option 4); Upgrading an Existing Study (Option 5); or, Citing an Existing Study (Option 6). If a
registrant depends on another's data, he/she must choose among: Cost Sharing (Option 2); Offers to
Cost Share (Option 3); or, Citing an Existing Study (Option 6). If a registrant does not want to
participate in a batch, the choices are Options 1,4, 5, or 6. However, a registrant should know that
choosing not to participate in a batch does not preclude other registrants in the batch from citing his/her
studies and offering to cost share (Option 3) those studies.
Two products were found which contain TFM as the active ingredient. These products have
been placed into two batches, in accordance with the active and inert ingredients and type of
formulation. Based on the existing acute toxicity data available to the Agency, and based on the
differences between the formulation types of the two batches, the Agency is requiring that data for each
batch be submitted separately.
NOTE: The technical acute toxicity values included in this document are for informational purposes
only. The data supporting these values may or may not meet the current acceptance criteria.
Batch
1
Batch
2
EPA Reg. No.
6704-45
% Active Ingredient
38.8
EPA Reg. No.
6704-86
% Active Ingredient
23.0
Formulation Type
Formulation Type
solid block
157
-------
fortio, reduce jhejirne, resources and number of animals needed to fulfill the acute
_gg£ity3ate requirements for reregistration of products containing ^I^LQg^jyyjjjj-g ^ ^ active
I ,. , ' 9 • ' '
I ingredient, the Agency has batched products which can be considered similar for purposes of acute
; an3 inert it
^ percent composition and biological activity), type of formulation (e.
g jg||p][, wettable ip_owder,i granular; etc_.), and ilabeling ^e.g., signal word, use classification,
, efi
lenlca!
™^5?-,^^lg available information, batching has been accomplished by the process described in the
' Notwithstanding the hatching process., the Agency reserves thp right tn rgqiiire.,
I
CWffi^iii&gJstiants of products within a batch may choose to cooperatively generate, submit, or cite a
.'^ije Eattery_ of six aciiite ip^cological studies_ to rep^sent al the pjroducts within that bateE E is Sie
'' option to particq5ate in the process with all other regjslrants, only some of the other
" *
I
SPTsteante, or ony ther own procets withn a batc], or to generate a the required acute xicological
^^^f^, ..... ^jrea^ofjhejrown ipjcoducts. "" ff a regjsteant chooses to |geneiate ^ data for a batch, |he/she
~vH3EQst use one of the products within the batch as the test material. If a registrant chooses to rely upon
y sSmitteS acute toxicity 3ata", gg/sEe may do so provided' fhat the Sta" base is complete and
standards (see acceptance criteria attached), the formulation tested is considered by
SSilSJSSStyj aa<^ th-e fomndation has not been sigrificanty altered since
submission and acceptance of the acute toxicity data. Regardless of whether new data are generated
or existing data are referenced, registrants must clearly identify the test material by EPA Registration
Number. If more than one Confidential Statement of Formula (CSF) exists for a product, the registrant
must indicate the formulation actually tested by identifying the corresponding CSF.
In deciding how to meet the product specific data requirements, registrants must follow the
directions given in the Data Call-in (DCI) Notice and its attachments appended to the RED. The DCI
JH^^ jjj§ Notice contains two response forms which are to be completed and submitted to the Agency within 90
days of receipt The first form, 'Data Call-in Response," asks whether the registrant will meet the data
requirements for each product The second form, "Requirements Status and Registrant's Response,"
lists the product specific data required for each product, including the standard six acute toxicity tests.
A registrant who wishes to participate in a batch must decide whether he/she will provide the data or
depend on someone else to do so. If a registrant supplies the data to support a batch of products,
he/she must select one of the following options: Developing Data (Option 1); Submitting an Existing
Study (Option 4); Upgrading an Existing Study (Option 5); or, Citing an Existing Study (Option 6). If a
158
ill • 'ill:, I ill i|ii incfl 1 i id I )• ,|
'ill '! I
-------
registrant depends on another's data, he/she must choose among: Cost Sharing (Option 2); Offers to
Cost Share (Option 3); or, Citing an Existing Study (Option 6). If a registrant does not want to
participate in a batch, the choices are Options 1,4,5, or 6. However, a registrant should know that
choosing not to participate in a batch does not preclude other registrants in the batch from citing his/her
studies and offering to cost share (Option 3) those studies.
Five products were found which contain NICLOSAMIDE as the active ingredient. These
products have been placed into three batches, in accordance with the active and inert ingredients and
type of formulation.
NOTE: The technical acute toxicity values included in this document are for informational purposes
only. The data supporting these values may or may not meet the current acceptance criteria.
Batch
1
EPA Reg. No.
6704-88
% Active Ingredient on
most-recent label
96%
Formulation Type
technical; solid
Batch
2
EPA Reg. No.
6704-87
6704-89
% Active Ingredient
70%
70%
Formulation Type
wettable powder
wettable powder
Batch
3
EPA Reg. No.
6704-90
6704-91
% Active Ingredient on
most-recent label
5%
32%
Formulation Type
granular
granular
159
-------
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5. List of All Registrants Sent This Data Call-In Notice
161
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Appendix E. LIST OF AVAILABLE RELATED DOCUMENTS AND
ELECTRONICALLY AVAILABLE FORMS
Pesticide Registration Forms are available at the following EPA internet
site:
http://www.epa.gov/opprdQ01/forms/.
Pesticide Registration Forms (These forms are in PDF format and require the Acrobat reader)
Instructions
1. Print out and complete the forms. (Note: Form numbers that are bolded can be filled out
on your computer then printed.)
2. The completed form(s) should be submitted in hardcopy in accord with the existing
policy.
3. Mail the forms, along with any additional documents necessary to comply with EPA
regulations covering your request, to the address below for the Document Processing
Desk.
DO NOT fax or e-mail any form containing 'Confidential Business Information1 or
'Sensitive Information.'
If you have any problems accessing these forms, please contact Nicole Williams at
(703) 308-5551 or by e-mail at williams.nicole@epamail.epa.gov.
The following Agency Pesticide Registration Forms are currently available via the internet:
at the following locations:
8570-1
8570-4
8570-5
8570-17
8570-25
8570-27
Application for Pesticide
Registration/ Amendment
Confidential Statement of Formula
Notice of Supplemental Registration of
Distribution of a Registered Pesticide
Product
Application for an Experimental Use Permit
Application for/Notification of State
Registration of a Pesticide To Meet a Special
Local Need
Formulator's Exemption Statement
http://www.eDa.eov/opDrd001/forms/8570-l.pdf.
htto://www.eDa.eov/ooDrdOO 1 /forms/8570-4.pdf.
htto ://www.eoa.sov/ODDrdOO 1 /forms/8570-5 .pdf.
http://www.eDa.eov/onnrd001/forrns/8570-17 nrlf
httD://www.eoa.eov/oDDrd001/forms/8570-25.pdf.
httn://www.ena.20v/opprd001/forms/8570-27.Ddf.
163
-------
Certification of Compliance with Data Gap
Procedures
Pesticide Registration Maintenance Fee
Filing
Certification of Attempt to Enter into an
Agreement with other Registrants for
Development of Data
Certification with Respect to Citations of
Data (in PR Notice 98-5)
Data Matrix (in PR Notice 98-5)
Summary of the Physical/Chemical
Properties (inPRNotice98-l)
httD://www.epa.gov/opprd001/forms/8570-28.ndf.
http://www.eDa.gov/opprdOO 1 /forms/8570-30.pdf.
http://www.epa.gov/opprd001 /forms/8570-32.pdf.
http://www.epa.gov/opppmsdl/PR Notices/pr98-5.pdf.
http://www.epa.gov/opppmsd l/PR_Notices/pr98-5.pdf.
http://www.epa.gov/opppmsdl/PR Notices/pr98-l,pdf.
Self-Certification Statement for the
Physical/Chemical Properties (in PR Notice
98-1)
http://www.epa.gov/opppmsdl/PR Notices/pr98-l .pdf.
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-------
Pesticide Registration Kit www.epa.gov/pesticides/registrationkil/.
Dear Registrant:
For your convenience, we have assembled an online registration kit which contains the following
pertinent forms and information needed to register a pesticide product with the U.S. Environmental
Protection Agency's Office of Pesticide Programs (OPP):
1. The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food,
Drug and Cosmetic Act (FFDCA) as Amended by the Food Quality Protection Act
(FQPA) of 1996.
2. Pesticide Registration (PR) Notices
a.
b.
c.
d.
e.
f
g-
h.
83-3 Label Improvement Program-Storage and Disposal Statements
84-1 Clarification of Label Improvement Program
86-5 Standard Format for Data Submitted under FIFRA
87-1 Label Improvement Program for Pesticides Applied through Irrigation
Systems (Chemigation)
87-6 Inert Ingredients in Pesticide Products Policy Statement
90-1 Inert Ingredients in Pesticide Products; Revised Policy Statement
95-2 Notifications, Non-notifications, and Minor Formulation Amendments
98-1 Self Certification of Product Chemistry Data with Attachments (This
document is in PDF format and requires the Acrobat reader.)
Other PR Notices can be found at http://www.epa.gov/opppmsdl/PR Notices.
3. Pesticide Product Registration Application Forms (These forms'are in PDF format and will
require the Acrobat reader.)
a.
b.
c.
d.
e.
EPA Form No. 8570-1, Application for Pesticide Registration/Amendment
EPA Form No. 8570-4, Confidential Statement of Formula
EPA Form No. 8570-27, Forrnulatpr's Exemption Statement
EPA Form No. 8570-34, Certification with Respect to Citations of Data
EPA Form No. 8570-35, Data Matrix
General Pesticide Information (Some of these forms are in PDF format and will require the
Acrobat reader.)
a.
b.
c.
d.
e.
Registration Division Personnel Contact List
Biopesticides and Pollution Prevention Division (BPPD) Contacts
Antimicrobials Division Organizational Structure/Contact List
53 F.R 15952, Pesticide Registration Procedures; Pesticide Data Requirements
(PDF format)
40 CFR Part 156, Labeling Requirements for Pesticides and Devices (PDF format)
165
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of Reviews of Pesticide Data (November 27,1985)
IIS^^^^^^^^^^^^^^^^^ !•
I I £• 40 CFR Pa$ 158., Data Requirements for Registration (PDF format)
I I I l|ll I'g.. 50 FJR. 48833, Disclosure of R< " ----- -
IM\^ I'lJp w ^f?rc ^.bmitting your application for registration, you may wish to consult some additional sources
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of information. These include:
III ' III1
n iiiiiiiiiiiiiiiiiii vinnnii 111 win in' iiiiiiii1 iiiiiiiiiiiiiiiiiiiinnln ni innlinn iinninnnlnnnniniinnnninnini i in "'I'liitingiNii in' n it iiiUllliiiiii1 nnniniinnnnnnn i1 niiiiiiiiiiiiiiiini iiinilllnnnni I'lnnnnn iiiiiiiiiiiiiiii|ngnn inn i iiiiiiiini|ii 111111 n i in
1. The Office of Pestidde
iil'2. The booklet "General Information on Applying for Registration of Pesticides in the United
States", ^92^21811^ available through the National Technical Information Service
, - ............................................. .........
I ' ' !! !
• g^^^
• i i i i i
i [[[ i [[[ [[[ I [[[ I ........................................... I
Natipna] Technical Information Service (NTIS)
5285, Port Royal Road
Springfield, VA 22161
i ' ' i
,i ' , i ................................. a.!., ................. , .............. i .................................. , ......... : ............. : ........................................... : ....... [[[ ; [[[ ! ...... i .................... ........ I .............................................. i ............ i .......... || ............................ i ................................ i ........ i .................. ......... ................ ; [[[ i: ..................... ! ................
The telephone number for NTIS is (703) 605-6000. Please note that EPA is currently in
J^Pf ^l^ Process ..... ofjKEdating tt®? booklet to reflect the changes in the registration program
resulting "Sam tie passage of the FQPA and the reorganization of the Office of Pesticide
'll'i Programs. We anticipate that this publication will become available during the Fall of 1998.
ii '"' ....... 7& " ........ ..... ; ........ I ......... I ' - [[[ ; .................................................. : ............................... ;: ....... -- ............ — ...................
' "' •'•' • 11 • ' "
3. The National Pesticide Information Retrieval System (NPIRS) of Purdue University's
Center for Environmental and Regulatory Information Systems. This service does charge a
fee for subscriptions and custom searches. You can contact NPIRS by telephone at (765)
494-6614 or through their Web site.
i , v " ' '" ' I
4, The National Pesticide Telecommunications Network (NPTN) can provide information on
(| •" :active;; mgredients, uses, toxicology, and chemistry of pesticides. You can contact NPTN by
' "' ' * at^Sffi) 85g:737g 5M£o5iE1heEWeb site: 1
.The Agjncjr will return a notice of receipt of m application for registration or amended
"registration experimental^ use permit^ or amendment to a petition if fee applicant or
'geSSoner enclpses wife Ms submission a stamped^ self-addressed postcard. The postcard
Hi
-------
To assist us in ensuring that all data you have submitted for the chemical are properly coded
and assigned to your company, please include a list of all synonyms, common and trade
names, company experimental codes, and other names which identify the chemical
(including "blind" codes used when a sample was submitted for testing by commercial or
academic facilities). Please provide a CAS number if one has been assigned.
Documents Associated with this RED
The Mowing documents are part of the Administrative Record for this RED document and may
included in the EPA's Office of Pesticide Programs Public Docket. Copies of these documents are not
available electronically, but may be obtained by contacting the person listed on the respective Chemical
Status Sheet.
a.
b.
Health and Environmental Effects Science Chapters.
Detailed Label Usage Information System (LUIS) Report.
167
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