UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: February 27,2013 

SUBJECT: 3-Tritluoro-Methyi-4-Nitro-Phenol and Niclosamide. Revised Human Health 

Risk Assessment Scoping Document in Support of Registration Review. 

PC Code: 07740 I ,03620 I 

Decision No.: 475122 

DP Barcode: D409179 

Registration No.: 6704-45, 6704-86, 6704-91,6704-87 

Petition No.: NA Regulatory Action: Registration Review 

Risk Assessment Type: NA 

TXR No.: NA 

Case No.: 3082, 2455 

CAS No.: 88-30-2 

MRJDNo.: NA 40 CFR: NA 

FROM: 

THRU: 

TO: 

Seyed 

Linda Taylor, 

Tadayon

PhD, 

, Risk 

Toxi~~

Assessor ~C ~ • 

Health 

Peter Savoia

Effects 

, Chemist 

Division (7509P) 

__./ .k -1;_.{_ ~ 

Office of Pesticide Programu 

Michael Metzger, Chief, I /J J) Risk Assessment Branch V 0.[ u 

Health Effects Division (7509P) 

Office of Pesticide Programs 

Kelly Ballard, CRM 

Risk Management and Implementation Branch II 

Pesticide Re-evaluation Division (7508P) 

Office of Pesticide Programs 

Attached is the Health Effects Division's (HED) human health risk assessment scoping 

Document (status update) for 3-trifluoro-methyl-4-nitro-phenol (TFM) and 2'5-dichloro-4'-

nitrosalicylanilide (niclosamide) to support the registration review process. 

Page 1 of20 
Executive Summary 

The Health Effects Division (HED) has considered the available human health risk assessments 

for 3-trifluoro-methyl-4-nitro-phenol (TFM) and 2'5-dichloro-4'-

nitrosalicylanilide (niclosamide). HED performed this evaluation in order to determine the scope 

of work necessary to support the existing registrations during registration review. The primary 

sources of information for this evaluation were the 1998 risk assessments for TFM and 

niclosamide (D248544, D248546, D248563 and D248560). 

Niclosamide and TFM are used by the U.S. Fish and Wildlife Service (USFWS) to control the 

sea lamprey population in the Great Lakes region of the United States. The USFWS is the 

primary registrant of these lampricide ingredients. TFM and niclosamide have been addressed in 

a single document since both compounds are typically used together (during stream treatments 

niclosamide is used to augment the efficacy ofTFM applications). TFM is the primary control 

agent used. 

TFM and niclosamide are formulated as either liquid or solid formulations although applications 

are predominantly applied as a liquid. Liquids may be applied by metered pump or backpack 

sprayers. TFM and niclosamide application methods and rates depend on the characteristics of 

the stream to be treated, sea lamprey populations, and the populations of non-target species. 

Extensive guidance on applications is provided by the USFWS lampricide application manual 

(EPA MRID 44003502). This manual also describes the USFWS program that closely governs 

the use ofTFM and niclosamide. This feature is important as it contains stringent risk mitigation 

and monitoring components that are designed to minimize occupational exposures and exposures 

to the general population through direct contact or other use of treated waters. 

There are no established food tolerances for niclosamide and TFM. Both chemicals are classified 

as low-volume and non-food use chemicals. Neither chemical is applied to areas where there is 

commercial fishing and, since residues degrade rapidly, there is no expectation that people would 

be exposed through consuming drinking water or through secondary residues in noncommercially caught fish. Dietary risk assessments are not needed for the TFM and niclosamide 

lampricide use. 

There are no residential uses for niclosamide or TFM. In addition, the registered lampricide uses 

are not expected to result in any significant non-occupational exposures to the public. While the 

potential for postapplication exposure may exist for recreational activities (swimming, boating), 

that potential is minimal based on the use patterns and institutional risk mitigation measures 

associated with the use of niclosamide and TFM. Aggregate risk assessments are not needed. 

No additional data related to human health risk assessment have been submitted. to the Agency 

since the most recent risk assessments conducted in 1998 to support the Reregistration 

Eligibility Decision (RED) which was issued in November 1999. 

In 1998 HED considered the toxicology database for TFM/niclosamide to be limited/incomplete 

but sufficient to assess the human health risk for the expected exposures and durations of 

exposure. However, based on the current 40 CFR Part 158 Toxicology Data requirements, 

Page 2 of20 
Page 3 of 20

subchronic dermal toxicity, developmental toxicity, 2-generation reproductive toxicity, acute 

neurotoxicity, subchronic neurotoxicity, and immunotoxicity studies are required for non-food 

use chemicals. The HED Hazard and Science Policy Council (HASPOC) met on 11/7/12 and 

granted waivers to all the above requirements. This decision was based on the following 

considerations: an extensive level of risk mitigation for each application event, which is 

intended to protect those occupationally exposed and the public from exposure through drinking 

water sources and also from other uses of the treated waterways (e.g., swimming and boating) 

and a program that monitors the use of TFM and niclosamide by minimizing occupational 

exposures and other exposures to the general population through direct contact or other use of 

treated waters. 

The only toxicity endpoint selected for the 1998 risk assessments was for assessing short-term 

dermal exposure to handlers of TFM. Quantitative assessments are not required for niclosamide 

or for other routes/ durations for TFM. For the TFM occupational assessment, HED selected an 

oral study for short-term dermal risk assessment, since no dermal toxicity study was submitted. 

The point of departure (POD) was selected from the developmental toxicity study in rats, with 

the NOAEL of 125 mg/kg/day.

In 1998 a screening level occupational risk assessment was performed for TFM handler exposure 

scenarios using conservative assumptions (J. Dawson, D248560). The resulting MOEs were 

above 100 (the level of concern) except for the high-end treatments using the metered pump 

applications which resulted in MOEs of 73 and 75. Those MOEs were not considered of concern 

given the very conservative nature of the assessment, i.e., it was assumed that the entire maximum 

treatment amount (7000 lbs) was handled in one day by a single mixer/loader/applicator. 

As part of the registration review scoping process, HED has performed a revised screening level 

short-term dermal assessment for TFM handlers using updated unit exposures and body weights 

(see attachment 6). Assumptions regarding usage per day have been refined as well, and reflect 

more likely scenarios than those used in 1998.

The current screening assessment is based on the TFM liquid formulation which is expected to 

result in higher potential exposures than the solid bar applications and is the formulation used 

most often. Treatment rates reported in the 1997 USFWS data indicate that individual streams 

received anywhere from 33 lbs to 7000 lbs of TFM per the annual treatment. For mixing and 

applying via direct metering pump, very large treatments would typically be performed by 

multiple (3-5) workers over a multi- day (3-5 days) period. As such, it is not realistic to assume 

that one person would apply 7000 lbs in one day. For the purpose of this exercise, HED assumes 

that 7000 lbs is applied over a 3.5 day period (approximately 2000 lbs per day) by only two 

workers; thus each worker handles 1000 lbs TFM per day. Short-term dermal handler MOEs for 

this scenario are over 100 (the level of concern) and are not of concern. The handling assumption 

is conservative and represents the very high end of expected exposure using direct metering 

pump applications of TFM. 

The handler screen for backpack applications considers the maximum that an individual could 

potentially apply with a typical 2 gallon backpack sprayer in a day. It is assumed that a 

maximum of 12 lbs of TFM could be applied in a day, taking into consideration the time it takes 
Page 4 of 20

to reload the tanks and apply each load. Short-term dermal handler MOEs are greater than 100 

for this scenario and are not of concern. The handling assumption is conservative and represents 

the very high end of expected exposure using back pack sprayer applications of TFM. 

There are no outstanding exposure or toxicity data requirements for TFM and niclosamide except 

for the immunotoxicity study (guideline 870.7800). 

Introduction

TFM and niclosamide have been used to control larval sea lamprey (Petromyzon

marinus) in tributaries of the Great Lakes since the early 1960s. The U.S. Fish and Wildlife 

Service (USFWS) is the primary registrant and user of these materials.

The nomenclature and physiochemical properties of TFM and niclosamide can be found in 

Attachment 1.

The following registered formulations are used: For niclosamide there is a 70% wettable powder 

formulation (EPA Reg. No.6704-87) and 3.2% granular formulations (EPA Reg. No. 6704-91). 

The public health mollusicide use of niclosamide against snails that carry vectors for swimmer's 

itch has been voluntarily canceled by the registrant. There are two formulations of TFM, which 

include a 38% liquid concentrate (EPA Reg. No. 6704-45) and a solid bar (23 % TFM embedded 

in an inert chemical matrix (EPA Reg. No. 6704-86). 

Applications of liquid FTM and niclosamide, the most common form of application, may be 

made by direct metering pump and backpack sprayers. Solid formulations may be applied by hand.

TFM and niclosamide application methods and rates depend on the characteristics of the stream 

to be treated, sea lamprey populations, and the populations of non-target species. In order to 

obtain acceptable sea lamprey control and minimize effects on non-target species, a working 

concentration range is developed for each specific application according to guidance specified in 

the USFWS lampricide application manual (EPA MRID 44003502). This manual also describes

the USFWS program that closely governs the use of TFM and niclosamide. A key feature of this 

program is the risk mitigation component that is designed to minimize occupational exposures 

and exposures to the general population through direct contact or other use of treated waters.

Hazard Identification/Toxicology

In 1999, a reduced set of toxicology studies was required to support registration of non-food use 

chemicals. Although these required studies were available for both niclosamide and TFM, most 

of the studies were classified unacceptable for various reasons. HED considered the database to 

be limited/incomplete but sufficient to assess the human health risk for the expected exposures 

and durations of exposure. Neither chemical appears to be acutely toxic by the dermal route of 

exposure and niclosamide by the oral route of exposure.TFM is in Toxicity Category II 

following oral exposure. There is no acute inhalation study for either chemical. The effects 

observed following subchronic oral exposure of rats and dogs to TFM were decreased body 

weight. No effects were observed in the subchronic rat and dog studies on niclosamide. In the 
Page 5 of 20

TFM rat developmental toxicity study, maternal toxicity consisted of mortality and salivation, 

but developmental toxicity was not observed. No effects (maternal or fetal) were observed in the 

rabbit developmental toxicity study on niclosamide. In a chronic cancer study on niclosamide 

conducted by the National Cancer Institute (NCI) with mice and rats, there was no evidence of 

carcinogenicity in rats (both sexes) and female mice; inconclusive for male mice due to 

inadequate survival. Niclosamide was negative in a dominant lethal test (only mutagenicity test 

available). TFM was negative in the Ames assay and in the in vivo mouse micronucleus assay 

but induced chromosomal aberrations in the in vitro cytogenetic assay both with and without S9 

activation. 

Based on the current 40 CFR Part 158 Toxicology Data requirements, subchronic dermal toxicity 

(870.3250), developmental toxicity (870.3700b), 2-generation reproductive toxicity (870.3800), 

acute neurotoxicity (870.6200a), subchronic neurotoxicity (870.6200b), and immunotoxicity 

(870.7800) studies are required for non-food use chemicals. The Hazard and Science Policy 

Council (HASPOC) met on 11/08/2012 to discuss toxicology data requirements to support the 

registered uses of niclosamide/TFM. HASPOC (TXR No. 0056516) granted waivers to all the 

above requirements. This decision was based on the following considerations: an extensive 

level of risk mitigation for each application event, which is intended to protect those 

occupationally exposed and the public from exposure through drinking water sources and also 

from other uses of the treated waterways (e.g., swimming and boating) and a program that 

monitors the use of TFM and niclosamide by minimizing occupational exposures and other 

exposures to the general population through direct contact or other use of treated waters. 

Although the toxicology database is not complete, the available studies indicate that both TFM 

and niclosomide show evidence for low toxicity and a critical study was available to assess risks 

via dermal exposure. Consequently, there are no other outstanding toxicity data requirements for 

TFM or niclosamide.

Toxicity endpoints were not selected for the 1998 risk assessment for niclosamide and only 

short-term dermal endpoints (for occupational workers) were selected for TFM. Endpoints for 

dietary exposure were not required because the registered uses were determined to be non-food 

(and this has not changed). Residential exposure assessments were not required for niclosamide

or TFM and are not required under registration review. This decision was based on the low 

potential for exposure to persons entering treated sites following application because of restricted 

use designation and risk mitigation and monitoring requirements to protect the public from 

exposure. Quantitative occupational exposure assessments were not required for niclosamide 

because the Agency determined that there was low potential for exposure to occupational 

handlers based on no evidence of acute dermal toxicity, extremely low usage, and the risk 

mitigation measures such as the requirement to wear vapor respirators when handling 

niclosamide. An occupational risk assessment for TFM dermal exposure was conducted.

For the TFM occupational assessment, HED selected an oral study for short-term dermal risk 

assessment, since no dermal toxicity study was submitted. The endpoint and dose were selected 

from the developmental toxicity study in rats, with the NOAEL of 125 mg/kg/day based on 

clinical signs (salivation) and mortality in dams at the LOAEL of 250 mg/kg/day. The study was 

considered to be the most relevant for occupational dermal risk assessment and, although no 

male rats were evaluated, the endpoint has been applied to account for exposures to the general 
Page 6 of 20

population including males and females. In the absence of dermal absorption data, HED 

conservatively assumed 100% dermal absorption for TFM. 

Dietary Exposure

There is no reasonable expectation of human exposures to TFM/niclosamide residues in the diet 

via water, fish, irrigated crops, and livestock due to the low use volume applied, the infrequency 

of use, infinite dilution as treated stream water enters the Great Lakes, and rapid and complete 

dissipation of TFM/niclosamide residues from treated streams.

 

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 patterns 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

Conclusions: There is no expectation of dietary exposure to TFM and niclosamide, therefore, 

they are considered to be non-food chemicals and acute and chronic dietary risk assessments are 

not required

Residential (Non-Occupational) Exposure

There are currently no products containing TFM or niclosamide that are marketed for 

homeowner or residential uses. In addition, the registered lampricide uses are not expected to 

result in any significant non-occupational exposures to the public. While the potential for 

postapplication exposure may exist for swimmers, boaters, or other riparian water users, that 

potential is minimal based on the use patterns and institutional risk mitigation measures 

associated with the use of niclosamide and TFM. 

Conclusion: Because TFM and niclosamide are not registered for use in residential settings, there 

is currently no risk concern for residential exposure. If exposure data and methodologies for 

estimating exposure have changed for issues such as volatilization and spray drift, then a new 

exposure assessment may be required.

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. 

Since there are no residential uses or exposure from food or drinking water for either 

niclosamide or TFM, an aggregate risk assessment is not required. 

Conclusion: no aggregate risk assessment is required

Occupational Exposure

There are potential occupational handler exposures associated with the lampricide uses of 

niclosamide and TFM. Any handler exposures would be short-term in duration based on the use 
Page 7 of 20

pattern. There are no post-application occupational exposures expected for niclosamide and 

TFM.

The two potential niclosamide exposure scenarios are mixing/loading/application of niclosamide 

wettable powder slurry and loading/application of niclosamide granules using powered 

backpack blowers applications. Toxicological endpoints were not selected for niclosamide and a 

quantitative occupational assessment has not been performed. That decision was based on no evidence 

of acute dermal toxicity, extremely low usage (<350 lbs/yr), the infrequency of use, and the risk 

mitigation measures already implemented by USFWS, such as the requirement to wear vapor 

respirators when handling niclosamide. A quantitative occupational risk assessment is not 

needed for niclosamide under registration review.

Similarly, TFM can result in potential exposures when mixing/loading/application of liquid TFM for 

direct metering pump and for backpack sprayers. Toxicological points of departure (based on oral 

studies) were previously selected only for assessing short-term dermal occupational exposures for 

handlers. Intermediate- and long-term dermal exposures are not expected based on TFM lampricide use. 

Inhalation toxicity endpoints were not selected for TFM and there are no inhalation studies available. 

However, the HASPOC waived the requirements for inhalation studies based on the extensive level of 

risk mitigation and monitoring required for the lampricide use. In addition, previous screens 

indicated that inhalation exposure to TFM is not a significant contributor to the overall risks 

associated with the use of TFM (J. Dawson, D259427).

In 1998 a screening level occupational risk assessment was performed for TFM handler exposure 

scenarios using conservative assumptions (J. Dawson, D248560). Use information provided by 

USFWS for the years 1994 through 1997 were used, with data from 1997 selected as being 

representative of TFM use patterns. Treatment rates reported in the 1997 USFWS data indicate 

that individual streams received anywhere from 33 lbs to 7000 lbs of TFM per the annual 

treatment. The range of rates were assessed and resulting MOEs were above 100 (the level of 

concern) except for the high-end treatments using the metered pump applications which resulted 

in MOEs of 73 and 75. Those MOEs were not considered of concern given the very 

conservative nature of the assessment, i.e., it was assumed that the entire treatment amount was

handled in one day by a single mixer/loader/applicator. The USFWS informed the Agency that larger 

applications are made by a crew of 3-5 handlers over a period of 3-5 days. 

Since the 1998 TFM handler assessment was completed, HED has updated the unit exposures 

used to assess handlers and assumptions for average body weights have been changed to reflect 

the most recent Exposure Factors Handbook. As part of the registration review scoping process, 

HED has performed a revised screening level short-term dermal assessment for TFM handlers 

using updated unit exposures and body weights (see attachment 6). Assumptions regarding usage 

per day have been refined as well, and reflect more likely scenarios than those used in 1998.

The current screening assessment is based on the TFM liquid formulation which is expected to 

result in higher potential exposures than the solid bar applications and is the formulation used 

most often. The scenarios assessed, as identified in the USFWS manual, were 

mixing/loading/application of liquid TFM via direct metering pump and 
Page 8 of 20

mixing/loading/application of TFM using backpack sprayers. The screen assumed the use of the 

recommended FWS PPE of double layer of clothing, rubber boots and chemical resistant gloves.

Treatments using direct metering pump are used for treating larger bodies of water. This method 

accounts for the vast majority of TFM use. Treatment rates reported in the 1997 USFWS data 

indicate that individual streams received anywhere from 33 lbs to 7000 lbs of TFM per the 

annual treatment. Very large treatments would typically be performed by multiple (3-5) workers 

over a multi- day (3-5 days) period. As such, it is not realistic to assume that one person would 

apply 7000 lbs in one day. For the purpose of this exercise, HED assumes that 7000 lbs is 

applied over a 3.5 day period (approximately 2000 lbs per day) by only two workers; thus each 

worker handles 1000 lbs TFM per day. Short-term dermal handler MOEs for this scenario are 

over 100 (the level of concern) and are not of concern. The handling assumption is conservative

and represents the very high end of expected exposure using direct metering pump applications 

of TFM.

TFM treatments using a back pack sprayer are used less frequently than the metered pump 

applications and are typically used to treat small areas of stagnant water. This handler screen 

considers the maximum that an individual could potentially apply with a typical 2 gallon 

backpack sprayer in a day. It is assumed that 12 lbs of TFM could be applied in a day. This rate

is derived by assuming that in an 8 hour day, an applicator could fill and apply 16 tank loads (32 

gallons) based on 30 minutes per tank. Short-term dermal handler MOEs are greater than 100 for 

this scenario and are not of concern. The handling assumption is conservative and represents the 

very high end of expected exposure using back pack sprayer applications of TFM. 

Conclusion: the revised screening level short-term dermal assessment for TFM handlers using 

conservative assumptions show acceptable risk of concern. HED will evaluate the new usage 

data during registration review. If there are significant changes in the use pattern a new 

occupational risk assessment will be required. 

Tolerance Assessment and International Harmonization

Niclosamide and TFM are non-food use chemicals and there are no established tolerances.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice.pdf). The Office 

of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal 

use of a pesticide when conducting human health risk assessments, including, but not limited to, 

people who obtain drinking water from sources near agricultural areas, the variability of diets 

within the U.S., and people who may be exposed when harvesting crops. Should these highest 

exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure 

that the risk estimates are based on the best available information. 
Page 9 of 20

Because TFM and niclosamide are applied directly to water bodies, the potential for 

contamination of fish and shellfish was considered. However, because of the high dilution and 

rapid breakdown of these chemicals, contamination of fish and shellfish which might lead to 

residues in commercially-caught fish, or which might be consumed by recreational or 

subsistence fishers is unlikely. 

Endocrine Disruptor Screening Program 

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its reregistration decision, EPA reviewed these data and selected 

the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard 

database. However, as required by FFDCA section 408(p), TFM/Niclosamide is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

TFM/Niclosamide are not among the group of 58 pesticide active ingredients on the initial list to 

be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future 

EDSP orders/data call-ins, requiring the submission of EDSP screening assays for

TFM/Niclosamide. For further information on the status of the EDSP, the policies and 

procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening 

battery, please visit our website: http://www.epa.gov/endo/.

Human Studies
Page 10 of 20

TFM/Niclosamide human health risk assessments rely, in part, on data from studies in which 

adult human subjects were intentionally exposed to a pesticide or other chemical. These data, 

which include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), are subject 

to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with 

applicable ethics requirements.

Public Health and Pesticide Epidemiology Data

Updated reviews of TFM/Niclosamide incident reports were recently prepared by HED (S. 

Recore, D409182, 02/14/2013). For TFM this evaluation, the OPP Incident Data System (IDS) 

and NIOSH SENSOR-Pesticides indicated no incidents involving TFM. Low frequency and 

severity was reported for niclosamide in the IDS database. No cases reported for niclosamide to 

the NIOSH SENSOR-Pesticides database; and niclosamide not being included in the AHS.

The Agency will continue to monitor the incident information and if a concern is triggered, 

additional analysis will be included in the risk assessment.

Data Requirements

None.

References

Dawson, J., ORE Aspects of HED RED Chapter for Niclosamide & TFM, September 10, 1998. 

DP Barcodes D248563 & D248560.

William J. Hazel, Ph.D., Niclosamide, Human Health Risk Assessment for the Reregistration 

Eligibility

Decision September 30, 1998. DP Barcode D248544.

William J. Hazel, Ph.D., TFM, Human Health Risk Assessment for the Reregistration Eligibility

Decision September 30, 1998. DP Barcode D248546.

USEPA, 11/1999, Reregistration Elegibility Decision (RED) 3-Trifluoro-Methyl-4-Nitro-Phenol 

and Niclosamide.

Dawson, J., 9/15/99, Response to USFWS Comments on the document entitled ORE Aspects of 

HED RED Chapter for Niclosamide & TFM [Case 819174, Chem. Code 077401, DP Barcode 

D259427]

Van Alstine, J. 2/xx/13, Niclosamide/TFM: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting on November 8, 2012: Recommendations on the Waivers of 

Toxicity Data Required for Registration Review. TXR No. 0056516. 

Manual for Application of Lampricides in the US Fish and Wildlife Service Sea Lamprey 

(Petromyzon marinus) Control Program Including Standard Operating Procedures (EPA MRID 

440035-02);
Page 11 of 20

Attachments

Attachments1. Chemical Identity Tables

Attachment 2. Summary of toxicological doses and endpoints for use in the most recent human 

health risk assessment for Niclosamide and TFM

Attachment 3. Toxicity Profile for Niclosamide and TFM

Attachment 4. TFM/Niclosamide Products and Use Sites 

Attachment 5. Toxicology Data Requirements

Attachment 6. Scoping Occupational Assessment 
Page 12 of 20

Attachment 1

Table 1.1. Chemical Identity – TFM

Common Name TFM

Chemical Name (CAS) α, α , α trifluoro-4-nitro-m-cresol,

IUPAC name 3-trifluoromethyl-4-nitrophenol

PC Code 036201

Chemical Abstracts No. 88-30-2

Chemical Class Lampricide

Chemical structure

Table 1.2. Physicochemical Properties of TFM

Parameter Value Reference

Melting point/range NA (Liquid) NA

Boiling point/range 135-138 c MRID 42295401

pH 3.15 MRID 42295401

Density 1.463 g/ml MRID 42295401

Water solubility (25 °C) 0.498 g/100 g water MRID 42295401

Vapor pressure (25 °C) NA NA

Dissociation constant, pKa Not Available NA

Octanol/water partition coefficient, KOW at 25 °C NA (lampricide is a polar organic ai.) MRID 42295401

UV/visible absorption spectrum Not Available NA
Page 13 of 20

Table 1.3. Chemical Identity – Niclosamide

Common Name Niclosomide

Chemical Name (CAS) 2'5-dichloro-4'- nitrosalicylanilide

IUPAC name 5-chloro-N-(2-chloro-4-nitrophenyl)-2- hydroxybenzamide

PC Code 077401

Chemical Abstracts No. 1420-04-8

Chemical Class Lampricide

Chemical structure

Table 1.4. Physicochemical Properties of Niclosamide

Parameter Value Reference

Boiling point/range Not Available NA

pH Not Available NA

Density 1.59 g/cm3at 22 C MRID 42295401

Water solubility (25 °C) 1.05 x 10-5g/100 mL MRID 42295401

Vapor pressure (25 °C) 9.7 x 10-8Pa MRID 42295401

Dissociation constant, pKa Not Available NA

Octanol/water partition coefficient, KOW at 25 °C NA (lampricide is a polar organic ai.) MRID 42295401 

UV/visible absorption spectrum Not Available NA
Page 14 of 20

Attachment 2. Summary of toxicological doses and endpoints for use in the most recent 

human health risk assessment for Niclosamide and TFM

Table 2.1 Acute Toxicity of TFM Technical

Guideline No./Study Type MRID No. Results Toxicity Category

870.1100 Acute Oral Toxicity-Rat 40999204

41898102

LD 50 = 9.3 g/kg II

870.1200 Acute Dermal Toxicity -

Rabbit

40999205

41898103

LD50 > 20 g/kg III

870.1300 Acute Inhalation Toxicity -Rat no study

-

870.2400 Acute Eye Irritation- Rabbit 40999207

41898104

No eye irritation III

870.2500 Acute Dermal IrritationRabbit 40999206

41898105

No dermal irritation IV

870.2600 Skin sensitization - Guinea pig 41898106 Not a dermal sensitizer NA

Table 2.2 Acute Toxicity of Niclosamide

Guideline No./Study Type MRID No. Results Toxicity Category

870.1100 Acute Oral Toxicity-Rat 42552301* LD 50 > 1000 mg/kg 

Single dose (no deaths or clinical 

signs)

III

870.1200 Acute Dermal Toxicity -

Rabbit

42552301* LD50 > 2000 mg/kg no 

mortality or clinical signs

III

870.1300 Acute Inhalation Toxicity -

Rat -

870.2400 Acute Eye Irritation- Rabbit 42552305* Evidence of eye irritation (iritis, 

corneal opacity, chemosis, 

redness at 72 hours)

Category not 

assigned because 

eyes not examined 

after 72 hours

870.2500 Acute Dermal IrritationRabbit42552305 No dermal irritation IV

870.2600 Skin sensitization - Guinea 

pig

42552306 Moderate dermal sensitizer NA

Submitted studies unacceptable to fulfill guideline but provide useful information for risk assessment

Table 2.3. Summary of Doses and Endpoints Used in the Human Health Risk Assessment for TFM 

Exposure

Scenario

Dose Used in Risk 

Assessment, UF 

Special FQPA SF* and 

Level of Concern for Risk 

Assessment

Study and Toxicological Effects

Short-term 

dermal

NOAEL = 125 mkd

Default 100% DAF

UFA 10x

UFH 10x

Rat developmental toxicity

LOAEL = 250 mkd, based on mortality 

(2/25) and salivation
Page 15 of 20

Attachment 3. Toxicity Profile for Niclosamide and TFM

Table 3.1. Toxicity Profile of Niclosamide /TFM. 

Guideline No./ Study Type MRID No. (year)/ Classification 

/Doses

Results

NICLOSAMIDE

870.3100

Subchronic oral toxicity 

(Sprague-Dawley rat)

MRID 42552307 (1974 )

Unacceptable (numerous 

parameters not monitored)

0, 30, 125, 500 mkd; 

NOAEL=500 mkd

LOAEL no treatment-related findings

870.3150

Subchronic oral toxicity

(dog)

MRID 42552309 (1974)

Unacceptable (3/sex; numerous 

parameters not monitored); 

0, 1.6, 6.2, 25 mkd; 

NOAEL= 25 mkd

LOAEL not identified.

870.3100

Subchronic oral toxicity 

(Syrian hamster)

MRID 42552308 (1974)

0, 39, 177, 726 mkd

NOAEL = 177 mkd

LOAEL = 726 mkd, based on decreased body weight/gain (both 

sexes)

870.3200b

21-day Dermal Toxicity 

(rabbit)

45256101 (1990) guinea pigs

45256102 (1990) rabbits

Not evaluated by HIARC

870.3700a

Developmental Toxicity in 

rodents (rat)

870.3700b

Developmental Toxicity in 

non- rodents (rabbit)

MRID 42552310 (1975)

MRID 42552311 (1074) RF

Unacceptable/not upgradeable

0, 20, 60, 180 mkd 

GD 8-18

LOAELs not established. no maternal toxicity; no treatment-related 

findings in fetuses

870.3800

Reproduction and fertility 

effects (rats)

59380 (1975)

unacceptable

Not evaluated by HIARC

870.4100

Chronic toxicity (dogs)

42552309 (1974)

Unacceptable (3/sex; numerous 

parameters not monitored); 

0, 1.6, 6.2, 25 mkd; for 180 days

NOAEL= 25 mkd

LOAEL not identified.

870.4200

Chronic toxicity (rat)

42698001 (1982)

unacceptable

Not evaluated by HIARC

870.4300

Chronic toxicity/ 

carcinogenicity in rodents 

(Osborne-Mendel rat)

NCI (1978) NIH 78-1341

0, 14216 ppm or 28433 ppm (0, 

711, 1421 mkd) for 78 weeks;

no evidence of carcinogenicity in either sex

870.4200

Carcinogenicity study 

(B6C3F1 mice)

NCI (1978) NIH 78-1341

0, 274 ppm or 549 ppm (0, 39, 

78 mkd)

Unacceptable 

inadequate survival of males; no evidence of carcinogenicity in 

females

870.5100

Mutagenicity: gene 

mutation (bacterial)

870.5300

In vitro mammalian cell 

gene mutation test

L5178Y mouse lymphoma 

cells

MRID 43677901 (1995)

Acceptable/guideline

-S9 (30-80 μg/mL cytotoxic); 

2.5-25 μg/mL 

No increase in mutant frequency at cytotoxic doses
Page 16 of 20

Table 3.1. Toxicity Profile of Niclosamide /TFM. 

Guideline No./ Study Type MRID No. (year)/ Classification 

/Doses

Results

+S9 (1.25-40 μg/mL)

870.5375

Mutagenicity: in vitro

chromosomal aberration

1996 Mutation Res 370 (1): 1-9 In vivo sister chromatid exchange (SCE) and chromosome 

aberration studies positive in both assays.

870.5385 in vivo

cytogenetic mutagenicity 

assay

(mammalian bone marrow 

chromosomal aberration test

Crl:CD)ICR)BR mice)

MRID 43677902 (1995)

Acceptable

1250, 2500, or 5000 mg/kg

No evidence of chromosome aberration in bone marrow cells

In Vivo Mammalian cell 

Assay

MRID 42552312 (1975)

Unacceptable; 500 mkd; 

dominant lethal; no effects seen but no + control data

870.5550

Mutagenicity: Unscheduled 

DNA synthesis

TFM

870.3100

Subchronic oral toxicity 

(rat)

MRID 00112726 /7(1971)

0, 500, 900, 1620, 2916, 5248 

ppm

MRID 00112727 (1971)

0, 500, 900, 1620, 2916, 5248 

ppm

Study 1:NOAEL 525 mkd (5248 ppm)

Study 2: NOAEL 162 mkd; LOAEL 292 mkd, based on↓BW

870.3150

Subchronic oral toxicity

(dog)

MRID 00112725 (1973) NOAEL 31 mkd; 

LOAEL 125 mkd, based on ↓BW/BWG

870.3700a

Developmental Toxicity 

(COBS CD(SD) BR rat)

00131201 (1983)

0, 25, 125, or 250 mkd

GD 6-15

Maternal NOAEL 125 mkd (2/25 salivation)

Maternal LOAEL 250 mkd, based on mortality (1 on GD 6, 1 on GD 

12) and salivation (22/25)

Developmental NOAEL 250 mkd (HDT)

870.3700b

Developmental Toxicity 

(rabbit)

00138481 (1975)

00150476 (1975)

Unacceptable

not considered by HIARC

870.3800

Reproduction and fertility 

effects (rats)

870.4100

Chronic toxicity (dogs)

870.4200

Chronic toxicity (rat)

870.4300

Chronic toxicity/ 

carcinogenicity (rat)

MRID 00112718 (1975) Not evaluated by HIARC

870.4200

Carcinogenicity (mice)

870.5100

Mutagenicity: gene 

mutation (bacterial)

MRID 42551801 (1977) Negative
Page 17 of 20

Table 3.1. Toxicity Profile of Niclosamide /TFM. 

Guideline No./ Study Type MRID No. (year)/ Classification 

/Doses

Results

870.5375

Mutagenicity: in vitro

chromosomal aberration

MRID 40999201 (1988)

Chinese hamster ovary cell 

assay

Induced Chromosomal aberrations in Chinese hamster ovary cells; 

with and without metabolic activation

870.5395 in vivo 

Mammalian erythrocyte 

micronucleus test

MRID 42187101 (1989) Negative 

870.5550

Mutagenicity: Unscheduled 

DNA synthesis

MRID 40999202 (1988) Negative in rat primary hepatocytes

Attachment 4. Niclosamide/TFM Products and Use Sites.

Table 4.1 Use Patterns for End-use Product Formulations of Niclosamide/TFM

EPA Reg. No. & (Formul. 

types) % AI Use sites & (Applicable ORE Review) Application equipment 

Niclosamide (D248563&D248560)

6704-87 70(WP) Lampricide in Great Lakes, Finger 

Lakes, and Lake Champlain Direct Metering Pump, Back pack Sprayer 6704-91 3.2(G)

TFM(D248563&D248560)

6704-45 36-38 (EC) Lampricide in Great Lakes, Finger 

Lakes, and Lake Champlain

Direct Metering Pump, Back pack Sprayer

6704-86 23 (solid bar) Hand

Abbreviations used: AI = active ingredient, EC = emulsifiable concentrate, NA = not applicable, G = granule, WP 

=Wettable Powder,
Page 18 of 20

Attachment 5. Toxicology Data Requirements 

Table 5.2 Summary of Toxicological Data Requirements for Niclosamide 

Test

Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

Yes

Yes

Yes

Yes

Yes

Yes

No

No

No

No

Yes

Yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation*

CR

CR

NR

Yes

CR

WA

W

W

W

W

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

Yes

Yes

Yes

W

W

W

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

CR

CR

CR

CR

CR

W

W

W

W

W

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5385 Mutagenicity—Mammalian Bone Marrow 

 Chromosome Aberration Aberrations

870.5550 Mutagenicity—Unscheduled DNA Synthesis

Yes

Yes

Yes

Yes

yes

W

W

W

W

W

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Developmental Neurotoxicity

Yes

Yes

CR

W

W

W

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

CR

CR

Yes

W

W

W

AWaived by HED HASPOC (TXR # 0056516)
Page 19 of 20

Table 5.2 Summary of Toxicological Data Requirements for TFM 

Test

Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation*

CR

CR

NR

Yes

CR

WA

W

W

W

W

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

Yes

Yes

Yes

Yes

W

W

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

CR

CR

CR

CR

CR

W

W

W

W

W

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5385 Mutagenicity—Mammalian Bone Marrow 

 Chromosome Aberration Aberrations

870.5550 Mutagenicity—Unscheduled DNA Synthesis

Yes

Yes

Yes

Yes

yes

Yes

Yes

Yes

W

W

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Developmental Neurotoxicity

Yes

Yes

CR

W

W

W

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

CR

CR

Yes

W

W

W

AWaived by HED HASPOC (TXR # 0056516)
Page 20 of 20

Attachment 6. Screening Occupational Assessment 

Table 6.1Occupational Handler Dermal Exposures and Risks For TFM

Dermal 

Exposures

(ug/lb ai)1

Usages estimate

Lbs2 Dermal Doses 

(mg/kg/day)3 Short-term MOE

Mix/Load for metering pump

29.1

(Double layer &glove)

1000 0.37 340

Mix/Load/Apply with a back pack sprayer

4120

(Double layer &glove)

12 1.24 200

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); includes data from PHED /AHETF. 

2 Usage estimates (lbs) used for scoping assessment.

3 Dose (mg/kg/day) = Unit exposure (mg/lb ai) x Usage Estimate) x % Absorption (100% dermal) / Body weight. The body 

weight is 80 kg for dermal dose. 

4

Short-term MOE = short-term dermal NOAEL (125 mg/kg/day) / Dermal Doses (mg/kg/day)