UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON D.C.,_ 20460 

MEMORANDUM 

DP 403903 

August 2, 2012 

Subject: 

To: 

Through: 

From: 

Registration Review- Revised Problem Formulation for the Ecological Risk and 

Drinking Water Exposure Assessments for Acetaminophen (PC Code 109509; DP 

Barcode D396364) 

Patricia Parrott, Branch Chief 

Bonnie Adler, Chemical Review Manager 

Risk Management and Implementation Branch V (}._ ~ 

Pesticide Reevaluation Division (7508P) ~X], B / L I 't<l\ ..,___ 

~=sr:.:~~=~~~~f,,J~ '-

Environmental Risk Branch 3 

E:o.vironmental Fate and Effects Division 

Office of Pesticide Programs ~ 

Nicholas 

Environmental 

James K. 

Mastrota, 

Wolf, 

Risk 

Ph.D., 

Ph.D., 

Branch 

Environmental 

Wildlife 

3 

Biologis

Scientist 

~ 

--- · 

Environmental Fate and Effects Division (7507P) · 

t!;)_/ I).__ 

-~ ~ 'b w!Ai2--

The Environmental Fate and Effects Division (EFED) has updated the problem formulation 

(attached) for the ecological risk, environmental fate, endangered species, and drinking water 

assessments to be conducted as part of the Registration Review of acetaminophen, a pesticide to 

control the brown treesnake (Boiga irregularis) in U.S. Territory of Guam (Guam) and the 

Commonwealth of the Northern Mariana Islands (CNMI). The problem formulation draws 

information from both open literature and from studies submitted by the technical registrants in 

response to data requirements. This revised Problem Formulation incl_udes additional 

information about potential exposure to the endangered Mariana crow that inhabits the Mariana 

Islands. This document is intended to provide an overview of what is currently known regarding 

the environmental. fate and ecological effects associated with acetaminophen and its 

transformation products and outlines uncertainties regarding attributes of the parent compound 

and its transformation products. It describes the preliminary ecological risk hypothesis and the 

processes that will be used during the completion of ecological risk assessment in support of 

registration review. 

1 
2

The registered use of acetaminophen is unique because it involves distribution of bait consisting 

of acetaminophen tablets inserted into the carcasses of mouse pups. As the majority of the 

acetaminophen bait is expected to remain contained within the mouse pups and to be consumed 

by brown treesnakes and other wildlife, exposure to aquatic habitat is believed to be minimal. 

Considering the low toxicity of acetaminophen to aquatic invertebrates, the risk posed by this use 

to aquatic organisms is considered discountable. Likewise, exposure to terrestrial plants is 

believed to be minimal, and risk to terrestrial plants is considered discountable. The ecological 

risk assessment will focus on native terrestrial wildlife species of Guam and the CNMI, in 

particular native species that may feed on the baited mouse pups or scavenge on dead snakes. As 

all of the mammalian predators on these islands are exotic invasive species that are considered 

pests, the assessment will focus on native birds and terrestrial crabs. The Agency plans to 

conduct quantitative risk assessments to evaluate the potential risk of adverse effects to native 

birds, including threatened and endangered species, from both primary exposure (direct 

consumption of the bait) and secondary exposure (consumption of contaminated snakes). 

Adverse effects to terrestrial crabs will be assessed qualitatively.
3

 

Problem Formulation for the Ecological Risk 

in Support of the Registration Review of 

Acetaminophen (CAS No. 103-90-2)

Prepared by:

Nicholas Mastrota, Ph.D., Biologist

James K. Wolf, Ph.D., Environmental Scientist U. S. Environmental Protection Agency

Office of Pesticide Programs

Environmental Fate and Effects Division

Environmental Risk Branch 3

1200 Pennsylvania Ave., NW

Mail Code 7507P

Washington, DC 20460

Reviewed by:

Rosanna Louie-Juzwiak, RAPL

Dana S. Spatz, Branch Chief

Date:

August 1, 2012

Office of Chemical Safety 

and Pollution Prevention
4

Table of Contents

I. Purpose of Problem Formulation.......................................................................................... 5

II. Nature of Regulatory Action................................................................................................... 5

A. Acetaminophen Regulatory History .................................................................................. 5

III. Stressor Source and Distribution ........................................................................................ 6

1. Nature of the Chemical Stressor ......................................................................................... 6

2. Overview of Pesticide Usage ........................................................................................ 10

IV. Receptors........................................................................................................................... 11

1. Aquatic and Terrestrial Effects..................................................................................... 11

2. Ecosystems Potentially at Risk ..................................................................................... 14

3. Incident Databases Review............................................................................................... 15

V. Assessment Endpoints .......................................................................................................... 15

VI. Conceptual Model............................................................................................................ 16

1. Risk Hypothesis............................................................................................................ 16

2. Conceptual Diagram ..................................................................................................... 16

VII. Analysis Plan Options.................................................................................................... 18

1. Analysis of Risk to Terrestrial Organisms........................................................................ 18

2. Analysis of Risk to Aquatic Organisms............................................................................ 20

3. Analysis of Risk to Terrestrial Plants............................................................................... 22

4. Potential Future Use of Acetaminophen in Other Locations............................................ 22

VIII. Endangered Species Assessment ...................................................................................... 22

IX. Drinking Water Assessment ............................................................................................. 24

X. Clean Water Act.................................................................................................................... 24

XI. Endocrine Disruptor Screening Program...................................................................... 25

XII. Anticipated Data Needs .................................................................................................... 25

XIII. Open Literature ................................................................................................................. 27

XIV. Bibliography ........................................................................................................................ 27
5

I. Purpose of Problem Formulation

The purpose of this problem formulation is to provide the foundation for the ecological risk 

assessment being conducted for acetaminophen for brown treesnake (Boiga irregularis) control. 

As such, it articulates the purpose and objectives of the risk assessment, evaluates the nature of 

the problem, and provides a plan for analyzing the data and characterizing the risk (USEPA, 

1998). The action area for this assessment is the U.S. Territory of Guam (Guam) and the 

Commonwealth of the Northern Mariana Islands (CNMI), which are the only locations in the 

United States where this snake is currently established. 

II. Nature of Regulatory Action

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), all pesticides sold or 

distributed in the United States generally must be registered by the Environmental Protection 

Agency (EPA or the Agency). In determining whether a pesticide can be registered in the U.S., 

EPA evaluates its safety to non-target species based on a wide range of environmental and health 

effects studies. In 1996, FIFRA was amended by the Food Quality Protection Act (FQPA), and 

EPA was mandated to implement a new program for the periodic review of pesticides, i.e., 

registration review (http://www.epa.gov/oppsrrd1/registration_review/). The registration review 

program is intended to ensure that, as the ability to assess risk evolves and as policies and 

practices change, all registered pesticides continue to meet the statutory standard of no 

unreasonable adverse effects to human health and the environment. Changes in science, public 

policy, and pesticide use practices will occur over time. Through the registration review 

program, the Agency periodically reevaluates pesticides to make sure that as change occurs, 

products in the marketplace can be used safely.

As part of the implementation of the new Registration Review program pursuant to Section 3(g) 

of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the Agency is beginning its 

evaluation of acetaminophen to determine whether it continues to meet the FIFRA standard for 

registration. This problem formulation for the environmental fate, ecological risk, and 

endangered species assessment chapter in support of the registration review will be posted in the 

initial docket opening the public phase of the review process. 

A. Acetaminophen Regulatory History

Acetaminophen, N-(4-Hydroxyphenyl) acetamide, is derived from the interaction of paminophenol and an aqueous solution of acetic anhydride. Acetaminophen is an odorless, 

slightly bitter tasting white crystalline powder. Acetaminophen, also known as paracetamol, is

commonly used as a nonprescription analgesic and antipyretic drug similar to aspirin. It is the 

active ingredient (a.i.) of over-the-counter pain-relief medications (e.g., Tylenol®).

The only registered pesticidal use of acetaminophen is for brown treesnake control on Guam and 

the CNMI (EPA Reg. No. 56228-34). In 1999, the USDA/APHIS was granted a FIFRA Section 

18 emergency exemption for the use of a product containing the active ingredient, 
6

acetaminophen, for the control of the brown treesnake on Guam and the CNMI. APHIS 

reapplied for a new exemption for the same use in July 2002 (MRID 45716700). Acetaminophen 

was conditionally registered on March 21, 2003. 

Series 835 environmental fate guideline studies were not submitted by the registrant 

(USDA/APHIS); however, they did submit limited environmental fate and chemistry data 

available in the public literature (MRID 457167-08) to support the pesticidal use. APHIS 

requested data waivers for hydrolysis (161-1/835.2120), photodegradation in water (161-

2/835.2240), aerobic soil metabolism (162-1/835.4100), leaching/adsorption/desorption (163-

1/835.1230), and terrestrial field dissipation (164-1/835.6100) studies (May 31, 2002). 

Additional environmental fate data were not requested at the time of registration because of the 

limited use area and the fact that the pharmaceutical use of acetaminophen far exceeds the 

pesticidal use to control brown treesnakes. EFED identified additional fate data in public 

literature, which were also considered (Table III.1). A number of the monitoring studies which 

have identified the presence of a number of pharmaceuticals, including acetaminophen, in 

surface water, ground water, and sewage treatment plants (STPs) are discussed later in this 

document (Table III.2).

In 2001, the registrant submitted data to the Agency on the ecological effects of acetaminophen. 

Acute toxicity studies were submitted to fulfill guideline requirements for testing avian acute 

oral avian toxicity (850.2100) and avian dietary toxicity (850.2200). The Agency has reviewed 

these studies and determined them to be acceptable. The registrant has also supplied copies of 

papers from the open literature that provide information on the acute toxicity of acetaminophen 

to aquatic invertebrates (MRID 457167-11). In 2001, the registrant submitted a waiver request 

for acute toxicity testing for freshwater fish (850.1075).

An ecological risk assessment was conducted in OPP when this use was initially considered for 

registration in 2002 (DP Barcode D286627). The regulatory decision at that time was that the use 

of acetaminophen to control brown treesnakes would not cause unreasonable adverse effects to 

non-target terrestrial and aquatic organisms, and the risk posed to threatened and endangered 

species by the brown treesnake would likely be greater than the risk posed by use of this 

pesticide to control them. 

III. Stressor Source and Distribution

1. Nature of the Chemical Stressor

Physical/chemical properties and environmental fate data available for acetaminophen are 

summarized in Table III.1 and briefly discussed in the following section. 
7

Table III.1. Nature of the Chemical Stressor

Property Value Source of Information

Common name Acetaminophen

(Paracetamol)

Chemical name N-(4-hydroxyphenyl)-acetamide

N-(4-hydroxyphenyl)acetamide

N-acetyl-p-aminophenol

MRID 457167-08

Pesticide type Acetaminophen is part of the class of 

pharmaceutical drugs known as "aniline

analgesics". Acetaminophen is not currently 

registered as a pesticide for uses in food 

commodities, but is registered as a pesticide 

used to control brown treesnake in Guam or 

the Northern Mariana Islands.

Chemical class p-aminophenol, acetic anhydride MRID 457167-08

CAS number 103-90-2 MRID 457167-08

Empirical formula C8H9NO2 MRID 457167-08

Molecular mass (g/mol) 151.16 MRID 457167-08; El-Obeid and

Al-Badr, 1985.

Vapor pressure 0.0005 mmHg to 1.65E-07 mmHg for the 

temperature range 74°C to 40°C

Williams et al. 2011.

Solubility in water 12,780 mg/L @ 20 °C

14,285 mg/L

Granberg and Rasmuson, 1999

MRID 457167-08

Dissociation Constant (pKa) 9.5 @ 25oC

9.38

MRID 457167-08

Löffler et al., 2005; Hari et al., 

2005; Lorphensri et al., 2006

Log Kow 0.27

0.46

Yamamato et al., 2005

Hari et al., 2005

Koc (organic carbon normalized partition 

coefficient)

2.7(±0.0) x102 L/kgoc (soil; %OC=2.7)

3.3 (±0.9) x103 L/kgoc (river sediment; 

%OC=0.79%)

Yamamato et al., 2005

Kd 7.7 (±0.9) L/kg (soil)

2.6 (±0.7) L/kg (river sediment)

0 (Not significant in soils with variable 

charge (i.e., soils with a pH dependent 

charge)

Yamamato et al., 2005

Lorphensri et al., 2006 

Environmental Fate/Exposure Summary:

Acetaminophen is a white, highly water soluble, odorless crystalline powder. A saturated 

aqueous solution has a pH of about 6 and is stable but stability decreases in acid or alkaline 

conditions, slowly degrading to acetic acid and p-aminophenol (Paracetamol Information Centre,

2011).
8

Persistence

Löffler et al. (2011) reported that radiolabeled acetaminophen (paracetamol) transformed in 

water (water (pH 8.5)/sediment (pH 7.7) study) into volatile transformation products (TP) 

[undefined TP except for CO2], resulting in a DT50 of 3.1 days. Upon contact with the sediment, 

the majority of acetaminophen was bound to the sediment as non-extractable residues. The study 

suggested that acetaminophen did not remain in the water phase, but was rapidly bound to the 

sediment. The bound TP residues were more persistent, potentially accumulating in the sediment 

(Löffler et al., 2011). Lam et al. (2009) evaluated the aquatic persistence of eight 

pharmaceuticals, including acetaminophen, in a microcosm study. In the 30 day study, hydrolytic 

and microbial degradation were not significant degradation pathways, as acetaminophen did not 

degrade in sterile or non-sterile pond water samples stored in the dark. Degradation was 

observed to occur when exposed to direct or indirect light, suggesting that exposure to sunlight is 

an important process in the degradation of acetaminophen. The average half-lives [t1⁄2] of 

acetaminophen at four treatment levels (n=4) were 1.1, 0.7, 0.9 and 1.0 days for ultra-high to low 

treatment concentrations1. The overall average half-life was 0.9 ± 0.2 days.

In addition to the pesticidal use of acetaminophen to control brown treesnakes in Guam and the

CNMI, acetaminophen is also a widely used pharmaceutical. The pharmaceutical use can also 

introduce acetaminophen into the environment in several ways. One important pathway is 

through discharge of acetaminophen residues remaining in treated effluent from sewage 

treatment plants, most of which predate the identification of pharmaceuticals as potential water 

contaminants and, as a result, are not designed for complete removal of these microcontaminants (Kinney et al., 2006). Septic system effluent discharge and disposal of sewage 

sludge are other potential mechanisms that can introduce pharmaceuticals to surface water, 

groundwater, and soil. Kinney et al. (2006) investigated the presence and distribution of a 

number of pharmaceuticals, including acetaminophen, in soil irrigated with water containing 

acetaminophen (mean acetaminophen concentrations ranged 8.1 to 65.3 ng/L) derived from 

urban waste water treatment sources. Although this study does not allow for determination of a 

half-life (degradation or dissipation), acetaminophen (integrated mass with depth and time) 

tended to “increase in mass during the irrigation period” during the course of the study, 

suggesting that acetaminophen was somewhat persistent.

Mobility

The ionization of acetaminophen (a non-hydrophobic chemical) is strongly dependent upon the 

system pH, pKa (~9.4), hydrophobicity, and the nature of the surface charge of the sorptive media 

(Lorphensri et al., 2006). Lorphensri et al. (2006) found that acetaminophen showed no sorption 

(at pH 7) to two pure minerals (silica and alumina) and a hydrophobic medium (Porapak P2

). 

Yamamato et al. (2005) reported mean Kd of 7.7 and 2.6 L/kg and Koc of 270 and 330 for Elliot 

Silt Loam soil and Suwannee River sediment, respectively. In order to standardize the qualitative 

 1 Treatment concentrations were chosen based upon distributional analysis of the upper exposure centiles (e.g., 95th, 

99th, 99.5th, 99.9th) estimated from actual surface water concentrations (0.83, 33.98, 132.0 and 2190 μg/L for low, 

medium, high, and ultrahigh treatment levels, respectively (Lam et al., 2004).

2 Porapak P is a cross-linked polymer of divinyl-benzene/styrene purchased from Supelco.
9

descriptors used to report the chemical mobility in soil of pesticides in exposure assessments, the 

Agency has adopted the standardized classification scheme published by the Food and 

Agricultural Organization (FAO) of the United Nations (Bradbury, 2006). Based upon this 

scheme, acetaminophen would be classified with a medium mobility class (Koc range of 150 to 

500).

The length of time, or persistence, that a pesticide or metabolism/transformation products will 

remain in the environment is influenced by both biotic and abiotic processes, sorption to soil 

material, and the environmental factors (temperature, precipitation, length of day, water 

turbidity, etc.) which act upon the chemical. Acetaminophen is formulated as a tablet and then 

placed in a “bait” (dead mouse), and thus is not directly applied to water, soil, or vegetation.

Therefore, while in the bait, photolysis would not be anticipated to be significant. Based upon 

the limited data noted above, acetaminophen is expected to be fairly stable in the bait (in the 

dead mouse), due to limited photolysis and direct exposure to environmental conditions. Storage 

and field stability data shown in Johnston et al. (2002; Table 2), suggest that the acetaminophen 

will have a half-life of about 90 days in the mouse bait. Acetaminophen appears to be rapidly 

transformed in the water phase when exposed to light. It is anticipated that based upon the 

pesticidal use of acetaminophen, the potential to contaminate surface water via runoff would be 

minimal.

Monitoring Data

The US Geological Survey recently conducted a nationwide reconnaissance of the occurrence of 

pharmaceuticals, hormones, and other organic waste contaminants (OWCs) in water resources. 

Ninety-five OWCs, including acetaminophen, were detected in water sampled from a network of 

139 streams across 30 states during 1999 and 2000 (Kolpin et al., 2002). Other literature sources 

(Table III.2.) have also identified acetaminophen (paracetamol) residues in surface water, 

ground water, and effluent from sewage treatment plants (STP). These detects all are associated 

with the use of acetaminophen as a pharmaceutical product.

Table III.2. A Selection of Water Monitoring Studies, Water type, Frequency of Detection, and 

Maximum Acetaminophen (Paracetamol) Concentration

Study ID. Water Type (Location) Frequency of 

Detections (%)

Maximum

(μg/L)

Kolpin et al. 2002 U.S. Streams susceptible to human, 

industrial, and agricultural wastewater 23.8 10.0

Lucia et al., 2010 Sewage Treatment Plants ns

1 4.3 

Lucia et al., 2010 Surface water ns1 78.2 

Kinney et al., 2006 Reclaimed water used for irrigation ns1 65.3

Focazio et al., 2008 Ground Water and Surface Water2 8.1 0.16

Barnes et al., 2008 Ground Water (18 states) 6.4 0.38

Fram and Belitz, 2011 Ground Water (California)2 0.32 1.89

1 ns = not specified

2 Drinking water sources
10

2. Overview of Pesticide Usage

As a pesticidal active, acetaminophen is an active ingredient in a product used by wildlife 

managers to control the brown treesnake in Guam and the CNMI. The mode of action of 

acetaminophen in the treesnake is not completely understood, but is believed to be the result of 

induced hepatic (liver) necrosis, as in mammals (MRID 457167-14, Savarie et al., 2002). In 

mammals, acetaminophen is biotransformed into a potentially toxic metabolite which is then 

detoxified by conjugation with glutathione. When the dose is large enough to deplete hepatic 

supplies of glutathione, the toxic metabolite becomes available for binding with cell membranes 

and hepatic necrosis ensues (Rumack and Lovejoy, 1986). Acetaminophen is also the active 

ingredient in a variety of over-the-counter medicines that results in potentially widespread 

exposure across the U.S. and its territories.

The label (EPA Reg. No.56228-34) states the Acetaminophen is comprised of 72.73 % active 

ingredient (a.i.) and 27.27% inert ingredients. The label also indicates that acetaminophen is 

formulated into 40- and 80-mg acetaminophen tablets. Because “acetaminophen” is the name of 

the product and also the a.i., it is unclear as to whether the 40- and 80-mg doses stated on the 

label reflects the mass of the a.i. in a tablet or the total mass of the tablet (a.i. plus inerts). In this 

assessment, we assume the dose is expressed in terms of active ingredient (i.e., 40- and 80-mg 

a.i./tablet).

Acetaminophen for brown treesnake control requires that the acetaminophen tablets be placed in 

a dead mouse pup to form a bait. The baits can be placed by ground or air. Broadcast application 

by air is necessary for inaccessible areas. Generally the intent appears to be to suspend the baits 

in the tree canopy as much as possible to make it accessible to the brown treesnake.

SINGLE BAIT PREPARATION – Manually insert one 80-mg or two 40-mg acetaminophen 

tablets into the throat of a dead mouse pup (approximate age: 10-15 days). 

BAIT STATIONS – Construct bait stations from lengths of PVC pipe that are 2 to 4 inches (5.1 to 

10.2 cm) in diameter and 12 to 18 inches (30.5 to 45.8 cm) in length. Alternatively, use wire 

mesh funnel traps. Hang bait stations in trees and on fences at heights of approximately 4.9 feet 

(1.5 meters) above ground. Place single mouse baits inside individual bait stations. Place bait 

stations at intervals of approximately 22 yards (20 meters) or greater in and around forested 

areas and along fence lines. Bait density must not exceed 15 baits per acre (36 baits per 

hectare). Bait stations may be restocked at a minimum interval of two days and may be operated 

continuously throughout the year.

BROADCAST APPLICATION – Baits may be hand broadcast or dropped from helicopters and 

fixed-winged aircraft. If the desired bait placement is in the forest canopy, attach a small piece 

of netting or other material to the bait. During one baiting period, apply no more than 15 baits 

per acre (36 baits per hectare) per drop, with a minimum interval between drops of 2 days. No 

more that 15 drops may occur in a single baiting period, No more than two baiting periods per 

acre or hectare may occur in a single year.
11

Several use restrictions are also included on the pesticide label (EPA Reg. No. 56228-34):

DO NOT apply this product in a manner that will contaminate food, feed, and water. 

DO NOT apply this product in a manner where it is accessible to children or domestic animals.

DO NOT apply treated baits in areas where there is a danger that threatened or endangered 

species will consume baits unless special precautions are taken to limit such exposures. Such 

precautions shall include applying treated baits inside bait stations that will exclude threatened 

or endangered species that otherwise might feed upon baits.

The registration review ecological risk assessment will consider only the pesticidal use of 

acetaminophen as an active ingredient for the control of the brown treesnake. However, it 

should be stressed that the non-pesticidal use of acetaminophen is expected to dominate both 

human and wildlife exposure to this chemical.

IV. Receptors

1. Aquatic and Terrestrial Effects

The receptor is the biological entity that is exposed to the stressor (USEPA, 1998). The use of 

acetaminophen (the stressor) in bait targeting the brown treesnake is expected to primarily 

expose terrestrial animals, including birds, mammals, terrestrial-phase amphibians, and terrestrial 

crustaceans (i.e., land crabs). These species may be exposed if they consume the baited mouse 

pups, or if they consume live or dead snakes which have ingested the bait. In particular, this 

assessment will focus on native terrestrial animals. Guam contains numerous invasive exotic 

animals such as feral dogs and cats, feral pigs, and monitor lizards. However, since these exotic 

species are considered pests which have significant negative impacts to the ecosystem, they will 

not be considered as receptors. To a lesser degree, soil and aquatic habitat may be exposed as 

residues leach out of the bait and carcasses of dead snakes, or are excreted by animals that 

consume the bait. Therefore, fish, aquatic invertebrates, and plants are also potential receptors.

Consistent with the process described in the Overview Document (USEPA, 2004), the planned 

risk assessment will use a surrogate species approach in its evaluation of acetaminophen. 

Toxicological data generated from surrogate test species, which are intended to be representative 

of broad taxonomic groups, are used to extrapolate to potential effects on a variety of species 

(receptors) included under these taxonomic groupings. Acute and chronic toxicity data from 

studies submitted by the pesticide registrant, along with the available open literature, are used to 

evaluate the potential direct effects of acetaminophen to the aquatic and terrestrial receptors 

identified in this section. This includes toxicity data on the technical grade active ingredient, 

degradates, and formulated products (e.g. “Six-Pack” studies of mammalian toxicity). The open 

literature studies are identified through EPA’s ECOTOX database (http://cfpub.epa.gov/ecotox/), 

which employs a literature search engine for locating chemical toxicity data for aquatic life, 

terrestrial plants, and wildlife. The evaluation of both sources of data can also provide insight 
12

into the direct and indirect effects of acetaminophen on biotic communities from loss of species 

that are sensitive to the chemical and from changes in structure and functional characteristics of 

the affected communities.

Table IV.1 provides a summary of acute toxicity findings for taxonomic groups, along with their 

corresponding surrogate species, that the Agency plans to use to assess acute risk of 

acetaminophen to non-target animals. In addition, the table provides a preliminary overview of 

acute toxicity classifications based on these findings. Results for acute oral and sub-acute dietary 

toxicity to birds are based on acceptable guideline studies submitted by the registrant. An acute 

oral toxicity study (guideline number 850.2100) was conducted with the northern bobwhite, and 

a sub-acute dietary study (guideline number 850.2200) was conducted with both the northern 

bobwhite and the mallard. In all three of these studies, no mortality was observed at the highest 

test concentration, yielding non-definitive endpoint estimates, and establishing the acute toxicity 

category as “practically nontoxic.” Results for acute toxicity to mammals were obtained from 

data published in the open literature. Among the species tested, the most sensitive mammal was 

the house mouse (Mus musculus), which was considerably more sensitive than the Norway rat 

(LD50 range 1944 to 4450 mg/L, MRID 457167-15). Acute toxicity to the house mouse 

categorizes acetaminophen as “moderately toxic” to mammals.

Toxicity findings for aquatic species are limited to acute toxicity tests with aquatic invertebrates 

published in the open literature. These studies are summarized in MRID 457167-11. The aquatic 

risk assessment will be based on the most sensitive aquatic invertebrate species, the Sudanese 

fairy shrimp (Streptocephoreum proboscideus). A test with the waterflea (Daphnia magna),

which is considered a preferred test species, has an only slightly higher EC50 value of 40.7 mg/L 

(Calleja et al., 1993). Results from both of these tests categorize acetaminophen as slightly toxic 

to aquatic invertebrates. No LC50 estimate is available for acute toxicity to fish or marine/

estuarine invertebrates.

Table IV.1. Test Species Evaluated for Assessing Potential Ecological Effects of Acetaminophen and the Associated 

Acute Toxicity Findings 

Taxonomic 

Group Surrogate Species Acute Toxicity2 CitationMRID

Acute Toxicity 

Classification

Birds1

Northern Bobwhite

(Colinus virginianus)

and

Mallard (Anas 

platyrhynchos)

LD50 > 2250 mg a.i./kg MRID 457167-12

(bobwhite)

Practically 

nontoxic LC50 > 5000 mg a.i./kg feed3

NOAEC = 5000 mg a.i./kg feed3

MRID 457176-01 

(bobwhite)

MRID 457167-13 

(mallard)

Mammals Laboratory mouse

(Mus musculus)

LD50 = 338 mg a.i./kg

95% CI : 306 - 373 mg a.i./kg

MRID 457167-15

(Starmer et al., 1971)

Moderately

toxic

Freshwater 

invertebrates

Sudanese fairy 

shrimp 

(Streptocephalus 

proboscideus)

EC50 = 29.5 mg a.i./L

95% CI : Not reported

MRID 457167-11

(Calleja et al., 1993) Slightly toxic

1 Birds represent surrogates for terrestrial-phase amphibians and reptiles; fish serve as surrogate species for the aquatic 

phase. 2 These values may be revised if future studies or literature become available. 3 Results for the northern bobwhite and mallard were identical.
13

The toxicity values that will be used in the risk assessment are the lowest toxicity values

obtained from scientifically valid studies with mammalian and invertebrate test species. The 

acute toxicity values for mammals and invertebrates are presented in Table IV.1.

Pen studies with wild caught fish crows (Avery et al., 2004; Johnston et al., 2002) provide 

further information on the toxicity of acetaminophen to birds. One study examined the acute 

toxicity of acetaminophen to the fish crow (Corvus ossifragus), which served as a surrogate for 

the endangered Mariana crow (Corvus kubaryi) of Guam. Five crows were each force-fed two 

40-mg tablets of acetaminophen, for a dose of 80 mg/bird. This is the same amount of active 

ingredient that is placed within a single mouse pup as bait to control brown treesnakes. The study 

was then repeated with a dose of 4 tablets (160 mg/bird). At the 80-mg dose, 4 out of 5 birds 

appeared lethargic after dosing and 3 of the birds vomited, but all birds survived. At the 160 mg 

dose, all five of the crows regurgitated the acetaminophen tablets. One of the five crows died 

three hours after repeated regurgitation. Based on the weight of recovered vomited tablets, 

compared to weights of intact tablets, 12% to 75% of the administered dose remained ingested 

after vomiting, with the greatest percentage (75%) being in the bird that died.

While the number of birds tested is too small to draw definitive conclusions, this study indicates 

that that ingestion of two 40-mg tablets of acetaminophen (a.i.) causes lethargy but is not lethal 

to crow-size birds, whereas the ingestion of four 40-mg tablets can be lethal. These limited 

findings suggest that, in the unlikely event that an endangered Mariana crow ingests two or more 

whole baited mouse pups, it may be at risk. As the fish crow has a body weight of approximately 

300 mg (NatureServe, 2011), administration of 160 mg to a fish crow is equivalent to an acute 

oral dose of 533 mg a.i./kg BW. Thus, this study suggests that crows may be more sensitive to 

acetaminophen than the northern bobwhite, for which no mortality was observed with acute oral 

doses up to 2250 mg/kg BW (MRID 457167-12).

In a second study, crows were offered dead mouse pups treated with two 40-mg acetaminophen 

tablets and observed. Ten crows were first observed feeding on an untreated mouse pup in 5

daily trials, and then were observed feeding on a treated mouse pup on one final trial, for a total 

of 60 trials altogether. The crows were observed to mainly feed on the pups by tearing them 

apart bit by bit. They generally picked the acetaminophen tablets from the carcass and either set 

them aside or drop them from the perch. Only one out of ten birds was observed to swallow the 

whole pup intact, with the tablets inside, and this bird did so only in one out of six instances. 

This avoidance of the acetaminophen tablets by birds feeding on carcasses may reduce the 

exposure and risk of the baited mouse pups to scavenging birds in the wild (Avery et al., 2004; 

Johnston et al., 2002).

Information on the chronic toxicity of acetaminophen is limited to mammals. The registrant 

submitted a report that summarizes data on chronic toxicity to mammals (MRID 457167-15). 

Submitted chronic studies that showed frank effects relatable to ecological risk, which included

effects on growth, survival and/or reproduction, were used to select a chronic toxicity estimate 

that will be used to assess ecological risk to mammals. Studies which provided frank effects from 

chronic exposure include a mouse prenatal development toxicity study (Hess, 1984) and a twogeneration mouse reproduction toxicity study (National Toxicology Program, 1984). The 

prenatal developmental study found that exposure at a daily dose of 250 mg/kg (approximately 
14

5000 mg/kg-diet) caused a reduction in bodyweight and developmental abnormalities. Exposure 

at 140 mg/kg (approximately 2800 mg/kg-diet) did not affect bodyweight but did result in a low 

frequency of abnormalities. In the two-generation reproduction study, the most sensitive 

endpoints were body weights of F1 pups. Exposure at 2500 mg/kg diet resulted in significant 

decreases in body weights, relative to the control, of male and female pups at 28 and 74 days. 

Body weight gain of pups also was reduced at this exposure level. Relative to the control, pup 

body weights decreased by 6-10% at 2500 mg/kg-diet, 8-16% at 5000 mg/kg-diet, and 16-34% at 

10,000 mg/kg-diet. Reproductive and fertility endpoints were not affected at the expose levels of 

2500 and 5000 mg/kg-diet level. Exposure to 10,000 ppm (1%) resulted in reduced number of 

litters per pair and reduced number of live male pups. While these studies do not provide a 

NOAEL for frank effects on mammals, they do indicate that significant frank effects begin to 

occur at dietary exposures of approximately 2500 mg/kg-diet. Thus, 2500 mg/kg-diet will be 

used as an approximate threshold of chronic effects for assessing chronic risk to mammals.

One published paper provided information on the toxicity of acetaminophen to terrestrial plants.

Bartha et al. (2009) studied the uptake, translocation, toxicity, and detoxification of 

acetaminophen in the Indian mustard (Brassica juncea). In this study, 8-week-old test plants 

were treated by administration of a 1-mM (151-mg/L) solution of acetaminophen to the growth 

medium for one week. Exposure to this concentration was found to cause oxidative stress that 

resulted in irreversible damage to the plants. Leaves of treated plants showed bleaching and 

lesions after 72 h, and necrosis after 168 h. Between 72 and 168 h, roots of treated plants turned 

dark brown and ceased to show lateral development. Plant pigments (chlorophyll a, b, and 

caratenoids) showed a 50% decrease after 72 h and 70% decrease after 1 week. While this study 

shows that soil exposure to a 1 mM solution of acetaminophen may cause phytotoxicity to plants, 

the relationship of this exposure to environmentally relevant exposure levels resulting from the 

pesticidal use of acetaminophen bait is unknown.

 2. Ecosystems Potentially at Risk 

The distribution of mouse pup bait containing acetaminophen tablets for control of the brown 

treesnake will release acetaminophen into the terrestrial and freshwater environments. Terrestrial 

ecosystems would potentially be at risk because nontarget terrestrial animals may consume the 

baited mouse pups directly, or may consume living or dead snakes or other animals which have 

ingested the bait. Some active ingredient is expected to leach from the bait into the soil, where 

soil-dwelling animals and plants could be exposed. Small quantities of active ingredient may 

reach freshwater ecosystems, being transported from contaminated soil via surface water runoff. 

While the label for the registered use of acetaminophen for treesnake control contains the 

environmental hazard statement “do not apply directly to water,” aerial broadcast applications of 

bait may result in a small amount of inadvertent placement of bait in freshwater bodies such as 

streams, ponds, and wetlands. Bait may also be placed in gullies where runoff may wash it into 

streams, ponds, wetlands and lakes. Some exposure to freshwater ecosystems on treated islands 

therefore may occur. However, considering the relative low toxicity of acetaminophen to aquatic 

invertebrates, ecological risks to aquatic organisms is considered to be discountable (see Section 

VII.2)
15

Residues of acetaminophen that enter flowing freshwater would drain into estuaries and marine 

habitats. However, as acetaminophen contamination of freshwater habitats is expected to be 

minor, and contaminated freshwater would be diluted with large amounts of uncontaminated 

seawater in estuary and marine habitats, the concentrations of acetaminophen in estuarine and 

marine habitats is expected to be very small. Considering the low toxicity of acetaminophen to 

aquatic invertebrates (and presumably aquatic vertebrates as well), risk to estuarine and marine 

organisms is expected to be minimal and discountable.

3. Incident Databases Review

The Ecological Incident Information System (EIIS, version 2.1.1) and the Avian Incident 

Monitoring System (AIMS), will be searched for any ecological incidents related to this use of 

acetaminophen. At this time, a preliminary search of these databases found no reported 

ecological incident related to this ingredient.

V. Assessment Endpoints

Assessment endpoints represent the actual environmental value that is to be protected, defined by 

an ecological entity (species, community, or other ecological entity) and its attributes or 

characteristics (USEPA, 1998). For the acetaminophen risk assessment, the ecological entities 

may include all species of native and naturalized animals and plants inhabiting Guam and the 

CNMI with the exception of introduced exotic species that that are known to have adverse 

impacts on the native ecosystem. Native species of terrestrial wildlife that the Agency expects to 

be exposed to acetaminophen by feeding on the baited mouse pups or scavenging on dead snakes 

are the Mariana crow (Corvus kubaryi), the Guam rail (Gallirallus owstoni), and various crabs. 

The only carnivorous and omnivorous mammals that may feed on mouse pups are feral dogs, 

feral cats, wild pigs, and rats, all of which are pest species that cause significant harm to the 

native ecosystem (Johnston et al., 2002; Guam National Wildlife Refuge, 2009). The monitor 

lizard (Varanus indicus), a carnivorous reptile that occurs on these island, is also an exotic pest 

species (Johnston et al., 2002; Guam National Wildlife Refuge, 2009). Thus, the Mariana crow, 

the Guam rail, and terrestrial crabs are assumed to be the terrestrial wildlife entities that need to 

be protected. 

Other ecological entities include terrestrial and aquatic plants, fish, and aquatic invertebrates. 

The attributes for each of the ecological entities may include growth, reproduction, and survival. 
16

VI. Conceptual Model

For a pesticide to pose an ecological risk, it must reach ecological receptors in biologically 

significant concentrations. An exposure pathway is the means by which a pesticide moves in the 

environment from a source to an ecological receptor. For an ecological pathway to be complete, 

it must have a source, a release mechanism, an environmental transport medium, a point of 

exposure for ecological receptors, and a feasible route of exposure.

A conceptual model provides a written description and visual representation of the predicted 

relationships between the active ingredient, potential routes of exposure, and the predicted 

effects for the assessment endpoint. A conceptual model consists of two major components: risk 

hypothesis and a conceptual diagram (USEPA, 1998).

 1. Risk Hypothesis

For acetaminophen, the following ecological risk hypothesis will be employed for the risk 

assessment:

Acetaminophen, when used in accordance with the current label, may result in 

contamination of ecosystems and adverse effects upon the survival, growth, and 

reproduction of native non-target terrestrial and aquatic organisms on Guam and the 

CNMI, including organisms that are Federally-listed as threatened and endangered 

species.

 2. Conceptual Diagram

For the use of acetaminophen to control brown treesnakes, the potential exposure pathways and 

effects to non-target terrestrial and aquatic organisms and plants are depicted in Figures VI.1

and VI.2, respectively. Solid arrows depict the most significant routes of exposure and effects; 

dashed lines depict potential routes of exposure not considered likely to contribute significantly 

to the risks of acetaminophen use. 

As depicted in Figure VI.1, the primary exposure routes in the terrestrial ecosystem are assumed 

to be direct ingestion of the bait and secondary exposure from consumption of other animals 

which have ingested the bait. Transport mechanisms (e.g., sources) for the specified use of 

acetaminophen may result in a small amount of movement of the pesticide from the bait into soil,

where it may be taken up by plants. However, this exposure route is expected to be minor. 
17

Figure VI.1. Conceptual model depicting stressors, generic exposure pathways, and potential effects to 

terrestrial animals and plants from the use of acetaminophen. Dotted lines indicate exposure pathways that 

have a low likelihood of contributing to ecological risk.

As depicted in Figure VI.2, the registered use of acetaminophen in bait for the brown treesnake

is not predicted to result in significant exposure to aquatic organisms from any mechanism of 

transport. Because the acetaminophen is formulated into tablets which are inserted in the bait

(mouse pups), transport through spray drift is not relevant. Also, because acetaminophen has a 

very low vapor pressure and is formulated as a tablet, volatilization and inhalation exposure are 

expected to be negligible. A small amount of acetaminophen may leach out of the baited mouse 

pups into the soil, and then may be transported to water via surface runoff, but this route is 

expected to result in minor contributions to aquatic exposure. A few of the placed baited mouse 

pups may inadvertently be dropped in or transported to water bodies, in which case the active 

ingredient may dissolve and disperse into the ambient water. But again, this route is expected to 

result in little contamination of surface water. A risk screen presented in Section VII.2 of this 

document indicates that aquatic exposure levels from this route would be far below levels of 

concern for aquatic animals.
18

Figure VI.2. Conceptual model diagram depicting stressors, exposure pathways, and potential effects to 

aquatic animals and plants from the use of acetaminophen. Dotted lines indicate exposure pathways that 

have a low likelihood of contributing to ecological risk.

VII. Analysis Plan Options

1. Analysis of Risk to Terrestrial Organisms

The only terrestrial species that are expected to receive significant exposure to acetaminophen 

from the registered use for brown treesnake control are those that would directly consume the 

baited mouse pups (primary exposure), and those that might prey or scavenge on treesnakes that

consume the bait (secondary exposure). As mentioned previously, the only native terrestrial 

animalsthat are expected to feed on either the mouse pups or the treesnakes are the Mariana 

crow, the Guam rail, and native crabs (Johnston et al., 2002, Guam National Wildlife Refuge,

2009). A risk assessment for effects to terrestrial mammals is therefore not required. The 

Agency does not have standardized risk assessment methods for quantitatively assessing risk to 

terrestrial crabs. Therefore, a quantitative terrestrial risk assessment will be limited to avian risk 

assessments focused on the Mariana crow and the Guam rail. Risk to terrestrial crabs may be 

assessed qualitatively. As much as is possible, species-specific information on exposure and 

toxicity will be used to make the assessment reflect risk to these species of concern.

As a first-tier risk assessment, primary exposure to terrestrial animals will be modeled based on 
19

the assumption that the baited mouse pups are consumed in entirety and that all of the active 

ingredient within the contained tablets is ingested. Based on information provided on the label,

80 mg of acetaminophen active ingredient3 will be inserted into each mouse pup in one or two 

tablets. Risk quotients (RQs) will be calculated using a dietary concentration approach, in which 

the dietary concentration of acetaminophen in a baited pups is compared to the avian dietary 

LC50, and a dose-based approach, in which the predicted dose from a single day of feeding on 

baited mouse pups is compared to the avian acute oral LD50. For the dietary approach, the 

dietary concentration of acetaminophen will be the amount of active ingredient inserted into a 

mouse pup (80 mg) divided by the weight of the pup. For the dose-based, the daily dose will be 

the amount of active ingredient in one baited pup (80 mg) multiplied by the number of pups an 

individual would be expected to consume in one day. The latter will be estimated based on the 

average daily food intake of species of concern, and the average weight of a mouse pup. The 

daily food intake rate of the Mariana crow and the Guam rail will be estimated based on 

available data for species that most closely represent these species. The weight of a mouse pup 

will be assumed to be 5 g, as was assumed in the previous published risk assessment of Johnston 

et al. (2002). Since dose is expressed as mg a.i./kg BW, the predicted dose per birds will be 

divided by average bodyweight of the Mariana crow and the Guam rail. 

To calculate RQs, exposure values will be divided by the non-definitive acute toxicity endpoints 

(LD 50 > 2250 mg a.i./kg BW and LC50 > 5000 mg/kg-diet). Because these endpoint is nondefinitive, the RQs will be expressed as an inequality (RQ < x). Since the Mariana crow and the 

Guam rail are both endangered species, the RQ will be compared to the terrestrial endangered 

species Level of Concern (LOC) of 0.1. If this analysis fails to show that the RQ is less than 

0.1, the tier-1 risk assessment will fail to preclude concern for risk to terrestrial wildlife, and a 

higher tier assessment will be conducted. The higher-tiered assessment may consider other 

factors that may influence exposure, such as the proportion of diet consisting of contaminated 

food, regurgitation, and avoidance behavior.

Johnston et al. (2002) and Avery et al. (2004) discussed avoidance behavior as a primary factor 

that may reduce exposure of birds to acetaminophen. Avery et al. (2004) found that fish crows 

usually avoided consuming the acetaminophen tablets when they fed on baited mouse pups, and 

usually regurgitated acetaminophen tablets when they were force-fed. Avoidance and 

regurgitation responses will be qualitatively considered in the risk assessment as potential 

mechanisms that may reduce exposure of non-target birds, particularly the Mariana crow. Use of 

bait stations will also be considered for their potential to prevent access of nontarget organisms 

to baited mouse pups, and thereby mitigate the risk of primary exposure. The label recommends 

use of bait stations made of PVC pipe 2-4 inches in diameter and 12-18 inches in length. Avery 

et al. (2004) observed the response of fish crows to bait stations with a mouse pup inserted halfway in the pipe. They tested bait stations were PVC pipes at the extremes of the recommended 

dimensions (2 or 4 inches in diameter, and 12 or 18 inches long). They found that the longer 

pipes significantly reduced the total number of pups that were accessed. They found that some 

crows succeeded in accessing the mouse pups from all except the long and narrow bait stations. 

When short and wide stations were used, 5 out of 10 crows were able to access at least one pup. 

Based on these results, use of bait stations likely would reduce the ingestion of the baited mouse 

 3 The label does not specify if the 80 mg dose per mouse pup is in terms of active ingredient or formulated product. 

The Agency will assume that this dose is in terms of active ingredient unless the registrant informs us otherwise.
20

pups by the Mariana crow, but they would not eliminate it unless they are constructed with the 

longest length and narrowest width recommended on the label.

Other factors that may increase or decrease exposure and toxicity may also be considered, 

qualitatively if not quantitatively, in the higher-tiered assessment. In particular, the feeding 

behavior of the Guam rail and the land crabs of Guam will be investigated to evaluate the 

potential for these species to consume acetaminophen tablets that placed inside dead mouse 

pups.

In addition to the assessment of risk from primary exposure to the acetaminophen bait, a second 

risk assessment will be conducted to assess risk to birds from secondary exposure, which would 

occur when a bird ingests the tissue of brown treesnakes poisoned by acetaminophen bait. This 

assessment would be appropriate for assessing risk to non-target animals from placement of 

acetaminophen bait in bait stations. The use of bait stations would only reduce the risk of 

primary exposure, but would not reduce the risk of secondary exposure from animals feeding on 

poisoned snakes. 

In the secondary exposure risk assessment, the dose received by secondary exposure will again 

be based on the daily food intake rates and body weights of the Mariana crow and the Guam rail. 

The predicted dose from secondary exposure will be compared to both the avian acute oral LD50

value (using dose-based RQs) and the avian dietary LC50 values (using dietary-based RQs). All

of the daily food intake of these birds will be assumed to be composed of brown treesnakes that

have recently been poisoned by acetaminophen. The acetaminophen concentrations in tissue of 

brown treesnakes will be based on measured tissue concentrations published in Johnston et al. 

(2002), Primus et al. (2004), or other available published data. The dietary concentration of 

acetaminophen for a bird consuming snake tissue is assumed to be 735 mg ai/kg-diet, which was 

the highest concentration observed in the data published by Primus et al. (2004). As the dietary 

LC50 for both the northern bobwhite and mallard are considerably greater than this concentration 

(> 5000 mg/kg-diet, MRID 457176-01and 457167-13), the Agency expects that the risk 

assessment for secondary exposure will indicate minimal risk to non-target birds.

The Agency recognizes that the use of acetaminophen to control the brown treesnake incurs

considerable benefits to the survival and reproductive success of native terrestrial wildlife of 

Guam and the CNMI, as well as posing some potential risks. It is important to weigh the 

significant potential benefits of the use against the potential risks. While EFED does not conduct 

risk-benefit analyses, a discussion of the ecological benefits to wildlife that would incur from 

controlling the brown treesnake on these islands will be included in the ecological risk 

assessment.

2. Analysis of Risk to Aquatic Organisms

Methods traditionally used to estimate aquatic exposure from typical applications of agricultural 

pesticides are not appropriate for estimating exposure from the use of acetaminophen in bait for 

treesnake control. The bait will be distributed in tablets that will be placed inside mouse pups, 

and therefore will not be subjected to the same environmental degradation and transport 

mechanisms that would be in play for a pesticide that is broadcasted onto soil or foliage as a 
21

spray or granule. Much of the distributed bait is expected to be consumed by brown treesnakes or 

other animals. When the bait is consumed by an animal, only a fraction of acetaminophen that is 

excreted without transformation, or that is released when the animal dies and decomposes, would 

be introduced into the soil. Only this small fraction that is released onto the soil would be 

subjected to transport by runoff into aquatic habitats. Therefore, models developed for 

agricultural uses of pesticides likely would greatly overestimate the amount of acetaminophen 

bait that would reach water bodies. 

Because use of the traditional aquatic exposure models is not appropriate, an alternative 

approach will be used to estimate aquatic environmental exposure concentrations (EECs) from 

this use. As a worst-case scenario, baited mouse baits will be assumed to be placed directly into a 

body of water, and all of the active ingredient contained within that pup (80 mg per pup) will be 

assumed to dissolve into the ambient water. While the Environmental Hazards section of the 

label contains a statement that prohibits direct application to water, aerial broadcast application 

could result in a small number of baited pups inadvertently entering bodies of freshwater. Also, a 

small number of baited pups may be transported into water by rainwater runoff or movement by 

animals.

A first-tier screen for aquatic risk assessment can be conducted by determining the number of 

baited pups that must enter a pond for the water concentration in that pond to reach a level that 

would make the aquatic risk quotient (RQ) equal to the aquatic risk LOC. In this assessment, all 

of the active ingredient in the bait will be assumed to dissolve and be distributed evenly within 

the pond with no degradation. As acetaminophen is highly soluble in water (12,780 mg/L),

solubility is not expected to be a limiting factor. The standard pond the Agency uses to assess 

risk to aquatic organisms is a one hectare by two meter deep pond that contains 20,000 liters of 

water. As there are no listed threatened or endangered aquatic species in Guam or the CNMI 

(Table VIII.1), the LOC for non-endangered species, 0.5, will be used. Based on the acute LC50

of 29.5 mg a.i./L for the Sudanese fairy shrimp, the acetaminophen concentration in the pond 

would need to reach 14.8 mg a.i./L for the acute aquatic RQ to equal the LOC of 0.5. Any 

concentration less than this would be below the level of concern for aquatic species.

Based on label information, 80 mg of acetaminophen is placed in each mouse pup, and thus 80 

mg will added to the water per each mouse pup that enters the pond. Therefore the total number 

of mouse pups that must enter the 1-ha pond for the acute aquatic RQ to equal the LOC is 

calculated as follows:

14.8 mg a.i./L x 1 pup/80 mg a.i. x 20,000 L = 3700 pups 

This calculation shows that 3700 mouse pups would need to enter the 1-ha pond for the 

acetaminophen concentration in the pond to reach levels that would be of concern for aquatic 

organisms. Considering that the label prohibits application of this product directly to water, and 

doing so would clearly make the bait ineffective for controlling treesnakes, the Agency believes 

that the number of pups that would inadvertently reach a pond from the registered use likely 

would be well below this number. Thus, the Agency believes that the concentration of

acetaminophen in aquatic habitats will be well below the level of concern for aquatic life, and 

risk to aquatic life will be minimal and discountable. The Agency does not expect that any
22

further aquatic risk assessment will be needed for this registered use.

3. Analysis of Risk to Terrestrial Plants

The registered use of acetaminophen to control the brown treesnake is expected to result in very 

minimal exposure to terrestrial plants. The bait will be distributed as tablets placed inside of 

mouse pups. Most of these pups are expected to be consumed by snakes or other animals, and 

thus, most of the active ingredient is not expected to be directly released into the soil. Residues 

entering the soil would be limited to the amount that leach from the baited mouse pups that are 

not consumed, the amount that is excreted from animals that consume the bait, and the amount 

that is released when poisoned brown treesnakes die and decompose. None of these exposure 

routes are expected to result in significant contamination of soil or exposure to terrestrial plants. 

Therefore, the Agency believes that risk from the registered use to terrestrial plants will be 

minimal and discountable.

4. Potential Future Use of Acetaminophen in Other Locations

EPA considers the action area for the registered use of acetaminophen for control of the brown 

tree snake to be Guam and the CNMI. Presently, these are the only places in the United States 

where the snake is established. Should a need arise in the future to use the product in other 

locations in the United States, an ecological risk assessment and endangered species effects 

determination may need to be conducted for the additional locations. In particular, we are aware 

of the risk of possible invasion of the brown tree snake in the state of Hawaii, where active 

prevention programs are currently in place (Colvin et al., 2005).

While we are not including Hawaii in the current assessment, EFED notes that risks to nontarget 

wildlife on Hawaii would likely be similar to those assessed for Guam and the CNMI. Like 

Guam and the CNMI, no native species of terrestrial mammal or reptile that could be at risk from 

consumption of baited mouse pups or killed snakes occur on Hawaii. Some birds that inhabit 

Hawaii may feed on baited mouse pups or killed snakes, and risks to these species should be 

assessed. In particular, potential risk to the Hawaiian hawk (Buteo solitaries), an endangered 

bird of prey that is endemic to Hawaii should be considered.

VIII. Endangered Species Assessment

Consistent with the Agency’s responsibility under the Endangered Species Act (ESA), EPA will 

evaluate risks to Federally-listed threatened and/or endangered (listed) species from uses of

acetaminophen. This assessment will be conducted in accordance with the Overview Document 

(USEPA, 2004), provisions of the ESA, and the Services’ Endangered Species Consultation 

Handbook (USFWS/NMFS, 1998). 

The assessment of effects associated with registration of acetaminophen is based on an action 

area. The action area is considered the area directly or indirectly affected by the federal action, as 
23

indicated by the exceedance of Agency Levels of Concern (LOCs) used to evaluate direct or 

indirect effects. The Agency’s approach to defining the action area under the provisions of the 

Overview Document (USEPA, 2004) considers the results of the risk assessment process to 

establish boundaries for that action area with the understanding that exposures below the 

Agency’s defined LOCs constitute a no-effect threshold. For the purposes of this assessment, 

attention will be focused on the footprint of the action (i.e., the area where acetaminophen 

application occurs), plus all areas where offsite transport (i.e., runoff, volatilization and longrange atmospheric transport, etc.) may result in potential exposure that exceeds the Agency’s 

LOCs. Specific measures of ecological effect that define the action area for listed species include 

any direct and indirect effects and/or potential modification of its critical habitat, including 

reduction in survival, growth, and reproduction as well as the full suite of sub-lethal effects 

available in the effects literature. Therefore, the action area extends to a point where 

environmental exposures are below any measured lethal or sub-lethal effect threshold for any 

biological entity at the whole organism, organ, tissue, and cellular level of organization. 

As the brown treesnake currently only occurs on Guam and the CNMI, the assessment of 

acetaminophen exposure and risk to threatened and endangered species will be limited to those 

species that occur on these islands. Currently, the listed species that occur on these islands 

consist of 9 terrestrial birds, 2 fruit bats, 2 marine turtles, and 3 terrestrial plants (Table VIII.1). 

Based on the conceptual model and problem formulation for terrestrial wildlife, the registered 

use of acetaminophen is not expected to result in significant exposure or risk to marine turtles. 

The threatened and endangered fruit bats are also predicted to be at no significant risk of harm 

from the registered use of acetaminophen because they feed only on fruit, and therefore would 

not likely consume the baited mouse pups. The natural history and feeding habits of the 9 

endangered birds of these islands will be investigated to determine if they would likely be 

exposed by the registered use of acetaminophen for brown treesnake control. Currently, only the 

Mariana crow (Corvus kubaryi) and the Guam rail (Gallirallus owstoni) have been identified as 

species that might be harmed by this use since they are the only terrestrial wildlife species that

may consume the baited mouse pups and tissue of contaminated treesnakes (Johnston et al.,

2002).

Three species of endangered plants occur on these islands. Serianthes nelsonii occurs on the 

island of Guam and in the CNMI, and Nesogenes rotensis and Osmoxylon mariannense occurs in 

the CNMI (USFWS, 2011). The Agency has insufficient data on the phytotoxicity of 

acetaminophen to conduct a risk assessment to these plants. However, as discussed earlier, the 

Agency believes that exposure to terrestrial plants will be minimal and the potential risk posed 

by this registered use to terrestrial plants is discountable. Nevertheless, the Agency will 

investigate the growth habits and ranges of these species to determine if species-specific risk 

mitigations measures could further minimize the potential for harm to these listed plant species.

As described in Section VII.4., the brown treesnake does not currently occur in the Hawaiian 

Islands, but they are at risk of being invaded by this species the future. If this happens, and if 

acetaminophen needs to be used to control the snake there, then additional threatened or 

endangered species could be at risk, including but not limited to the Hawaiian hawk (Buteo 

solitaries).

Table VIII.1. Federally Listed Threatened and Endangered Species Occurring in Guam and the 
24

Commonwealth of the Northern Mariana Islands (CNMI) (based on USFWS, 2011)

Common Name Scientific Name Federal Listing Distribution Critical 

Guam CNMI Habitat

Mammals

Bat, Little Mariana 

Fruit

Pteropus tokudae Endangered X ND2

Bat, Mariana Fruit Pteropus mariannus 

mariannus

Threatened X X Guam

Birds

Crow, Mariana Corvus kubaryl Endangered X X Guam, 

Rota3

Kingfisher, Guam 

Micronesian

Todiramphus 

cinnamominus 

cinnamominus

Endangered X1 ND2

Moorhen, Mariana 

Common

Gallinula chloropus 

guami

Endangered X X ND2

Rail, Guam Gallirallus owstoni Endangered X1 ND2

Reed-Warbler, 

Nightingale

Acrocephalus luscinia Endangered X1 ND2

Swiftlet, Mariana Aerodramus bartschi Endangered X X ND2

White-eye, Guam 

Bridled

Zosterops conspicillatus 

conspicillatus

Endangered X ND2

White-eye, Rota Zosterops rotensis Endangered X ND2

Reptiles

Turtle, Green Sea Chelonia mydas Threatened X X ND2

Turtle, Hawkbill Eretmochelys imbricate Endangered X ND2

Plants

Hayun Lagu (Guam)

Tronkon Guafi (Rota)

Serianthes nelsonii Endangered X X ND2

(No common name) Nesofenes rotensis Endangered X ND2

(No common name) Osmoxylon mariannense Endangered X ND2

1

Extirpated in the wild in Guam. 2 ND = not defined

3 Rota is an island that is part of the CNMI.

IX. Drinking Water Assessment

Given that the pharmaceutical use of acetaminophen far exceeds the pesticidal use to control 

brown treesnakes; EFED does not anticipate conducting a drinking water exposure assessment to 

quantify the potential concentration of acetaminophen residues from its pesticidal uses in 

drinking water during registration review.

X. Clean Water Act

Acetaminophen is not identified as a cause of impairment for any water bodies listed as impaired 

under section 303(d) of the Clean Water Act4

. In addition, no Total Maximum Daily Loads 

(TMDL) have been developed for acetaminophen5. More information on impaired water bodies 

and TMDLs can be found at the Agency’s website6. The Agency invites submission of water 

 4 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

5 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_group_name=PESTICIDES 6 http://www.epa.gov/owow/tmdl/
25

quality data for this pesticide. To the extent possible, data should conform to the quality 

standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired 

Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and 

Management Process7 in order to ensure they can be used quantitatively or qualitatively in 

pesticide risk assessments.

XI. Endocrine Disruptor Screening Program

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (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, and 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.

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. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Acetaminophen is not among the group of 58 pesticide active ingredients receiving EDSP test 

orders. For information on the status of the orders issued under the EDSP for each chemical, 

please visit our website at http://www.epa.gov/endo/ and click on the "Status of EDSP 

Orders/DCIs" in the Highlights Box. Additional information on the EDSP, including the policies 

and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, can 

also be found at this website.

XII. Anticipated Data Needs

 

The Agency does not anticipate that additional environmental fate and ecotoxicity data will be 

needed to conduct a risk assessment for the registered use of acetaminophen for controlling the 

brown treesnake on Guam and the CNMI. 

In support of the registration of this use, the registrant submitted several published and 

unpublished reports containing information on the toxicity of acetaminophen to non-target 

organisms which may be useful for assessing ecological risk (MRID 457167-11). One of these 

 7 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm
26

papers was the following report on the acute toxicity of acetaminophen to the fish crow:

Avery, M.L., E.A. Tillman, P.J. Savarie. 2001. Acute toxicity of acetaminophen to the 

fish crow and response of captive fish crows to acetaminophen baits. Unpublished 

Interim Progress Report for QA-819, National Wildlife Research Center, Fort Collins, 

CO. 7 p.

This report is described as an “interim progress report.” The Agency requests that the registrant 

now submit the final report of this project (laboratory project number QA-819).

As discussed in previous sections, the Agency has concluded that risk for ecological effects is 

limited to terrestrial wildlife that may consume the baited mouse pups or scavenge on the tissue 

of dead treesnakes. Excluding introduced exotic species that cause ecological harm on these 

islands, the terrestrial species of concern are limited to birds and terrestrial crabs. Adequate 

toxicity data for assessing risk to birds from acute exposure to acetaminophen have been 

submitted (MRID 457167-12, 457167-13, and 457176-01). Avian reproduction studies with

acetaminophen are not needed. A reproduction study with mammals found that exposure to 

acetaminophen did not cause any adverse effects on the fecundity of mice except at very high 

dietary concentrations (10,000 mg a.i./kg-diet, MRID 457167-15), and thus reproductive toxicity 

in birds is expected to also be low. The target species of this use, the brown treesnake, is known 

to cause very serious harm to the reproductive success of birds on these islands, and thus the 

ecological benefits derived from controlling the population of this exotic species with 

acetaminophen are expected to far outweigh any potential adverse effects on avian reproduction 

that may be caused by exposure to acetaminophen. Therefore, no assessment of chronic 

reproductive effects from exposure to acetaminophen will be conducted.

As discussed in Section VII.2, even when using a worst-case scenario of baited mouse pups 

directly entering a body of water, a screening-level aquatic risk assessment using the available 

data on acute toxicity to aquatic invertebrates indicates that aquatic exposure levels will not 

approach levels that are toxic to aquatic invertebrates. As aquatic invertebrates are typically more 

sensitive to contaminants than fish, risk to fish are expected to be even less than that for aquatic 

invertebrates. Therefore, the Agency has sufficient information on acetaminophen to conclude 

that significant adverse effects to aquatic organisms from the registered use of acetaminophen for 

brown treesnake control are highly unlikely, and therefore no additional data on the toxicity of 

acetaminophen to aquatic organisms are required.

As described in Section VII.3, the Agency presumes that this use of acetaminophen for control of 

the brown treesnake will pose minimal risk to terrestrial plants. Therefore, at this time, the 

Agency is not requesting the registrant to submit data on the effects of acetaminophen to 

terrestrial plants.
27

XIII. Open Literature

The Agency will conduct a search of the open literature to determine if any ecotoxicity data 

relevant to acetaminophen are available. If so, an evaluation will be made as to whether or not 

the data are adequate for quantitative or qualitative use in a risk assessment. The Agency uses 

the ECOTOX database as its mechanism for searching the open literature. ECOTOX integrates 

three previously independent databases - AQUIRE, PHYTOTOX, and TERRETOX - into a 

system, which includes toxicity data derived predominately from the peer-reviewed literature for 

aquatic life, terrestrial plants, and terrestrial wildlife, respectively. 

XIV. Bibliography

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Barnes, K.K., Kolpin, D.W., Furlong, E.T., Zaugg, S.D., Meyer, M.T, Barber, L.B. 2008. A 

national reconnaissance of pharmaceuticals and other organic wastewater contaminants in 

the United States — I) Groundwater. Sci. Total Environ. 402:192-200.

Bartha, B., C. Huber, R. Harpaitner, and P. Schröder. 2010. Effects of acetaminophen in 

Brassica juncea L. Czern.: Investigation of uptake, translocation, detoxification, and the 

induced defense pathways. Environ. Sci. Pollut. Res. 17:1553-1562.

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Calleja, M.C., G. Persoone, and P. Geladi. 1993. The predictive potential of a battery of 

ecotoxicological tests for human acute toxicity, as evaluated with the first 50 MEIC 

chemicals. ATLA 21:330-349.

Colvin, B.A., M.W. Fall, L.A. Fitzgerald, and L.L. Loope. 2005. Review of brown treesnake 

problems and control programs: Report of observations and recommendations. U.S. 

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Connors, K.A., Gordon, L.A., and Valentino, J.S. 1986. Chemical Stability of Pharmaceuticals: 

A Handbook for Pharmacists. 2nd Ed. John Wiley & Sons, New York, pp. 163.

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snakes on Guam: Evaluation of baits, snake residues, and potential primary and 

secondary hazards. Environ. Sci. Technol. 36(17):3827-3833.

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31

Citations of Studies Submitted by the Registrant

MRID NO. STUDY IDENTIFICATION

457167-00 USDA Animal and Plant Health Inspection Service (2002) Submission of Product 

Chemistry, Efficacy and Toxicity Data in Support of the Application for 

Registration of Acetaminophen for Brown Treesnake Control. Transmittal of 15 

Studies. 2 pp.

457167-01 Petersen, B.; Hurley, J. (2002) Product Identity and Composition: "Acetaminophen 

for Brown Treesnake Control": Lab Project Number: QA-900. Unpublished study 

prepared by National Wildlife Research Center. 17 p. {OPPTS 830.1550}

457167-08 Petersen, B.; Eisemann, J. (2002) Acetaminophen Data Requirements: Product 

Physical and Chemical Characteristics: Lab Project Number: QA-900. Unpublished 

study prepared by National Wildlife Research Center. 89 p. {OPPTS 830.6302, 

830.6303, 830.6320, 830.7000, 830.7200, 830.7300, 830.7370, 830.7840, 

830.7950} 

457167-11 Petersen, B.; Eisemann, J. (2002) Acetaminophen Data Requirements: Ecological 

Effects: Lab Project Number: QA-900. Unpublished study prepared by National 

Wildlife Research Center. 57 p.

457167-12 Gallagher, S.; Beavers, J. (2001) Acetaminophen: An Acute Oral Toxicity Study 

with the Northern Bobwhite: Lab Project Number: QA-922: 247-105. Unpublished 

study prepared by Wildlife International, Ltd. 32 p. {OPPTS 850.2100}

457167-13 Miller, V. (2002) Acetaminophen--Dietary Toxicity Test With the Mallard Duck 

(Anas Platyrhynchos): Lab Project Number: 13777.4101: QA-903. Unpublished 

study prepared by Springborn Smithers Laboratories. 147 p.

457167-15 Petersen, B.; Eisemann, J. (2002) Acetaminophen Data Requirements: Human 

Health Effects: Lab Project Number: QA-900. Unpublished study prepared by 

National Wildlife Research Center. 1112 p. {OPPTS 870.1100, 870.1200, 

870.1300, 870.2400, 870.2500, 870.2600, 870.3100, 870.5265, 870.5375, 

870.5900, 870.6100, 870.7485}

457176-01 Miller, V. (2002) Acetaminophen--Dietary Toxicity Test with the Northern 

Bobwhite Quail (Colinus virginianus): Lab Project Number: 13777.4100: QA-902: 

13772.4100. Unpublished study prepared by Springborn Smithers Laboratories. 

138 p.