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],** 

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Environmental Risk Branch 3 E:o.vironmental Fate and Effects Division
Office of Pesticide Programs**~**

Nicholas Mastrota, Ph.D., Wildlife**Biologis ~**  James K. Wolf, Ph.D., Environmental Scientist Environmental Risk Branch 3

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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.

12 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 tree snakes 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 cons idered 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 , i n pa rticular native species that may feed on the baited mouse pups or scavenge on dead snakes . As all of the mammal ian predators on these islands are exotic invasive species that are considered pests , the assessment will focus on native birds and terrestrial c rabs. 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 exposu re ( consumption of contaminated snake s)

. 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. 1 03

- 90

- 2 )

Prepared by: Nicholas Mastrota

, Ph.D., Biologist James K. Wolf , Ph.D.

, Environmental Scientist U. S. Environmental Protection Agency Office of Pestic ide 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 Polluti on Prevention4 

### 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 Terrestri al 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 Terrest rial 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

................................ ................................ ................................ ........................ 275 

### 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 artic ulates 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 ( US EPA, 1998). The action area for this assessment is the U.S. Territory of Guam (Guam) a nd 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 spe cies 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 re gistered 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 endange red 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 p

aminophenol and an aqueous solution of acetic anhydride. Acetaminophen is an odorless, slightly bitter tast ing white crystalline powder

. Acetaminophen , also known as paracetamol, is commonly used as a nonprescription analgesic and anti pyretic drug similar to aspirin . It is the active ingredient (a.i.) of over

- the

- counter pain

- relief medication s ( e.g. , Tylenol ® ).

T he only registered pesticidal use of acetaminophen is for brown treesnake control on Guam and the CNMI (EPA Reg. No. 56228

- 3 4)

. 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 b rown t reesnake on Guam and the CNMI. APHIS reapplied for a new exemption for t he same use in July 2002 (MRID 45716700). Acetaminophen was conditionally registered on March 21, 2003.

Series 835 environmental fate g uideline studies were not submitted by the registrant (USDA/APHIS) ; however

, they did submit l imited 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 ), leach ing/adsorption/desorption (163

- 1 /835.1230 ), and terrestrial field dissipation (164

- 1 /835.6100 ) studies (May 31, 2002). Additional environmental fate data w ere not requested at the time of registration because of the limited use area and the fact that the p harmaceutical use of acetaminophen far exceeds the pesticidal use to control b rown t reesnakes. EFED identified addition al fate data in public literature

, which w ere also considered (Table III.1)

. A number of the m onitoring studies which have identified the presence of a number of pharmaceuticals, including acetaminophen, in surface water, ground water, and sewage treatment plants (STP s ) are discussed later in this document (Table III.2)

.
In 2001, the registrant submitted data to the Agency on the ecologica l 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 b e 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 20 01 , 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 init i ally considered for regist ration in 2002 (DP Barcode D286627). Th e regulatory decision at that time was that the use of acetaminoph en 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 o f 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 summarize d in Table III.1 and briefly discussed in the follo wing 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 commoditi es, 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 C 8 H 9 NO 2 MRID 457167

- 08

Mo lecular 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 K ow 0.27

0.46 Yamamato et al

. , 2005
Hari et al., 2005

K oc (organic carbon normalized partition coeffi cient) 2.7(±0.0) x10 2 L/kg oc (soil; %OC=2.7) 3.3 (±0.9) x10 3 L/kg oc (river sediment; %OC=0.79%) Yamamato et al., 2005

K d 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 depe ndent 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 stabil ity 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 CO 2 ], resulting in a DT 50 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 po nd water samples stored in the dark. Degradation was observed to occur when exposed to direct or indirect light

, s uggesting that exposure to sunlight is an important process in the degradation of acetaminophen. The average half

- li ves [t 1⁄2 ] of acetaminophe n at four treatment levels (n=4) were 1.1, 0.7, 0.9 and 1.0 days for ultra

- high to low treatment concentrations 1 . 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 t he CNMI , acetaminophen is also a widely used pharmaceutical. The pharmaceutical use can also introduce acetaminophen into the environment in several ways. One important path way is through discharge of acetaminophen residues remaining in treated effluent fr om 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 micro

contaminants (Kinney et al., 2006). Septic system effluent discha rge 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 acetamin ophen, 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 d issipation), 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, pK a (~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 p H 7) to two pure minerals (silica and alumina) and a hydrophobic medium (Porapak P 2 ). Yamamato et al. (2005) reported mean K d of 7.7 and 2.6 L/kg and K oc of 270 and 330 for Elliot Silt Loam soil and Suwannee River sediment, respectively. In order to standa rdize the qualitative

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

, 99 th , 99.5 th , 99.9 th ) 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 Nati ons (Bradbury, 2006 ). Based upon this scheme, acetaminophen would be classified with a medium mobility class (K oc range of 150 to 500).

The length of time, or persistence, that a pesticide or metabolism/transformation products will remain in the environm ent is influenced by both biotic and abiotic processes, sorption to soil material, and the environmental factor s (temperature, precipitation, length of day, water turbidity, etc.) which act upon the chemical. A cetaminophen is formulated as a tablet and th en 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 (Ko l pin 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 plant s (STP). These detects all are associated with the use of acetaminophen as a pharmaceutical product.

Table III.2

. A Select ion of Water Monitoring Studies, Water type, Frequency of Detecti on, and Maximum Acetaminophen (P aracetamol) Concentration

Study ID. Water Type (Location) Frequency of D etections (%) Maximum (μg/L)

Ko l pin et al . 2002 U.S. Streams susceptible to human, industrial, and agricultural wastewater 23.8 10.0

Lucia et al., 2010 S ewage T reatment P lants n s 1 4.3

Lucia et al., 2010 Surface water ns 1 78. 2
Kinney et al., 2006 Reclaimed water used for irrigation ns 1 65.3

F o cazio et al., 2008 Ground Water and Surface Water 2 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 sources10 2. Overview of Pesticide Usage

A s a pesticidal active

, a cetaminophen 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

a cetaminophen 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 membrane s 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.56 228

- 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 o f active ingredient (i.e., 40

- and 80

- mg a.i./tablet )

.
Acetaminophen for brown treesnake control requires that the acetamin ophen tablets be place d in a dead mouse pup to form a bait . The baits can be placed by ground or air. B roadcast application by air i s necessary for in accessible 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 acetaminoph en 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. Alternativ ely, 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 t he 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 pe riod, 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 sin gle 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 chil dren 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 ba its 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 co ntrol 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 b iological entity that is exposed to the stressor ( US EPA, 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 t errestrial 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. Gua m 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 rece ptors. 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 plant s are also potential recep tors.

Consistent with the process described in the Overview Document ( US EPA, 2004), th e planned risk assessment will use a surrogate species approach in its evaluation of acetaminophen

. Toxicological data generated from surrogate test species, which are i ntended 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 regis trant
, 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 acti ve ingredient, d egradates, 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 literatu re search engine for locating chemical toxicity data for aquatic life, terrestrial plants, and wildlife. The evaluation of both sources of data can also provide insight12 into the direct and indirect effects of acetaminophen on biotic communities from loss o f species that are sensitive to the chemical and from changes in structure and functional characteristics of the affecte d 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 dietar y 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 stud y (guideline number 850.2200) w as cond ucted 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 nont oxic.” 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 ( LD 50 r ange 1944 to 4450 mg/L, MRID 457167

- 15 )

. Acute t oxicity 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 op en literature. These studies are summarized in MRID 457167

- 11. The aquatic risk assessment will be based on the most sensitive aquatic invertebrate s pecies, the Sudanese fairy shrimp ( S treptocephoreum proboscideus ). A test with t he w aterflea ( Daphnia magna ), which is considered a preferred test species, has a n only slightly higher EC 50 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 LC 50 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 Toxicity 2 Citation MRID Acute Toxicity Classification

Birds 1 Northern Bobwhite ( Colinus vi r ginianus ) and Malla rd ( Anas platyrhynchos ) LD 50 > 2250 mg a.i./kg MRID 457167

- 12 (bobwhite) Practically

nont oxic LC 50 > 5000 mg a.i. /kg feed 3
NOAEC = 5000 mg a.i. /kg fee d 3 MRID 45717 6

- 01 (bobwhite) MRID 457167

- 13 (mallard)

Mammals Laboratory mouse ( M us musculus ) LD 50 = 338 mg a.i. /kg 95% CI : 306

- 373 mg a.i./kg MRID 457167

- 15 (Sta r mer et al.

, 1971) Moderately

t oxic

Freshwater invertebrates Sudanese fairy shrimp ( Str eptocephalus proboscideus ) EC 50 = 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 rept iles; fish serve as surrogate species for t he 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 value s obtained from sc ientifically 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

. , 200 4 ; Johnston et al

. , 2002) provide furth er information on the toxicity of acetaminophen to birds. O ne study examined the acute toxicity of acetaminophen to the fish crow ( Corvus ossifragus ), which served as a s urrogate for the endangered Mariana crow ( Corvus kubaryi ) of Guam. F ive crows were eac h 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 treesnake s. The study was then repeated with a dose of 4 tablets (160 m g/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, a ll five of the crows regurgitated the acetaminophen tablets. O ne 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 t he 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 c an be lethal. Th e s e limited finding s 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 b ody weight of approximately 300 mg ( NatureServe, 2011), admini stration 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 pick ed the acetaminophen tablets from the carcass and either set

t hem 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 i n one out of six instance s

. 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 repor t that summarizes data on chronic toxicity to mammals (MRID 457167

- 15). S ubmitted chronic studies that showed frank effects relatable to ecological risk, which include d 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 two

generation mouse reproduction toxicity study (National T oxicology Program

, 1984). The prenatal developmental study found that exposure at a daily dose of 250 mg/kg (approximately14 5000 mg/kg

- diet) caused a reduction in bodyweight and developmental abnormalities

. Exposure

at 140 mg/kg ( approximately 2800 mg/kg

- di et) did not affect bodyweight but did result in a low frequency of abnormalities. In the two

- generation reproduction study, the most sensitive endpoint s w ere body weights of F1 pups

. Exposure at 2500 mg/kg diet resulted in significant decreases in body we ights, 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

- 3 4% 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 studie s 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

use d as an approximate threshold of chro nic effects for assessing chronic risk to mammals.

One published paper provide d information on the toxicity of acetaminophen to terrestrial plants

. Bartha et al. (2009) studied the uptake, translocation, toxicity, and detoxification of acetaminophen in th e 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 w as found to cause oxidative stress th at 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 pigm ents (chlorophyll a, b, and caratenoids) showed a 50% decrease after 72 h and 70% decrease after 1 week. While this study show s that soil exposure to a 1 mM solution of acetaminophen may cause phytotoxicity to plants, the relationship of this exposure to e nvironmentally 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 br own treesnake will release acetaminophen into the terrestrial and freshwater environments. Terrestrial ecosystems would potentially be at risk because nontarget terrestrial animals may consume the bait ed mouse pups directly, or may consume living or dead s nakes 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 , be ing 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 ba it may result in a small amount of inadvertent placement of bait in freshwater bodies such as

streams
, ponds , and wetlands

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

. S ome exposure to freshwater eco systems 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 ecologic al 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

Assessmen t endpoints represent the actual environmental value that is to be protected, defined by an ecological entity (species, community, or other ecological entity) and its attribute s or characteristics ( US EPA, 1998). For the acetaminophen risk assessment , the e cological 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 e cosystem . Native species of terrestrial wildlife that the Agency expects to be exposed to acetaminophen by feeding on the baited mouse pups or scaveng ing on dead snakes are the Mariana crow ( Corvus kubaryi ), the Guam rail ( Gallirallus owstoni ) , and various crabs

. The only carnivorous an d 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 m onitor li zard ( 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 terre strial 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 

### V I. 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

en vironment 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 c onceptual 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 m ajor components: risk hypothesis and a conceptual diagram ( US EPA, 1998).

1. Risk Hypothesis

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

asses sment:

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 , in cluding organisms that are Federally

- listed as threatened and endangered species.

2. Conceptual Diagram

For the use of acetaminophen to control brown treesnake s, t he potential exposure pathways and effects to non

- target ter restrial and aquatic organisms and plants are depicted in Figure s 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 sig nificantly 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. T ransport mechanisms ( e.g

. , sources) for the s pecified use of acetaminophen may result in a small a mount 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 min or.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 expo sure 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 m echanism of transport. Because the acetaminophen is formulated in to tablets which are inserted in the bait (mouse pup s ) , 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 mi nor 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 expe cted 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 ecolo gical 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 tre esnake control are those that would directly consume the baited mouse pups (primary exposure)

, and those that might prey or scavenge on treesnake s that consume the bait (secondary exposure). As mentioned previously, the only native terrestrial

a nimals that a re expected to feed on either the mouse pups or the treesnake s 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 requi red. The Agency does not have standardized risk assessment methods for quantitatively assessing risk to terrestrial crabs. The refore

, a quantitative terrestrial risk assessment will be limited to avian risk assessments focused on the Mariana crow and the G uam 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 on19 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 acetaminop hen active ingredient 3 will be inserted in to 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 c ompared 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 woul d be expected to consume in one day. The la t ter 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. ( 200 2 ). 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 th e s e endpoint is non

definitive, the RQ s 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 f

actors 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 exp osure of birds to acetaminophen. Avery et al. (200 4 ) 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. A voidance and

regurg itation response s 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 acces s 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 fis h crows to bait stations with a mouse pup inserted half

way in the pipe. The y tested bait stations were PV C pipes at the extremes of the recommended dimensions (2 or 4 inches in diameter, and 12 o r 18 inches long). They found that the longer pipes signific antly reduced the total number of pups that were accessed. They found that some crows succeeded i n 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 ingredi ent unless the registrant informs us otherwise.20 pups by the Mariana crow

, but they would no t eliminate it unless the y 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, t he feeding behavior of the Guam rail and the land crabs of Guam will be investigated to evaluate the potential for th e s e 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 a ssessment will be conducted to assess risk to birds from secondary exposure

, which would occur when a bird ingest s the tissue of brown treesnake s 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 LD 50 value (using dose

- based RQs) and the avian dietary LC 50 values (using dietary

- based RQs). All of the daily food intake of these birds will be assumed to be composed of brown treesnake s that have recently been poisoned by acetaminophen. The acetaminophen concentrations in tissue of brown treesnake s will be based on measured tissue concentrations published in Johnston et al. (2002) , Primus et al. (2004), or other available published data. T he 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 LC 50 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 u se of acetaminophen to control the brown treesnake incur s considerable benefits to the sur vival 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 analys e s, 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

M ethods t raditional ly u sed to estimate aquatic exposure from typical application s of agricultural pesticides are not appropriate for estimating exposure from the use of acetaminophen in bait for

tree snake control . The bait will be distributed in tablets that will be place d insid e 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 on to soil o r foliage as a21 spray or granule. Much of the distributed bait is expected to be consumed by brown treesnake s 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 soi l. 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 t hat 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 wors t

- 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 E nvironmental Hazard s section of the label con tains 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 rainw ater 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 LC 50 of 29.5 mg a.i./ L for the Sudanese fairy shrimp, t he 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 = 37 0 0 pups

This calcul ation shows that 370 0 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 treesnake s, the Agency believes

t hat the number of pups that would inadvertently reach a pond from the registered use likely would be well below this number . Thus, the Agency belie ves 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 any22 further aquatic risk assessment will be ne ed ed 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 place d 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 treesnake s 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 sim ilar 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 Spe cies 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

are a. The action area is considered the area directly or indirectly affected by the federal action, as23 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 are a 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 thr eshold. 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 long

range atmospheric t ransport, 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 hab itat, 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 o r 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 thre atened 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 f r uit 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 treesnake s (Johnston et al.

, 2002).

Three species of endangered plants occur on these islands. Serianthes n elsonii 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. Ho wever, 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
I slands, 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 th e Hawaiian hawk ( Buteo solitaries ).

Table VIII.1. Federally L isted T hreatened and E ndangered S pecies Occurring in Guam and the24 Commonwealth of the Northern Mariana Islands (CNMI) (based on USFWS, 2011)

Common Name Scientific Name Federal Listing Distri bution Critical Habitat Guam CNMI
Mammals Bat, Little Mariana Fruit Pteropus tokudae Endangered X ND 2

Bat, Mariana Fruit Pteropus mariannus mariannus Threatened X X Guam

Birds Crow, Mariana Corvus kubaryl Endangered X X Guam, Rota 3 Kingfisher, Guam Micronesian Todiramphus cinnamominus cinnamominus Endangered X 1 ND 2

Moorhen, Mariana Common Gallinula chloropus guami Endangered X X ND 2

Rail, Guam Gallirallus owstoni Endangered X 1 ND 2

Reed

- Warbler, Nightingale Acrocephalus luscinia Endangered X 1 ND 2

Swiftlet, Mariana Aerodramus bartschi Endangered X X ND 2

White

- eye, Guam Bridled Zosterops conspicillatus conspicillatus Endangered X ND 2

White

- eye, Rota Zosterops rotensis Endangered X ND 2 Reptiles Turtle, Green Sea Chelonia mydas Threatene d X X ND 2 Turtle, Hawkbill Eretmochelys imbricate Endangered X ND 2

Plants Hayun Lagu (Guam) Tronkon Guafi (Rota) Serianthes nelsonii Endangered X X ND 2

(No common name) Nesofenes rotensis Endangered X ND 2 (No common name) Osmoxylon mariannense Endan gered X ND 2

1 Ext ir pated 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 ; EF ED 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 identi fied as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act 4

. In addition, n o Total Maximum Daily Load s (TMDL) have been developed for acetaminophen 5 . More information on impaired water bodies and TMD Ls can be found at the Agency’s website 6

. 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 th is pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impa ired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 7 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 ef fect 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 horm onal 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 subst ance, 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 a s 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 we bsite 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 batter y, can also be found at this website

.



### XI I

. 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 contro lling 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 us eful for assessing ecological risk (MRID 457167

- 11). One of these

7 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm26 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 regis trant 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 treesnake s. 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 dat a for assessing risk to birds f rom acute exposure to acetaminophen have been submitted (MRID 457167

- 12, 457167

- 13, and 457176

- 01). A vian reproduction studies with acetaminophen are not needed. A reproduction study with mammals found that exposure to acetaminophen did not cause any adver se 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. T he target species of this use, the brown treesnake

, is known

to ca use 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 av ian 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 mou se 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 t herefore no additional data on the toxicity of acetaminophen to aquatic organisms are required.

As described in Section VI I.3, t he Agency presumes that this use of acetaminophen for control of the brown treesnake will pose mi n imal 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 

### XII I

. 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.



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MRID NO. STUDY IDENTIFICATION

457167

- 00 USDA Animal and Plant Health Inspection Service (2002) Su bmission 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 p p

.

457167

- 01 Petersen, B.; Hurley, J. (2002) Product Identity and Composit ion: "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 Phy sical 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 Toxicit y 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 Platyrh ynchos): Lab Project Number: 13777.4101: QA

- 903. Unpublished study prepared by Springborn Smithers Laboratories. 147 p.

4 57167

- 15 Petersen, B.; Eisemann, J. (2002) Acetaminophen Data Requirements: Human Health Effects: Lab Project Number: QA

- 900. Unpublis hed 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 Tes t 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.