UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON D.C., 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

PC Code: 109509

DP Barcode: D399850 April 24, 2013

MEMORANDUM

SUBJECT:

FROM: Preliminary Ecological Risk and Endangered Species Assessment in Support of

the Registration Review of Acetaminophen

F. Nicholas Mastrota, Ph.D., Wildlife Biologist

# ~**~** 'f/J.'-1/13

James K. Wolf, Ph.D., Environmental Scientist

### ~(**W~** Rosanna Louie-Juzwiak, Risk Assessment Process L Va" der /1) ]

, ___ ,_ • 

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Environmental Risk Branch 3

### V~ 

### Z'1J 

### B

Environmental Fate and Effect Division
Office of Pesticide Programs

THROUGH: Dana Spatz, Branch Chief

### ~~--....~~'- Melissa Panger, Ph.D., Senior Biologist

James Hetrick, Ph.D., Senior Advisor

Environmental Risk Branch 3
Environmental Fate and Effects Division

TO: Bonnie Adler, Chemical Review Manager
Linda Arrington, Acting Chief

Risk Management and Implementation Branch 5

Pesticide Re-Evaluation Division (7508P)

This memorandum transmits the preliminary ecological risk and endangered species assessment
in support of the registration review of the use of acetaminophen for control of the brown tree
snake in Guam. Based on currently registered uses and labeled use information, this assessment presents the draft conclusions of potential risks to non-target organisms, including listed species

in Guam and the Commonwealth of the Northern Mariana Islands (CNMI). Currently, the brown

tree snake is only found in Guam, and is the action area that is the focus of this assessment when considering potential exposure to non-target organisms, including endangered species.

With the limited and transient exposure expected from acetaminophen uses (i.e

. , in baited mice),

EPA believes that a "no effect" determination can be made for all aquatic organisms.

12 Based on available data, there is a potential for smaller mammals to be exposed to an amount of acetaminophen that could exceed the acute level of concern for both nonlisted and listed
mammals

. Concerning listed mammals, the two endangered mammals found in Guam are bats that only feed on fruit and other plant matter. Therefore, EPA believes that adverse effects to the
listed fruit bats are not reasonably expected to occur because exposure is an ticipated to be
limited.

While there is a potential for birds that feed on carrion (and swallow an entire acetaminophen bait) to be exposed to acetaminophen, all known listed birds have since either been extirpated from Guam, or are in captivity ; theref ore, any inadvertent exposure of acetaminophen to listed
birds is not expected ( i.e. , will not be exposed to mouse pup carrion) that are used in the baiting programs to control the brown tree snake.

Exposure of other nontarget terrestrial organisms ( i.e. , insects and plants) to acetaminophen residues is expected to be low as a result of its consumption by the brown tree snake and other carrion feeders, as well as its decomposition in the environment. Thus, adverse effects are not reasonably expected to o ccur.

The conclusions of this assessment are consistent with the findings in the November 2, 2011 U.S.
Fish and W ildlife S ervice Biological Opinion (USFWS BiOp) issued as a result of the formal
consultation b etween the USDA APHIS Wildlife Service (USDA W S) and the USFWS on the pesticidal use of acetaminophen to control the brown tree snake in Guam.3 

## The Preliminary Ecological Risk and Endangered Species Assessment in Support of the Registration Review of

Acetaminophen (Paracetamol)
PC Code 109509

(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 Rosanna Louie

- Juzwiak, RAPL

Reviewed by: Melissa Panger, Ph.D., Senior Biologist
James A. Hetrick, Ph.D., Senior Advisor

Approved by: Dana S. Spatz, Branch Chief

April 26, 201 3 

### Office of Chemical Safety and Pollution Prevention4 

### Table of Contents

1.0 Executive Summary ............................................................................................................. 5

1.1 Nature of Chemical Stressor ............................................................................................ 5

1.2 Summary of Effects and Risk Conclusions ...................................................................... 5

1.3 Potential Risk to Federally Listed Threatened or Endangered Species ........................... 6

2.0 Problem Formulation ........................................................................................................... 7

2.1 Nature of Regulatory Action ............................................................................................ 7

2.2 Nature of Chemical Stressor ............................................................................................ 8

2.3 Overview of Pesticide Usage ........................................................................................... 8

2.4 Ecosystems Potentially at Risk ........................................................................................ 9

2.5 Receptors .......................................................................................................................... 9

3.0 Exposure Assessm ent......................................................................................................... 10

3.1 Environmental Fate and Transport Characterization ..................................................... 10

4.0 Effects Characterization ..................................................................................................... 14

5.0 Risk Characterization ......................................................................................................... 17

Risk Estimation and Risk Description ............................................................................... 17

5.1 Risk to Terrestrial Animals ............................................................................................ 17

Mammals .............................................................................................................................. 17

Birds, Reptiles and Terrestrial

- Phase Amphibians .......................................................... 17

Invertebrates ....................................................................................................................... 19

5.2 Risk to Aquatic Organisms ............................................................................................ 19

5.3 Risk to Terrestrial Plants ................................................................................................ 20

6.0 Endangered Species Assessment ....................................................................................... 20

6.1 Formal Consultation on the Aerial Application of Acetaminophen for Brown Treesnake
Control on Guam ....................................................................................................................... 24

7.0 References .......................................................................................................................... 265 

### 1.0 Executive Summary

1.1 Nature of Chemical Stressor

Acetaminophen, N

- (4 -Hydroxyphenyl ) acetamide, is derived from the interaction of p

aminophenol and an aqueous solution of acetic anhydride. Acetaminophen, also known as paracetamol, is commonly used as a nonprescription analgesic and antipyretic d rug similar to aspirin. It is the active ingredient (a.i.) of several over- the -counter pain- relief medications ( e.g., Tylenol ® ). The only registered pesticidal use of acetaminophen is for brown tree snake ( Boiga irregularis ) control on Guam and the Commonw ealth of the Northern Mariana Islands ( CNMI ) (EPA Reg. No. 56228-34). The use involves inserting acetaminophen tablets in a dead mouse pup to form a bait, which is then consumed by the brown tree snake . The baits can be placed by ground or air.

The mode of action of acetaminophen in the tree snake is not completely understood, but is believed to be the result of induced hepatic (liver) necrosis, as in mammals (MRID 45716714,
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).

1.2 Summary of Effects and Risk Conclusions

Aquatic Organisms

The registered use of acetaminophen in baits for control of the brown tree snake is not predicted to result in significant exposure to aquatic organisms from any mec hanism of transport.

Available submitted data on acetaminophen toxicity to aquatic species are limited to acute toxicity tests with aquatic invertebrates published in the open literature (MRID 45716711). The aquatic risk assessment is based on the most se nsitive aquatic invertebrate species, the Sudanese fairy shrimp (S treptocephoreum proboscideus ). A test with the waterflea ( Daphnia magna ), which is considered a preferred test species, has an 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 ac ute toxicity to fish or
marine/ estuarine invertebrates.

Terrestrial Organisms

The use of acetaminophen for brown tree snake control is expected to result in minimal exposure to terrestrial plants and animals, with the possible except ion of exposure to animals that may feed
on the baited mouse pups. There is a potential for terrestrial invertebrates to be exposed, including insects and land crabs, which are commonly found on Guam. However, given the limited and targeted application area, and the relatively short period of time that the acetaminophen -containing baits are expected to persist in the environment (approximately one week) due to scavengers eating mouse pups, picking around the acetaminophen tablet, such as land crabs, or degradation in the environment (USFWS BiOp, 2011), any direct exposure is6 expected to be very limited and negligible. Albeit an atypical behavior, available avian studies show that there may be rare behavior that could occasionally lead to an exposure that reaches a toxic dose ( i.e. , swallow the entire baited mouse, rather than pick at the carcass around the acetaminophen tablet).

The ava ilable acute toxicity data on acetaminophen indicate that it is categorized as practically nontoxic to birds, and moderately toxic to mammals. Due to potential concerns for exposure to listed birds ( i.e. , the Mariana crow

, Corvus kubaryl ), additional studi es conducted on surrogate birds ( i.e. , fish crow), to examine the potential acute toxicity from acetaminophen. Although regurgitation was observed in the majority of birds dosed (at 80 mg a.i./kg and 160 mg a.i./kg doses), one bird did die at the higher do se after repeated regurgitation, which also retained the highest percentage of the administered dose (75%). One published paper studied the toxicity of acetaminophen to terrestrial plants in the Indian mustard ( Brassica juncea ), showing that exposure to a 1mM solution of acetaminophen in soil may cause phytotoxicity to dicots ; however, it is unknown how soil exposure relates to environmentally relevant exposure levels resulting from acetaminophen baits, and the tablets became ex posed to the environment.

1.3 Potential Risk to Federally Listed Threatened or Endangered Species

The results of this preliminary risk assessment on the use of acetaminophen to control brown tree snake s indicate that , with the exception of potential risk to ce rtain

- sized mammals and birds, all other exposures to terrestrial organisms are below the EPA’s level s of concern. Currently, the two endangered mammals found on Guam are the Mariana f ruit bat ( Pteropus mariannus ) and
the Little Mariana f ruit bat ( Pteropus tokudae ). These two bats are not expected to be directly exposed to acetaminophen, as they only feed on plants (primarily fruit). In the 2011 BiOp, the
USFWS determined that, while aerial applications may adversely impact the Mariana fruit bat from a potential collision with a helicopter, this exposure is discountable. EPA expects that the same potential exposure and conclusions would apply to the Little Mariana f ruit bat. The only listed plant identified in Guam is the Serianthes nelsonii tree; however, a s determined in the 2011 USFWS BiOp, because of the proximity of the acetaminophen applications relative to the location of the tree, no adverse effects are expected

.

The November 2, 2011 USFWS BiOp concluded that while there is a potential to impact the

M ariana crow, this use will not jeopardize their survival or recovery in the wild, nor will their
critical habitat be affected.

Any potential acetaminophen exposure to aquatic organisms is expected to be very limited and below levels of concern; therefore, EFED concludes that there is a “no effect” for all listed aquatic species and their designated critical habitat. The potential for effects to listed species
from the assessed use are summarized in the table below ( Table 1 ). Aside from the conclusions
described for the Mariana fruit bat, the Little Mariana f ruit bat, and the Mariana crow, t he proposed use of acetominophen for brown tree snake control is not expected to result in adverse direct or indirect effects to any other federally listed threatened or endangered species ( Table 1 ).7 Table 1 . Potential Effects to Federally Listed Taxa Associated with Direct or Indirect Effects from the Use of
Acet a minophen for Brown Tree snake Control

Listed Taxon Direct Effects Indirect Effects

Aquatic nonvascular plants No No
Aquatic vascular plants No No

Freshwater fish No No
Amphibians, Aquatic

- phase No No

Freshwater Invertebrates No No

Marine/estuarine fish No No

Marine/estuarine invertebrates No No

Birds Yes* No

Mammals No No
Reptiles No No
Amphibians, Terrestrial

- phase No No

Terrestrial Invertebrates No No

Terrestrial Plants No No

* As discussed in the November 2, 2011 USFWS Biological Opinion, w hile there is a potential to impact the
Mariana crow

, the registered use of acetaminophen to control the Brown tree snake in Guam will not jeopardize their survival or recovery in the wild, nor will their critical habitat be affected. Additionally, as the Mariana crow was not observed during multiple recent s urveys of known habitat in Guam, USFWS believes that there are no
Mariana crows remaining in the wild, and only exists in captivity ( Earl Campbell, USFWS, personal communication).



### 2.0 Problem Formulation

Problem formulation provides a strategic framework for the risk assessment. By identifying the important components of the problem, it focuses the assessment on the most relevant chemical properties, exposure routes, and endpoints.

2.1 Nature of Regulatory Action

As part of the implementation of the Registrat ion Review program pursuant to Section 3(g) of FIFRA, the Agency is evaluating all curren t and active pesticide registrations for acetaminophen to determine whether it continues to meet the FIFRA standard for registration. The structure of
this risk asses sment is based on guidance contained in the Overview Document (USEPA, 2004)
and the U.S. EPA’s Guidance for Ecological Risk Assessment (USEPA , 1998a ).

The registration review ecological risk assessment consider s only the pesticidal use of acetaminophen as an active ingredient for the control of the brown tree snake . However, it should be stressed that the non-pesticidal use of acetaminophen is expected to dominate both human and wildlife exposure to this chemical. The only registered pesticidal use of acetaminophen is for brown tree snake control on Guam and the Commonwealth of the Northern
Mariana Islands ( CNMI ). Guam is currently the only place where acetaminophen is used for
brown tree snake control, and is the focus of the regulatory action being assessed.8 Although the use of acetaminophen is currently registered for use in Guam and the CNMI, EPA considers the action area for the registered use of acetaminophen for control of the brown tree
snake to be Guam. Presently, this is the only place in the United States or its territories where the brown tree snake is established. Should a need arise in the future to use the product in other locations, an ecological risk assessment and endangered species effects det ermination may need
to be conducted for the additional locations. For example , a risk exists for possible invasion of the brown tree snake in the state of Hawaii, where active prevention programs are currently in place (Colvin et al ., 2005).

2.2 Nature of Chemical Stressor

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 ). 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).

2.3 Overview of Pesticide Usage

Acetaminophen is an active ingredient in a product used only by wildlife managers to control the
brown tree snake in Guam and the CNMI. The directions for use on the product label states that the acetaminophen tablets be placed in a dead mouse pup to form a bait, which is then consumed by the brown tree snake. The baits can be placed by ground or air. In the 2011 USDA- WS Environmental Assessment, b roadcast application by air (via helicopter) was said to be necessary for inaccessible areas. Generally the intent is to suspend the baits in the tree canopy in order to maximize exposure to the target pest, i.e. , the brown tree snake.

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 of9 netting or other material to the bait. During one baiting period, apply no more than 90 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.

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 con taminate 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.

2.4 Ecosystems Potentially at Risk

The distrib ution of mouse pup bait containing acetaminophen tablets for control of the brown
tree snake is expected to release acetaminophen into the terrestrial and freshwater environments. Terrestrial ecosystems would potentially be at risk because non

- target terrestrial animals may consume the baited mouse pups directly, or by secondary exposure by consuming living or dead
snakes or other animals that have ingested the bait. Some acetaminophen may 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 tree snake
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 fall in gullie s where runoff may wash it into streams, ponds, wetlands and lakes. Some exposure to freshwater ecosystems on treated islands therefore may occur.

Residues of acetaminophen that enter flowing freshwater would drain into estuaries and marine
habitats. Howev er, 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 a nd marine habitats is expected to be very small.

2.5 Receptors

In ecological risk assessment, t he receptor is the biological entity that is exposed to the stressor (USEPA, 1998). For t he use of acetaminophen (the stressor) in bait targeting the brown tree snake, the highest potential for nontarget exposure is expected to be to terrestrial wildlife

, including birds, mammals, reptiles, terrestrial

- phase amphibians, and terrestrial invertebrates ( e. g. , land crabs). In particular, predator and scavenger species are the most significant potential
nontarget receptors because they may be exposed to a large dose of acetaminophen if they consume the dead mouse pups with the acetaminophen tablets intact , or if they consume live or
dead snakes that have ingested the bait. Soil and aquatic habitat may be exposed as residues that10 can leach out of the remaining bait s and carcasses of dead snakes, or are excreted by animals that consume the bait. Therefore, soil invertebrates and aquatic organisms are a lso potential
receptors.

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 ac etaminophen risk assessment, the ecological entities include all species of animals and plants inhabiting Guam and the CNMI. The attributes for each of the ecological entities may include growth, reproduction, and survival.



### 3.0 Exposure Assessment

The registe red use of acetaminophen in bait for the brown tree snake is not predicted to result in significant exposure to aquatic organisms from any mechanism of transport. Because the acetaminophen is formulated into tablets that 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, any volatilization and inhalation exposure are expected to be negligible. A ny remaining baits not consumed by the target pest or other opportunistic feeders may result in some amount s, albeit small , of acetaminophen to potentially leach out of the baited mouse pups into the soil, and then may be transported to water via surface runoff; however, this route is expected to result in trivial 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.

3.1 Environmental Fate and Transport Characterization

Physical and Chemical Properties

Acetaminophen is a white, highly water soluble (12,780 μg/L), odorless crystalline powder. A

sat urated 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). Acetaminophen (paracetamol) is rapidly transformed i n water into volatile transformation products (TP) [undefined TP except for CO 2 ], resulting in a DT 50 of 3.1 days. Acetaminophen is highly persistent and mobile in soil. Upon contact with the sediment, the majority of acetaminophen was bound to the sediment as non- extractable residues. 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. 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 s unlight is an important process in the degradation of acetaminophen.

Physical/chemical properties and environmental fate data available for acetaminophen are
summarized in Table 2 and briefly discussed in the following section. The USDA Animal and Plant Health Inspection Services (APHIS) requested data waivers for the following guideline environmental fate studies (hydrolysis, photodegradation in water, aerobic soil metabolism,11 leaching/adsorption/desorption, and field dissipation-soil studies (2002). They submitted (MRID 45716708) data from other sources to address the environmental fate and transport of data requirements for acetaminophen. The Agency also considered data available in literature ( Table
2 ). The structure of acetaminophen is shown in Figure 3

.

Table 2 . Physical and Chemical Properties of Acetaminophen
Property Value Source of Information

Common name Acetaminophen (Paracetamol)

Chemical name N- (4

- hydroxyphenyl)

- acetamide

N- (4

- hydroxyphenyl)acetamide

N

- acetyl

- p

- aminophenol MRID 45716708

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 tree snake in Guam or the
Commonwealth of Northern Mariana
Islands.

Chemical class p

- aminophenol, acetic anhydride MRID 45716708

CAS number 103

- 90

- 2 MRID 45716708
Empirical formula C 8 H 9 NO 2 MRID 45716708
Molecular mass (g/mol) 151.16 MRID 45716708;
El

- Obeid and Al

- Badr, 1985.
Vapor pressure 1.65 x 10
- 7 mmHg to 0.0005 mmHg for the temperature range 40°C to 74°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 coefficient) 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 dependent charge) Yamamato et al ., 2005

Lorphensri et al ., 200612 Figure 1

. Chemical s tructure of a cetaminophen

.

T he 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 t o water, soil, or vegetation. Therefore, while in the bait, photolysis is not 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. When exposed to the environment,

a cetamino phen 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.

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 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 [t 1⁄2 ] 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 concentrations 1 . The overall average half -life was 0.9 ± 0.2 days.

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

,13 In addition to the pesticidal use of acetaminophen to control brown tree snake s 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 micro

contaminants (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 tha t 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 a l ., 2006). Lorphensri et al . (2006) found that acetaminophen showed no sorption (@ pH 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 standardize the qualitative descriptors used to report the chemical mobility in soil of pesticides in exposure assessments, the Agency has adopted the standard ized 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 (K
oc range of 150 to 500).

Monitoring Data

Acetaminophen has been included in a number of surface and ground water monitoring programs designed to evaluate the occurrence of pharmaceuticals in water ( Table 3 ). The maximum surface water concentration was 10 μg/L and the maximum ground water concentration was 8.1 μg/L. The source of acetaminophen in these studies was from the pharmaceutical use (no monitoring data from Guam). The highest conce ntration detection was 78.2 μg/L from a sewage treatment plant (STP) discharge

.

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 ultra high treatment levels, respectively (Lam et al ., 2004).

2 Porapak P is a cross

- linked polymer of divinyl

- benzene/styrene purchased from Supelco.14 Table 3

. Summary of acetaminophen in detected in drinking, ground and surface water, and waste water.

Study Water Type Number of Samples Percent
Detections Maximum
Detection (μg/L) Reporting
Limit (μg/L)

Barnes et al ., 2004 Ground Water 5 0 0 0.009

Barnes et al ., 2008 Ground Water 47 6.4 0.38 0.009 Kolpin et al ., 2002 Surface Water 84 23.8 10 0.009

Focazio et al . 2008 Ground/Surface 74 23 8.1 0.009
Fram and Belitz, 2011 Ground Water 1231 0.32 1.89 0.06

Lee et al ., 2004 All water 1 131 15.3 16.0 0.009

Lucia et al ., 2010 Surface (STP) 2

- 3

- 78.2

- 1 Waste water, surface, ground and drinking water.

2 STP- Sewage Treatment Plant discharge

3

– not specified



### 4.0 Effects Characterization

Table 4 provides a summary of acute toxicity findings for taxonomic groups, along with their corresponding surrogate species, that the Agency used to assess acute risk of acetaminophen to non-target animals. In addition, the table provides an overview of acute toxicity classifications based on these findings. Results for acute oral and sub- acute dietary toxicit y 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.” Re sults 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 range 1944 to 4450 mg/L, MRID 45716715). 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 45716711. The aquatic risk assessment will be based on the most sensitive aquatic invertebrate species, the Sudanese fairy shrimp (S treptocephoreum proboscideus ). A test with the waterflea ( Daphnia magna ), which is considered a preferred test species, has an 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 t oxicity to fish or marine/
estuarine invertebrates.

The toxicity values that ar e used in the risk assessment are the most sensitive 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 4

.15 Table 4 . Test Species Evaluated for Assessing Potential Ecologic al 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 virginianus)
and Mallard ( Anas platyrhynchos ) LD 50 > 2250 mg a.i./kg
NOAEL = 2250 mg a.i./kg MRID 45716712 (bobwhite) Practically
nontoxic LC 50 > 5000 mg a.i./kg feed 3

NOAEC = 5000 mg a.i./kg
feed 3 MRID 45717601 (bobwhite)
MRID 45716713 (mallard)

Mammals Laboratory mouse (Mus musculus) LD 50 = 338 mg a.i./kg
95% CI : 306
- 373 mg a.i./kg MRID 45716715 (Starmer et al

., 1971) Moderately
toxic

Freshwater
invertebrates Sudanese fairy shrimp (Streptocephalus proboscideus) EC 50 = 29.5 mg a.i. /L
95% CI : Not reported MRID 45716711 (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 no rthern bobwhite and mallard were identical.

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 tree snake s. 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 fiv e 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 ing estion of four 40- mg tablets can be lethal. 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

cro ws 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 45716712).

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 them16 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 limit 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 45716715). 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 ecologica l risk to mammals. Studies that 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 5000 mg/k g-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 lev el. 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 terre strial 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 in mice bait s is unknown.17 

### 5.0 Risk Characterization

Risk Estimation and Risk Description

Methods traditionally used to estimate aquatic and terrestrial exposure from typical applications of agricultural pesticides are not appropriate for estimating exposure from the use of acetaminophen in bait for tree snake control. The bait are distributed in tablets that are placed inside mouse pups, and therefore are not 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 spray or granule. Ther e fore, this use is expected to result in limited direct exposure to
terrestrial plants; likewise for terrestrial invertebrates , with the exception of larger scavenging terrestrial invertebrates ( e.g. , land crabs), very minimal exposure is expected

. Much of the distributed bait is expected to be consumed by brown tree snake s. 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. Models developed for agricultural uses of pesticides likely would greatly over estimate the amount of acetaminophen bait that would reach water bodies, and are therefore not used in
this assessment

. Specific details for terrestrial and aquatic environments are given in the following sections.

5.1 Risk to Terrestrial Animals

Mammals

When using a dose-based approach, one can estimate the number of baited mouse pups that a
mammal would need to consume to reach the LD 50 . The LD 50 for the laboratory mouse is 338 mg a.i./kg-BW (MRID 45716715); therefore, a 1,000-g sized mammal would need to ingest 4.2 tablets (or at least four baited mouse pups) to reach the LD 50 . However, when scaling the exposure to a smaller mammal ( e.g ., 50 grams), the LD 50 is 16.9 mg a.i./50-g mammal, which is less than one acetaminophen tablet. Therefore, since the required ingestion rates are plausible for both the small and larger mammals, there is potential concern for exposure to mammals if they were to consume acetaminophen -baited mouse pups.

Birds, Reptiles and Terrestrial

- Phase Amphibians

As a first

- tier risk assessment to estimate potential acute risk , exposure to birds is modeled based on the assumption that the baited mouse pups are consumed in entirety and that all of the active ingredient within the contained tablets is ingested. Avian reproduction studies with acetaminophen are not available , and therefore, is an uncertainty. Based on information provided on the label, 80 mg of acetaminophen active ingredient are inserted into each mouse pup in one
or two tablets. For calculating the dietary concentration of acetaminophen, the weight of a mouse pup is assumed to be 5 g ( i.e. , 0.005 kg), as was assumed in the previous published risk
assessment of Johnston et al. (2002). Thus, the dietary concentration of acetaminophen in the baited mouse pup is 80 mg a.i./0.00508 kg or 15.7 mg a.i./kg-diet. The dietary LC 50 for both the northern bobwhite and the mallard is >5000 mg a.i./kg-diet. Thus, the dietary RQ for a bird feeding directly on the baited mouse pup is 15.7/>5000, or < 0.003. Thus, based on the dietary18 ris k quotient assessment , acute risk to birds that may feed directly on the baited mouse pups is
below the EPA’s level of concern.

A single dose acute oral study with the northern bobwhite found that a dose of 2250 mg a.i./kg caused no mortality and no observ able adverse effects. As was calculated for estimating potential exposure to mammals, when using a dose- based approach, one can estimate the number of baited mouse pups that a bird would need to consume to reach the NOAEL dose. The Mariana crow will be used as a model species. The average body weight of an adult crow is 242 g for females and 256 g for males (USFWS, 2005) therefore t he average weight for females is
used in this risk assessment. The oral dose of a bird the size of a Mariana crow that swallows one baited mouse pup (containing 80 mg of acetaminophen) is 80 mg a.i./0.242 kg-BW or 331 mg a.i./kg-BW. Dividing the NOAEL dose, 2250 mg a.i./kg, by this dose for one mouse pup yields 6.81 . This dose

- based assessment indicates that a crow would need to consume seven or more whole baited mouse pups before there could be a level of concern exceedance

.

Pen studies with the fish crow (Avery et al. , 2004), which are discussed in Section 4.0 of this document, showed somewhat greater acute toxicity in this species than predicted by the quantitative risk assessment. In a trial in which five fish crows were force -fed 80 mg of acetaminophen, four of the birds appea red lethargic after dosing and three of the birds vomited, but all of them survived. In a second trial in which five fish crows were given a 160-mg dose, all of the birds regurgitated and one of the birds died. These results indicate that a crow

- sized bird may suffer sublethal effects from consuming one whole baited mouse pup, and could di e from consuming two whole mouse pups within a short period.

Another study looked at the behavioral response of fish crow to mouse pups baited with acetaminophen (Avery et al ., 2004; Johnston et al ., 2002). In this study, the majority of the birds tested (9 out of 10) did not swallow the whole mouse pup with the acetaminophen tablets intact, but rather tore the bait apart bit by bit and discarded the tablets with their bill.

A second factor that is expecte d to minimize exposure risk to birds is the use of bait traps in some areas of baiting programs. 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 half-way in the pipe. They tested PVC pipes that were 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 pups by avian predators , but likely would not completely eliminate it unless they are constructed with the longest length and narrowest width

recommen ded on the label.

Birds represent surrogates for terrestrial -phase amphibians and reptiles ; therefore, r isk conclusions for birds also apply to reptiles and terrestrial-phased amphibians on Guam.19 Invertebrates

The Agency does not have standardized risk assessment method for quantitatively assessing risk
to terrestrial invertebrates for this type of use pattern; therefore, any potential exposure and risk is discussed qualitatively. Exposure to terrestrial invertebrates is expected to be minimal g iven
the majority of the baited mouse pups are consumed by the brown tree snake and that the acetaminophen tablets are inserted into a dead mouse pup with very limited dispersion throughout the mouse pup tissue. Exposure could occur if an invertebrate were to feed on the carcass as it decomposes ( e.g. , land crabs) , but would likely be minimal as they would likely consume tissue around the acetaminophen tablets without consuming the tablets themselves. Exposure through contact with contaminated soil is possible but is also expected to be minimal

. Therefore, while there is a potential for exposure to terrestrial invertebrates, EFED believes that

exposure is very limited and accompanying risk is very unlikely.

5.2 Risk to Aquatic Organisms

Because use of the traditional a quatic exposure models is not appropriate, as described above in the exposure assessment, an alternative approach is used to estimate aquatic environmental exposure concentrations (EECs) from this use. As a worst

- case scenario, baited mouse baits are

assum ed to be placed directly into a body of water, and all of the active ingredient contained within that pup (80 mg per pup) is assumed to dissolve into the ambient water. While the Environmental Hazards section of the label contains a statement that prohibit s 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 anim als.

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 aqua tic risk LOC. In this assessment, all of the active ingredient in the bait is 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 l imiting 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.
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.

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 application mechanism is intended to maximize the number of20 baited pups to remain hanging in tree limbs ( i.e. , dropping baited -mouse pups that are attached to cardboard on paper streamers that become entangled in tree limbs), the label prohibits application of this product directly to water, and doing so would clearly make the bait ineffec tive for controlling tree snake s, and the maximum number of baited mice allowed per acre is 90, it is unlikely that any inadvertent exposure to acetaminophen in the waterbody would reach or exceed the level of concern ( i.e ., equivalent to 3,700 baited pups relative to the most sensitive aquatic animal) . Thus, the Agency believes that the concentration of acetaminophen in aquatic habitats is well below the level of concern for aquatic species

.

5.3 Risk to Terrestrial Plants

The registered use of acetaminophen to control the brown tree snake is expected to result in very minimal exposure to terrestrial plants. The bait is distributed as tablets placed inside of mouse pups. Most of these pups are expected to be consumed by snakes, 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 am ount that is released when poisoned brown tree snakes 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 to terrestrial pl ants is negligible.



### 6.0 E ndangered Species Assessment

Consistent with the Agency’s responsibility under the Endangered Species Act (ESA ), EPA has evaluated risks to Federally

- listed threatened and/or endangered (listed) species from uses of acetaminophen for brown tree snake control in Guam . This assessment was 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 indicated by the exceedance of LOCs used to evaluate direct or indirect effects. The EPA ’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 actionarea with the understanding that exposures below the Agency’s defined LOCs constitute a noeffect threshold. For the purposes of this assessment, attention is focused on the footprint of the action ( i.e. , the area where acetaminophen application occurs), plus all areas where offsite
transp ort ( e.g. , runoff, volatilization and long- range atmospheric transport, etc.) may result in potential exposure that exceeds the LOCs. As acetaminophen is registered only for the con trol of the brown tree snake, which is currently establis hed only on Guam, both the foot print of a ction
and the action area of this endangered species assessment for acetaminophen is the island of
Guam. Since the brown tree snake persists throughout the island, the entire island of Guam is
included in the action area.21 While ther e are various federally listed endangered and threatened mammals, birds and reptiles, and plants listed for Guam and the CMNI, specific to the action area ( i.e. , Guam), listed species that occur (or have previously been found) on Guam consist of 6 birds, 2 fruit bats, 2 marine turtles, and 1 terrestrial plant ( Table 5 ). The food habits of these species are provided in Table 6

.

Table 5 . Federally Listed Threatened and Endangered Species Occurring in Guam and the Commonwealth of the Northern Mariana Islands (CNMI) (based on USFW S, 2011)

Common Name Scientific Name Federal Listing Distribution Critical
Habitat Guam CNMI

Mammals

Bat, Little Mariana
f ruit Pteropus tokudae Endangered X ND 2

Bat, Mariana f ruit Pteropus mariannus Threatened X X Guam 3

Birds

Crow, Mariana Corvus kubaryl Endangered X 1 X Guam 3

, Rota 4

Kingfisher, Guam
Micronesian Todiramphus

cinnamominus Endangered X 1 Guam 3

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 Endangered X ND 2

White

- eye, Rota Zosterops rotensis Endangered X ND 2

Reptiles

Turtle, Green Sea Chelonia mydas Threatened 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 Endangered X ND 2

1 Extirpated from the wild in Guam.

2 ND = not defined

3 Critical habitat is designated on the northern tip of Guam, within the Guam National Wildlife Refuge.

4 Rota is an island that is part of the CNMI.22 Table 6 . Food Habits of Federally Listed Threatened and Endangered Species Occurring in Guam and the
Commonwealth of the Northern Mariana Islands

Common Name Scientific Name Diet Reference

Bat, Little Mariana
f ruit Pteropus tokudae A wide variety of plant matter, primarily fruit 1

Bat, Mariana f ruit Pteropus mariannus A wide variety of plant matter, primarily fruit 1

Crow, Mariana Corvus kubaryl Fruit, seeds, foliage, and buds of trees; invertebrates (lepidopteran larvae, grasshoppers, mole crickets, praying mantis, earwigs, hermit crabs), reptiles (skinks, geckos), immature rats, bird eggs 2

Kingfisher, Guam
Micronesian Halcyon cinnamominus Skinks, geckos, insects, segmented worms (Annelida), hermit crabs, chicken chick s, rats 3

Moorhen, Mariana
Common Gallinula chloropus guami Plant matter, insects, and mollusks 4

Rail, Guam Rallus owstoni Seeds, palm leaves, carrion, gastropods, skinks, geckos 5

Reed

- Warbler, Nightingale Acrocephalus luscinia Terrestrial arthropods (insects, spiders), snails,
lizards 6

Swiftlet, Mariana Aerodramus bartschi Insects 7

White

- eye, Guam
Bridled Zosterops conspicillatus Primarily insects, small amount of fruit and

nectar 8

White

- eye, Rota Zosterops rotensis Insects, fruit, seeds, nectar 9

1. USFWS. 1990. Guam Mariana Fruit Bat and Little Mariana Fruit Bat Recovery Plan. Portland, Oregon, 63

pp. Available at : http://ecos.fws.gov/docs/recovery_plan/901102.pdf
2. USF WS. 2005. Draft Revised Recovery Plan for the Aga or Mariana Crow, Corv us kubaryi . Portland Oregon. 147 pp. Available at : http://ecos.fws.gov/speciesProfile/profile/speciesProfile.action?spcode=B05X
3. USFWS. 1990. Revised Recovery Plan for the Sihek or Guam Micronesia Kingfisher ( Haycyon

cinnamomina cinnamomina ). Portland, Oregon. 117 pp. Available at : http://ecos.fws.gov/docs/recovery_plan/081114.pdf
4. USFWS. 1991. Recovery plan for the mariana common moorhen (= Gallinule) Gallinula ch loropus guami

. U.S. Fish and Wildlife Service, Portland, Oregon. 55 pp. Available at : http://ecos.fws.gov/docs/recovery_plan/910928.pdf
5. USFWS. 1990. Native Forest Birds of Guam and Rota of the Commonwealth of the Northern Mariana Islands Recovery Plan. U.S. Fish and Wildlife Service., Portland, Oregon. 86 pp. http://ecos.fws.gov/docs/recovery_plan/900928b.pdf

6. USFWS. 1998. Recovery Plan for the Nightingale Reed warbler ( Acrocephalus luscinia ). Portland, Oregon. 62 pp. Available at : http://ecos.fws.gov/docs/recovery_plan/980410a.pdf

7. USFWS. 2009. Mariana Swiftlet or Chachaguak ( Aerodramus bartschi ): 5

- Year Review Summary and Evaluation. U.S. Fish and Wildlife Service, Honolulu, Hawaii. 10 pp. Available at : http://ecos.fws.gov/docs/five_year_review/doc3352.pdf
8. Species specific recovery plan available on F WS website, 1990. U.S. Fish and Wildlife Service, Portland, Oregon. 55 pp. Available at : http://ecos.fws.gov/docs/recovery_plan/900928b.pdf
9. USFWS. 2007. Recovery Plan for the Nosa Luta or Rota Bridled White

- Eye ( Zosterops rotensis ). Portland, Oregon. 139 pp. Available at : http://ecos.fws.gov/docs/recovery_plan/071019.pdf23 Based on the conceptual model and problem formulation for aquatic wildlife, the registered use of acetaminophen is not expected to result in significant exposure to organisms in the aquatic environment, and thus, the listed marine turtles are not expected to be affected.

With the exception of certain mammals and birds ( i.e. , those that feed on carrion), t he registered use of acetaminophen also is expected to result in minimal direct exposure to terrestrial organisms. T he two listed species of fruit bats that occur on Guam feed strictly on plant matter and thus would not consume the baited mouse pups or poisoned tree snakes.

As previously discussed, minimal exposure to terrestrial pla nts is expected resulting from acetaminophen bait applications . The only listed plant identified in Guam is the Serianthes
nelsonii tree ; however, as determined in the 2011 USFWS BiOp, because of the proximity of the acetaminophen applications relative to the location of the tree, no adverse effects are expected

.

The natural history and feeding habits of the 8 endangered birds of these islands were investigated to determine if they would likely be exposed by the registered use of acetaminophen
for brown tr ee snake control. Of these eight species, only the Mariana crow ( Corvus kubaryi ),
the Guam Micronesian kingfisher ( Halcyon cinnamominus ), and the Guam rail ( Gallirallus

owstoni ) are known to eat small mammals or carrion ( Table 6 ) . All three of these species are now extirpated from the wild in Guam. The Guam Micronesian k ingfisher and the Guam rail now exist only in captiv ity, and thus would not be exposed by baiting with acetaminophen. Until recently, small numbers of Mariana crow existed in extreme northern Guam, but the species now
have s ince been extirpated from the wild or solely are in captivity in Guam and currently occurs in the wild only on the island of Rota ( Earl Campbell

, USFWS, personal communication).

While the Guam Micronesian k ingfisher and the Mariana crow no longer exist in the wild in Guam, designated critical habitat still exist on that isl and. The critical habitat that is designated on Guam is the same for both species, consisting of 376 acres of protected forest on the extreme northern fringe of the island, near Ritidian Point (USDI, 2004). All of the critical habitat lies on
federal land within the Guam National Wildlife Refuge. Since baiting in this area with acetaminophen could cause direct effects to these two species, if they were present, registered use of acetaminophen for brown tree snake control could cause an adverse modification of the critical habitat. However, this adverse modification in the habitat is expected to be very transient, lasting only as long as the dead mouse pups remained intact in the environment. The dead mouse pups are expected to soon disappear primarily by consumption by tree snakes and decomposition. The acetaminophen tablets located within the dead mouse pups, once exposed to the environment, are expected to dissipate rapidly into the soil due to its high water solubility. Therefore, any potential adve rse mod ification to the habitat from the use of acetaminophen is expected to be transient.

Therefore, we expect that the Guam Micronesian kingfisher and Mariana crow could be reintroduced into this critical habitat without suffering any direct or indirect advers e effect from the acetaminophen baits , as long as the reintroduction effort does not overlap with baiting events.

Because direct adverse effects are not expected for any of the reptiles, amphibians, mammals, fish, and aquatic organisms found on Guam, and there is no reasonable expectation of effects to plants or terrestrial invertebrates, the EPA makes a No Effects (NE) determination for all24 Federally

- listed species . While there is a potential for acetaminophen exposure to occur to birds that may feed on carrion (and swallow an entire acetaminophen bait), all known listed birds have since either been extirpated from Guam, or are in captivity, and are not expected to feed on the acetaminophen baits ( i.e. , dead mouse pups) that are used in the baiting programs to control the brown tree snake. Given that any current exposure is expected to be transient in nature ( i.e. , does not persist for extensive periods in the environment), and consistent with the determination in the 2011 USFWS BiOp for the Mariana crow, a No Habitat Modification determination is made for all designated critical habitats for the currently registered uses of acetaminophen.

**6.1** Formal Consultation on the Aerial Application of Acetaminophen for Brown
Tree snake Control on Guam

At the time of the issuance of the November 2011 Biological Opinion, there was one male Mariana crow remaining in Guam

, the USDA -APHIS requested formal consultation on the proposed aerial application of acetaminophen (in baited mouse pups) for the control of brown

tree snake on Guam, and the potential exposure and effect s to the endangered Mariana crow ( Corvus kubaryi ), the Mariana fruit bat ( Pteropus mariannus) , and the Serianthes nelsonii , an endangered tree

. On November 2, 2011 USFWS issued a Biological Opinion, which completed the formal consultation request from USDA APHIS WS , initiated June 5, 2011. T his Biological Opinion included information that outlined the avoidance, minimization, and conservation

measures necessary to minimize potential impacts to these endangered species

. The conclusions
of EPA’s preliminary risk assessment are consistent with the findings in the Biological Opinion that described the potential exposure and impact to each listed organism, and the corresponding
effects

. The determination s made by the US FWS in 2011 are summarized below. Since then, this last Mariana crow has been removed from the wild, and thus the species currently occurs in the wild only on the island of Rota ( Earl Campbell, USFWS , personal communicatio n).

Mariana crow ( Corvus kubaryi )

The November 2011 Biological Opinion provided a summary of the proposed acetaminophen application project ( i.e. , baited mouse pups aerially dropped into tree canopies into targeted areas surrounding the Munitions Storage Area of Andersen Air Force Base), along with detailed information that outlined conservation measures to minimize potential impacts to the Mariana crow. The USFWS analysis considered the potential impacts from any direct exposure to the Mariana crow from the acetaminophen

- baited mouse pups, as well as the indirect effect attributed to any noise produced from the flying of a helicopter during an application , or in proximity adjacent to the application (drop) site.

This Biological Opinion was completed for a specific project involving the aerial application of acetaminophen in dead neonatal mice (DNM) in the Andersen Air Force Base on for control of
the brown tree snake. The conclusions do not directly address use of acetaminophen in bait stations; however, that use would be expected to incur less exposure to Mariana crow than the proposed aerial application.

Amount of Extent of Take Anticipated and Effect of the Take : Based on the proposed aerial application of acetaminophen

- baited mice , incidental take of one Mariana crow was expected to occur during the capture and translocation effort. Incidental take was expected in the25 form of harassment, injury and mortality may occur during the capture and translocation effort. If the capture was unsuccessful, in cidental take was expected to take the form of harassment for the 16-month implementation of the acetaminophen action due to noise and human disturbance caused from the helicopter, supplemental feeding, and monitoring. More relevant to the current

assessme nt, the Biological Opinion also stated that t here was the chance of incidental take due to the ingestion of DNM (dead neonatal mice, i.e. , the acetaminophen-baited mouse pups). USFWS concluded that after reviewing the current status of the Mariana crow, the environmental baseline of this species in the acetaminophen application area , and the effects of the proposed action, including cumulative effects, it is of [their] Biological Opinion that the proposed aerial toxicant research project on AAFB, Guam may adversely affect the Marian a crow, but will not jeopardize their survival and recovery in the wild, nor will the critical habitat for this species be affected.

Reasonable and Prudent Measure : Minimize impacts of the proposed aerial toxicant drops [acetaminophen- containing baits] on the Mariana crow.

Mariana fruit bat ( Pteropus mariannus )

At the time of the consultation, there was a small population of the Mariana fruit bat ( Pteropus

mariannus ) that existed in northern Guam. In the May 13, 2011 in formal consultation request (Ref. 2011-I-0270), which included proposed aerial applications of acetaminophen, there was the potential that low -flying aircraft could adversely affect fruit bats flying in the area due to
collisions or noise disturbance. How ever, since flights for the acetaminophen

- baited mouse pup applications were scheduled to occur at times when the fruit bats are less active, the very low population densities of fruit bats on Guam, and few reported incidents of fruit bat strikes by an
air craft [(one recorded incident in 1982 (Morton 1996)], the USFWS concurred that the effect of the acetaminophen action to this fruit bat would be discountable.

Serianthes nelsonii Tree

In the May 13, 2011 informal consultation request (Ref. 2011-I-0270), USFWS concluded that considering the distance of the tree from the action area, the acetaminophen application is not likely to adversely affect the one endangered tree remaining on Guam, because of the distance of
the tree from the action area of the proposed project.26 

### References

Avery, M.L., E.A. Tillman, P.J. Savarie. 2004. Response of captive fish crows ( Corvus ossifragus ) to acetaminophen baits and bait stations for brown tree s nake ( Boiga irregularis ) control on Guam. Bird Behavior . 16:1-6.

Barnes , K.K., Christenson, S.C., Kolpin, D.W., Focazio, M.J., Furlong, E.T., Zaugg, S.D., Meyer, M.T., and Barber, L.B. 2004. Pharmaceuticals and Other Organic Waste Water
Contaminants With in a Leachate Plume Downgradient of a Municipal Landfill. Ground Water Monitoring and Remediation 24:119-126.

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 o rganic 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.

Bradbury, S. 2006. Standardized Soil Mobility Classification Guidance. Environmental Fate and
Effects Divisio n, Office of Pesticide Programs. Arlington, VA.

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.

Campbell, Earl, Assistant Field Supervisor, Invasive Species & Terrestrial Marianas Issues. U.S.
Fish and Wildlife Services

– Pacific Islands Fish & Wildlife Office. Personal Communication, April 16, 2013.

Colvin, B.A., M.W. Fall, L.A. Fitzgerald, and L.L. Loope. 2005. Review of brown tree snake problems and control programs: Report of observations and recommendations. U.S. Department of Interior, Washington, DC. Available at: http://www.mesc.usgs.gov/resources/education/bts/resources/pdf/Colvin2005 Brown Tree snakeReviewPanelReport.pdf

El -Obeid, H.A. and Al-Badr, A.A. 1985. Acetaminophen In : Analytical Profiles of Drug Substances, Vol. 14; Florey, K. Ed.; Academic Press, Inc. Orlando pp. 552-590.

Focazio, M.J., Kolpin, D.W., Barnes, K.K., Furlong, E.T., Meyer, M.T., Zaugg, S.D., Barber, L.B., Thurman, M.E. 2008. A national reconnaissance for pharmaceuticals and other organic wastewater contaminants in the United States

— II) Untreated drinking water

sources. Sci. Total Environ. 402:201-216

.27 Fram, M .S., Belitz, K. 2011. Occurrence and concentrations of pharmaceutical compounds in groundwater used for public drinking-water supply in California. Sci. Total Environ

. 409:3409–3417.

Granberg, R.A. and Rasmuson, A.C. 1999. Solubility of Paracetamol in Pure Solvents. J. Chem. Eng. Data. 44:1391-1395

Guam National Wildlife Refuge. 2009. Guam National Wildlife Refuge: Comprehensive
Conservation Plan . Guam National Wildlife Refuge, Yigo, Guam and U.S. Fish and Wildlife Service, Honolulu, Hawaii. 2009. 355 pp.

Hari, A.C., Paruchuri, R.A., Sabatini, D.A., Kibbey, T.C.G. 2005. Effects of pH and Cationic and Nonionic Surfactants on the Adsorption of Pharmaceuticals to a Natural Aquifer
Material. Environ. Sci. Technol . 39:2592-2598.

Hess, K., R.F. Mankes, and R. LeFevre. 1984. Effects of ethanol, acetaminophen or combination of ethanol and acetaminophen on the offspring of mice. Toxicology . 4:166.

Johnston, J.J., P.J. Savarie, T.M. Primus, J.D. Eisemann, J.C. Hurley, and D.J. Kohler. 2002. Risk assessment of an acetaminophen baiting program for chemical control of brown tree snakes on Guam: Evaluation of baits, snake residues, and potential primary and secondary hazards. Environ. Sci. Technol. 36(17):3827-3833.

Kinney, C.A., Furlong, E.T., Werner, S.L., Cahill, J.D. 2006. Presence and Distribution of

Wastewater

- Derived Pharmaceuticals in Soil Irrigated With Reclaimed Water. Environ.
Sci. Technol. 25:317-326.

Kolpin, D.W., Furlong, E.T., Meyer, M.T., Zaugg, S.D., Barber, L.B., Buxton, H.T. 2002. Pharmaceuticals, Hormones, and other Organic Wastewater Contaminants in U.S. Streams, 1999-2000: A National Reconnaissance. Environ. Sci. Technol. 36:1202-1211.

Lam, M.W., Young, C.J., Brain, R.A., Johnson, D.J., Hanson, M.A, Wilson, C.J., Richards, S.M., Solomon, K.R., Mabury, S.A. 2004. Aquatic Persistence of Eight Pharmaceuticals in a Microcosm Study. Environmental Toxicology and Chemistry , 23:1431–1440.

Lee, K.E., Barber. L.B., Furlong, E.T., Cahill, J.D., Kolpin, D.W., Meyer, M.T., and Zaugg, S.D. 2004. Presence and Distribution of Organic Wastewater Compounds in Wastewater, Surface, Ground, and Drinking Waters, Minnesota, 2000-2002. USGS Scientific

In vestigation Report 2004-5138. Reston, VA. 53 pp. Available online at: http://pubs.usgs.gov/sir/2004/5138/20045138.pdf

Löffler, D., Römbke, J., Meller, M., Ternes, T. 2005. Environmental Fate o f Pharmaceuticals in Water and Sediment Systems. Environ. Sci. Technol. , 39:5209–5218.28 Lorphensri, O., Intravijit, J., Sabatini, D.A, Tohren, Kibbey, T., Osathaphan, K., Saiwan, C. 2006. Sorption of acetaminophen, 17a-ethynyl estradiol, nalidixic acid, and norfloxacin to silica, alumina, and a hydrophobic medium. Water Res . 40:1481-1491.

Lucia, H.M., Santos,L.M., Araujo, A.N., Fachini,A., Pena, A., Delerue- Matos, C., Montenegro, M.C.B.S.M. 2010. Ecotoxicological aspects related to the presence of pharmac euticals in the aquatic environment. J. Hazardous Materials . 175:45 -95.

National Toxicological Program. 1984. Acetaminophen: Reproductive and fertility assessment in
CD -1 mice when administered in the feed. National Toxicological Program, U.S. Department of Health and Human Services. Research Triangle Park, NC. Technical Report Series No 394. 284 p.

Nature S erve . 2012. NatureServe Explorer. Corvus ossifragus – Wilson 1812, Fish Crow. (accessed February 2013)

Paracetamol Information Centre. 2011. Highlands Barn, Hardwick Road. Starston, Harleston Norfolk IP20 9PJ UK, http://www.pharmweb.net/pwmirror/pwy/paracetamol/pharmwebpic6.html (accessed 10/28/11)

Primus, T.M., D.J. Kohler, C.A. Furcolow, M.J. Goodall, J.J. Johnston, and P.J. Savarie. 2004. Determination of acetaminophen residues in whole body brown tree snakes. J. Liquid Chromatography & Related Technologies. 27(5):897-909.

Rodda, G.H. and H.T. Fritts. 1992. The impact of the introduction of the colubrid snake Boiga irregularis on Guram’s lizard. Journal of Herpetology . 26:166-174.

Rumack, B.H. and F.H. Lovejoy, Jr. 1986. Clinical toxicology. In Casarett and Doull’s Toxicology: The Basic Science of Poisons. Third Edit ion. Klaassen, C.D., M.O. Amdur, and J. Doull, Eds.; MacMillan, New York, pp. 879-901 pp.

Savarie, P.J., J.A. Shivik, J. C. Hurley, and L. Clark. 2002. Field Evaluation of Acetaminophen
as an Oral Toxicant for Brown Tree snake s (Boiga irregularis) . Unpublished report – QA -716. National Wildlife Research Center. Fort Collins, Colorado. 98 p.

Savidge, J.A.. 1987. Extinction of an island forest avifauna by an introduced snake. Ecology

. 68:660-668.

Starmer, G.A., S. McLean, and J. Thomas. 1971. Analgesi c potency and acute toxicity of
substituted anilides and benzamides. Toxicol. Appl. Pharmacol. 19:20-28.

USDA. 2011. Final Environmental Assessment: Targeted aerial application of acetaminophen
for brown tree snake control on Guam. Animal and Plant Health Inspection Service, Barrigada Heights, GU. 50 pp.29 USDI. 2004. Endangered and threatened wildlife and plants; designation of critical habitat for the Mariana fruit bat and Guam Micronesian kingfisher on Guam and the Mariana crow on Guam and in the Commonwealth of the Northern Mariana Islands; final rule. Fish and Wildlife Service. Federal Register. 50 CFR Part 17 , Vol. 69, No. 208. October 28, 2004.
Available online at: http://ecos.fws.gov/docs/federal_register/fr4349.pdf

USEPA. 1998. Guidelines for Ecological Risk Assessment. Risk Assessment Forum, Office of Research and Development, U.S. Environmental Protection Agency, Washington, D.C. EPA/630/R-95/002F. April 1998.

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs, U.S. Environmental Protection Agency. Endangered and Threatened Species Effects Determinations. Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, D.C. January 23, 2004.

USDOI . 2005. Draft revised recovery plan for the Aga or Mariana Crow, Corvus kubaryi

. Portland, Oregon. US Department of Interior Fish and Wildlife Service. 147 pp.

USDOI . 2011. Guam and Commonwealth of the Northern Mariana Islands Animals &Plants: Updated February 2, 2011; Listed Species, as Designated under the U.S. Endangered Species Act. U.S. Department of Interior, Fish and Wildlife Service. Available online at: http://www.fws.gov/pacificislands/Publications/Guam%20and%20Commonwealth%20of
%20the%20Northern%20Mariana%2 0Islands%20Animals_ListedSpp.pdf (accessed 11/7/11).

USDOI . 2011. Formal Consultation on the Aerial Application of Acetaminophen for Brown Treesnake Control on Guam. L. Mehrhoff, US Department of the Interior Fish and Wildlife Service, to D. Vice, US Department of Agriculture APHIS. November 2, 2011. 45 pp.

Williams, D., Wilson D., Storey R., Basford. P. 2011. Vapour Pressure Determination of
Pharmaceutical Powders. Available online at: http://www.eurostarscience.org/conferences/abstrsph7/wilson.pdf

Yamamato, H., Hayashi, A, Nakamura, Y, and Jun Sekizawa. 2005. Fate and Partitioning of
Selected Pharmaceuticals in Aquatic Environment. Environmental Sciences . 12:347-358.