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U.S. Food and Drug Administration, is registered by EPA for use to control the in vasive brown tree snake in the U.S. territories, Guam and the Commonwealth of Northern Mariana. The product, Brown Tree Snake Control (EPA Reg. No. 56228

- 34) is the only registration for acetaminophen. The Section 18 quarantine emergency exemption ( July 1999 ) and application for registration of end use product (July 2002) were identified as the prima ry resource s for this

evaluation. In addition, a qualitative human health risk assessment was submitted by U.S. Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) as a part of a data requirement waiver for human health effects from acetaminophen

, and in support

of the 2002 application . Th e waiver request was accepted

. HED anticipates no dietary, drinking water, or occupational and residential exposure from the use of acetaminophen as a pesticide.

Acetaminophen (N

- (4

- hydroxyphenyl)

- acetamide) is a widely used analgesic and antipyretic agent that has been available as an ov er

- the

- counter drug since 1960. Centrilobular hepatocyte

necrosis in humans is a well

- recognized consequence of overdose for acetaminophen. Nephrotoxicity in humans has also been reported as a consequence of acetaminophen drug use. Toxicity data requirem ents have been waived for this acetaminophen pesticide use because of the extensive literature database and the approval by FDA for use as an over

- the

- counter drug.

Because no dietary, drinking water, or occupational and residential exposure are anticipat ed, a quantitative human health risk assessment is not required under registration review for the existing use of acetaminophen.

No data deficiencies were identified during the scoping process for toxicology, residue chemistry, or occupational and reside ntial exposure. There are no outstanding data requirements.

There are no aggregate, dietary, occupational or residential risks of concern for this Registration

Review chemical.

Introduction

The HED Acetaminophen Registration Review Team has evaluate d the potential for human exposure from use of the Brown Tree Snake Control product . The purpose of this screen is to

determine whether sufficient data are available and whether a human health risk assessment is required to support Registration Review. H ED considered the most recent documentation from OPP activity on acetaminophen and conducted an open literature search. The primary sources for the status update were the Section 18 quarantine emergency exemption and application for registration submitted in support of the brown tree snake use by USDA APHIS in 1999 and

2002 , respectively

. Other supporting documentation includes a publication of the scientific journal En vironmental Science Technology as submitted by USDA APHIS, which assesses the risk of the acetaminophen baiting program for control of brown tree snakes on Guam. A comprehensive list of all documentation considered is presented in the reference section of this

document.

Acetaminophen is used as a pesticide to control the invasi ve brown tree snake in two U.S. territories, Guam and the Commonwealth of Northern Mariana. The brown tree snake (Boiga irregularis) is a significant ecological, agricultura l, and economic pest on Guam. Originally , the species’ range include d the norther n and eastern coasts of Australia, Papua New Guinea, and nearby islands. It is believed that sometime in the 1950s brown tree snakes were inadvertentlyPage 3 of 8

transported from New Guinea to Guam, where they proliferated. By the mid

- 1960s, marked

decreases in Gu am’s bird life were observed. By the mid

- 1980s, brown tree snake densities were estimated at levels higher than those recorded for any other snake.

Acetaminophen is applied by hand or aerially via helicopter and/or fixed

- winged aircraft. Single

bait s ( dead mouse pup) are prepared by man ually inserting one 80 mg or two 40 mg acetaminophen tablets into the throat of the mouse pup . Bait stations are prepared by manually inserting a single mouse pup bait in a PVC pipe that are hung in trees or on fences (4 .9 feet above the ground) in and around forested areas and fence lines. Baits can also be hand broadcast or dropped from helicopters and fixed

- wing aircraft. Netting or other material may be attached to the dropped bait for placement in the forest cano py

.

Hazard Identification/Toxicology

Acetaminophen is a widely used analgesic and antipyretic agent. Recommended oral drug doses for acetaminophen range from 12 mg/kg every 6

- 8 hours for pre

- term neonates to 1000 mg every

6

- 8 hours for adults. Centrilobular hepatocyte necrosis in humans is a well

- recognized consequence of overdose for acetaminophen. The FDA web site advises: "Acetaminophen is one of the most commonly used medicines in the United States. When used according to the label directions, it has a well

- established record of saf ety and efficacy. Although acetaminophen overdose is very rare in the context of its broad usage, overdose can be toxic and lead to acute

liver failure". There is also the potential for interaction with ethanol and labels require

consumers to consult wit h their physician if they drink 3 or more alcohol drinks a day. Nephrotoxicity in humans has also been reported as a consequence of acetaminophen drug use.

Toxicity data requirements have been waived for this acetaminophen pesticide use because of the

e xtensive literature database and the approval by FDA for use as an over

- the

- counter drug.

Residue Chemistry

Acetaminophen is not currently registered as a pesticide for uses in food commodities; therefore, evaluation of residues in crops is not needed.

Dietary Exposure

The proposed pesticide use for brown tree snake control is not expected to result in any dietary

exposure. No food

- based exposure is anticipated as there are no registered food

- uses in agricultural commodities. Also, any drinking wate r exposures are expected to be negligible.

. The primary source of exposure to acetaminophen among the U.S. population is likely through analgesic drug use , which is regulated by the U.S. Food and Drug Administration . Based on these considerations, a die tary exposure assessment is not required for registration review.

Residential ExposurePage 4 of 8

No residential exposure (adult or child) is anticipated from the use of acetaminophen for brown

tree snake control . The product as labeled does not preclude prof essional application in residential areas (i.e., bait stations and broadcast in non

- crop areas); however, its use should not result in the potential for residential exposure. The label states, “DO NOT apply this product in

a manner where it is accessible to children,” and, therefore, the potential for exposure to children is unlikely. It is possible that an adult or child could come upon a mouse bait preparation dropped via broadcast application (helicopter or fixed

- winged aircraft) in to a residential are a; however, the probability of an adult or child accessing and contacting or the child ingesting the tablets lodged in the throats of the dead mouse pups is very low

. It is also unlikely that adults or children in residential areas will contact the bait s tations, which are required by the product label to be hung in trees and on fences and contained in PVC pipes

. A residential assessment is not required for the registration review of acetaminophen for the reasons described.

Aggregate Risk Assessment

Dietary , drinking water, and residenti al exposure to acetaminophen have not been assessed. As stated above, these routes of exposure are not anticipated given the use pattern (i.e., brown tree snake control) of the chemical and, therefore, an aggregate risk assessment will not be needed to support the registration review of acetaminophen.

Occupational Exposure

An occupational human health assessment of the use of acetaminophen for brown tree snake

control in Guam has not been previously conducted. Acetaminophen can be applied by single bait preparation, bait stations, or broadcast only by employees of the US State and Federal governments, the Government of Guam or the Commonwealth of the Northern Mariana Islands trained in brown tree snake control, or persons under their direct supervision.

Based on the use profile and the potential for exposure

, an assessment of occupational handler and appli cator is not required under registration review. While the handling of acetamino phen tablets is anticipat ed during insertion into dead mouse pups, the product label requires t hat handlers of the product wear: long

- sleeved shirt and long pants, socks and shoes, and waterproof or rubber gloves. The handling of acetaminophen tablets with the required gloves is anticipated to minimize the potential for any dermal contact with the product. The application of the mouse pup baits by hand, the creation of bait stations (PVC pipe) or aerial broadcast will not result in direct contact with acetaminophen tablets. Be cause dermal and inhalation exposure are not anticipated , an occupational risk assessment is not required for acetaminophen.

Public Health and Pesticide Epidemiology Dat a

The evaluation of the OPP Main Incident Data System (IDS) indicated no incidents i dentified in the United States from January 1, 2006, through November 2, 2011, for the single chemical acetaminophen. In Aggregate IDS, from January 1, 2006 to November 2, 2011, there are no incidents reported for acetaminophen. For acetaminophen, there appears to be a low potential for

exposure. Acetaminophen is not included in the Agricultural Health Study (AHS), and therefore,Page 5 of 8

does not provide information for this report. There does not appear to be a concern at this time

that would warrant further i nvestigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk

assessment.

Tolerance Assessment and International Harmonization

Tolerances are not established fo r acetaminophen since no registered pesticide uses in food commodities exist at this time. No Codex maximum residue limits (MRLs) have been established for acetaminophen. Therefore, there are no international harmonization issues.

Environmental Justice

Potential areas of environmental justice concerns, to the extent p ossible, was considered in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2

- 6

- EO_12898envjustice.pdf ) . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from t he legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when ha rvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure

that the risk estimates are based on the best available information.

Cumulative

The Food Quality Protection Act (FQPA) requires the Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxicity . At this time, a cumulative risk assessment to support registration review is not required for acetaminophen.

Human Studies

No human studies were relied upon for the registration of the pesticide use of acetaminophen.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxici ty, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturati on, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its 2002 decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database.Page 6 of 8

However, as required by FFDCA section 408(p), a cetaminophen is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlif e similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Acetaminophen is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as p art of registration review, EPA will issue future

EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for acetaminophen. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, fut ure lists, the test guidelines and the Tier 1 screening battery, please

visit our website: http://www.epa.gov/endo/

.

Data Requirements

No data deficiencies were identified during the scoping process for toxicology, residue chemistry, or occupational and residential exposure. There are no outstanding data requirements.

References

Author Barcode /MRID Date Title

S. Recore D399584 December

2011 Acetaminophen: Review of Human Incidents

Carl Bausch

to Meredith

Laws NA July 2002 Application for Registration of an End Use Product Containing a New Active Ingredient: Acetaminophen for Brown Tree snake

Control

J.J. Johnston,

et al NA July 2002 Risk assessment of an acetaminophen baiting program for

chemical control of brown tree snakes on Guam: evaluation of baits, snake residues, and potential to primary and secondary

hazards (Environmental Science and Technology, 2002, 36 (17), pp. 3827

- 3833)Page 7 of 8

Author Barcode /MRID Date Title

USDA

APHIS NA May 2002 Request for Data Requirement Waiver: Human Health Effects

J. Jones NA July 1999 Section 18

– Quarantine Exemption for the use of Acetaminophen

to control the invasive brown tree snake in Guam and the Commonwealth of Northern Mariana Islands (99

- DA

- 10) by

USDA/APHIS

B. Petersen,

J. Eisemann 45716715 2002 Acetaminophen Data Requirements: Human Health Effects

Textbooks

C. Klaassen NA November

2007 Casarett and Doull’s Toxicology, 7 th Edition

L. Goodman,

L. Limbird NA 1995 Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9 th Edition

Websites http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htm

Attachments

Attachment 1: Chemical Identity Table

Chemical Identity of Acetaminophen.

Structure

Reference: D286621, S. Mathur, 16

- DEC

2002 IUPAC Name N

- (4

- hydroxyphenyl) acetamide

Common Name Acetaminophen or paracetamol

Molecular Formula C 8 H 9 NO 2 Molecular Weight 151.16 g/mole

CAS Registry Number 103

- 90

- 2

PC Code Number 109509

Physical State Solid

Color White

Odor Odorless

Melting Point 170 C

Solubility 1 g in 70 mL water @ 25 C

pH 6.0Page 8 of 8

Tolerance/MRL Table

Not required for this action.

DCI Justifications

Not required for this action.