Final Data Collection on the Toxicity, Use, and Disposal of Hazardous Drugs Report

Prepared for:

U.S. Environmental Protection Agency Materials Recovery and Waste Management Division Office of Resource Conservation and Recovery 1200 Pennsylvania Avenue, NW Washington, D.C. 20460

Prepared by:

Eastern Research Group, Inc. 14555 Avion Parkway Suite 200 Chantilly, VA 20151-1102

September 2011

EPA Contract No. EP-W-10-055 Task Order SOL-HQ-11-00035

Contents

Page Contents ...... i List of Tables ...... ii Executive Summary ...... v

1. INTRODUCTION TO THE HAZARDOUS DRUG DATA COLLECTION ...... 1-1

2. RESOURCE CONSERVATION AND RECOVERY ACT REGULATIONS FOR U AND P LISTED WASTES ...... 2-1

3. IDENTIFICATION OF HAZARDOUS DRUGS AND REVIEW OF TOXICITY DATA ...... 3-1 3.1 NIOSH List of Hazardous Drugs ...... 3-1 3.2 OSHA List of Hazardous Drugs ...... 3-2 3.3 Proposed Additions and Deletions to the NIOSH Hazardous Drug List ...... 3-3 3.4 Collection of Toxicity Data ...... 3-3 3.4.1 Data Sources ...... 3-3 3.4.2 Data Collection Approach...... 3-6 3.4.3 Design of Hazardous Drugs Toxicity Data Spreadsheet ...... 3-6 3.5 Review of Lethal Toxicity Data ...... 3-6

4. EXTENT OF DRUG USE AND CURRENT DISPOSAL PRACTICES ...... 4-1 4.1 Extent of Drug Use ...... 4-1 4.2 Current Drug Disposal Practices ...... 4-3 4.2.1 Regulations Affecting Drug Disposal Practices ...... 4-5 4.2.2 Federal Drug Administration’s Recommendations for Flushing Unused Drugs...... 4-6

5. REFERENCES ...... 5-1

Appendix A: LIST OF HAZARDOUS DRUGS REVIEWED BY ERG

Appendix B: TOXICITY DATA

Appendix C: LIST OF CONTROLLED SUBSTANCES BY DEA SCHEDULE

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List of Tables

Page

3-1 Sources of Formulary Information...... 3-4

3-2 Sources of Lethal Dose Data...... 3-4

3-3 Sources of Toxicity Information ...... 3-4

4-1 Commonly Prescribed Drugs in 2005 and 2009 ...... 4-2

4-2 U.S. Production Ranges for Appendix A Drugs ...... 4-3

4-3 Current Drug Disposal Practices at Healthcare Facilities ...... 4-4

4-4 Drugs Recommended for Disposal By Flushing ...... 4-6

A-1 List of Drugs Reviewed by ERG and Tier Assignments ...... 1

C-1 Schedule I Controlled Substances ...... 1

C-2 Schedule II Controlled Substances ...... 4

C-3 Schedule III Controlled Substances ...... 6

C-4 Schedule IV Controlled Substances ...... 10

C-5 Schedule V Controlled Substances ...... 12

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ACRONYM LIST

ACGIH: American Conference of Government Industrial Hygienists AHFS DI: American Hospital Formulary Service Drug Information ASHP: American Society of Health-System Pharmacists BEI: Biological Exposure Indices CASRN: Chemical Abstracts Service Registry Number CCL3: Contaminant Candidate List 3 CFR: Code of Federal Regulations CPDB: Carcinogenic Potency Database CSA: Controlled Substances Act CSF: Cancer Slope Factor CUS/IUR: Chemical Update System/Inventory Update Rule DEA: Drug Enforcement Administration DSSTox: Distributed Structure-Searchable Toxicity DWEL: Drinking Water Equivalent Level EPA: U.S. Environmental Protection Agency ERG: Eastern Research Group, Inc. FDA: U.S. Food and Drug Administration FR: Federal Register HA: Health Advisories HSDB: Hazardous Substances Data Bank IARC: International Agency for Research on Cancer IDLH: Immediately Dangerous to Life or Health Concentration IRIS: Integrated Risk Information System IUR: Inhalation Unit Risk IV: Intravenous LC: Lethal Concentration LD: Lethal Dose LDL: Lowest Dose Causing Lethality LTHA: Lifetime Health Advisory MCL: Maximum Contaminant Level mg/kg: Milligrams per Kilogram mg/L: Milligrams per Liter MRDD: Maximum Recommended Daily Dose MRTD: Maximum Recommended Therapeutic Dose NCEA: National Center for Environmental Assessment NIH: National Institutes of Health NIOSH: National Institute for Occupational Safety and Health NLM: National Library of Medicine NTP: National Toxicology Program OEHHA: Office of Environmental Health Hazard Assessment ORCR: Office of Resource Conservation and Recovery OSHA: Occupational Safety and Health Administration OW: Office of Water PEL: Permissible Exposure Limit PhRMA: Pharmaceutical Research and Manufacturers of America RCRA: Resource Conservation and Recovery Act iii

REL: Recommended Exposure Limit RoC: Report on Carcinogens RfC: Reference Concentration RfD: Reference Dose RTECS: Registry of Toxic Effects of Chemical Substances TLV: Threshold Limit Value

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EXECUTIVE SUMMARY

With the advent of new chemotherapy (antineoplastic) drugs, as well as the development of a variety of new drugs that exhibit hazardous properties, it has become important for the U.S. Environmental Protection Agency’s (EPA’s) Office of Resource Conservation and Recovery (ORCR) to conduct additional research to update U and P coded hazardous wastes to address those drugs that present an acute toxicity risk or could cause serious irreversible illness if disposed of improperly. The disposal of hazardous drugs impacts both land and water, as improperly-disposed drugs can end up in the municipal waste landfills and waters of the United States. Eastern Research Group, Inc. (ERG) is supporting EPA in its collection and analysis of toxicity, use, and disposal data for drugs that exhibit hazardous properties under Task Order SOL-HQ-11-00035.

ERG collected toxicity, extent of use, and disposal data for 204 drugs: 172 drugs identified as hazardous by the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) and 32 drugs that NIOSH proposed for addition to its hazardous drug list. ERG then created a Microsoft Excel™ spreadsheet to capture the toxicity data for those drugs and analyzed the lethality data to determine the appropriate tier category for each drug (see Section 3.4). Based on the lethal dose data analysis, ERG found that 11 drugs on the NIOSH or OSHA lists of hazardous drugs meet the specific criteria set forth in Code of Federal Regulations (CFR) §261.11 for acute toxicity. Three of these drugs are already included on the federal Resource Conservation and Recovery Act (RCRA) list of hazardous chemicals (U list).

 Carmustine (154-93-8)  Mitomycin (50-07-7) – EPA Waste  Cisplatin (15663-27-1) Code U010  Colchicine (64-86-8)  Mitoxantrone HCl (70476-82-3)  Dactinomycin (50-76-0)  Oxytocin (50-56-6)  Mechlorethamine (51-75-2)  Thiotepa (52-24-4)  Melphalan (148-82-3) – EPA  Uracil mustard (66-75-1) – EPA Waste Code U150 Waste Code U237

An additional 114 drugs1 on the NIOSH or OSHA lists did not meet the specific criteria in §261.11 for acute toxicity, but did have lethal doses for other animals or humans.

ERG also reviewed available public literature to determine whether the 204 drugs are commonly prescribed in the United States. Based on data for 2009, 12 antineoplastic agents (chemotherapy drugs) and eight other classification drugs were among the top 200 prescribed. ERG did not identify any available data to determine quantities of drug waste disposed by healthcare facilities.

1 Two of the 114 drugs (Docetaxel and Mycophenolic acid) were categorized as Tier 2 drugs based on one of the Chemical Abstracts Service Registry Numbers (CASRNs); the drugs fall into the Tier 3 category based on the other CASRN. Seventeen of the 114 Tier 2 drugs have very little lethality data (borderline Tier 3). One of the 114 Tier 2 drugs almost meets the Tier 1 criteria (Podofilox [518-28-5]). v

1. INTRODUCTION TO THE HAZARDOUS DRUG DATA COLLECTION

On December 2, 2008, EPA proposed adding hazardous pharmaceutical (drug) wastes to the Federal universal waste program (73 Federal Register [FR] 73520) to provide a hazardous pharmaceutical waste disposal system that is protective of public health and the environment. Through the public comments on the proposal and via outside communications, stakeholders asserted that numerous drugs are harmful to human health and the environment when improperly disposed; however, these drugs have not yet been recognized as hazardous waste by EPA.

Drug waste includes discarded drugs and associated equipment generated by hospitals and other facilities that use such drugs. A number of drugs are included on the U and P coded hazardous waste lists as commercial chemical products. However, EPA created these lists more than 30 years ago and there are now many newer chemotherapy and other toxic drugs that should be assessed for potential listing as U or P wastes. This document summarizes data and other information collected for 204 drugs identified as hazardous or potentially hazardous by NIOSH and OSHA. Within this document, Section 2 presents a brief overview of the toxicity requirements for chemicals listed on the U and P coded hazardous waste lists; Section 3 describes how ERG collected and analyzed the data to categorize each drug into a tier; and Section 4 describes the extent of use for the drugs reviewed and provides an overview of current healthcare industry disposal practices.

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2. RESOURCE CONSERVATION AND RECOVERY ACT REGULATIONS FOR U AND P LISTED WASTES

Under the Resource Conservation and Recovery Act (RCRA), EPA may classify a chemical as hazardous if the chemical is specifically listed in the regulations or exhibits certain characteristics. Thus, a drug waste may be considered hazardous under RCRA if:

 The drug or its sole active ingredient is specifically listed on the P list: Acutely Hazardous Waste (40 CFR 261.33(e)) or the U list: Discarded Commercial Chemical Products (40 CFR 261.33(f)); and/or  The waste exhibits one or more hazardous waste characteristic as defined in 40 CFR 261.21-24, (ignitability, corrosivity, reactivity, or toxicity).

Furthermore, 40 CFR 261.11 outlines the criteria for listing a waste as acutely hazardous (i.e., P list). A waste is acutely hazardous if it has been found to be fatal to humans in low doses or, in the absence of data on human toxicity, the waste has been shown in studies to meet certain lethal dose (LD)50 (lethal dose that kills 50 percent of animals tested) or lethal concentration (LC)50 (lethal concentration that kills 50 percent of animals tested) values, or is otherwise capable of causing or significantly contributing to an increase in serious irreversible, or incapacitating reversible, illness. A drug is acutely hazardous waste if it meets one or more of the following LD50 and LC50 values:

 Oral LD50 toxicity (in rats) of less than 50 milligrams per kilogram (mg/kg);  Inhalation LC50 toxicity (in rats) of less than 2 milligrams per liter (mg/L); or  Dermal LD50 toxicity (in rabbits) of less than 200 mg/kg.

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3. IDENTIFICATION OF HAZARDOUS DRUGS AND REVIEW OF TOXICITY DATA

To identify the drugs for this project’s data collection and review, ERG compiled a list of drugs based on the NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010; a list of hazardous drugs developed by OSHA and included in the OSHA Technical Manual (effective date: January 1, 1999); and 32 drug chemicals proposed for addition to the NIOSH list. ERG identified 204 unique drugs using these three data sources. One drug, Arsenic trioxide, is already included on the P list of hazardous wastes; therefore, ERG did not collect any data for it. The NIOSH lists included “Ergonovine/ Methylergonovine” and “Valproic acid/Divalproex Sodium (Na)”; however, since each drug has a unique CASRN, ERG captured information for those drugs individually. ERG identified an additional drug, Denileukin diftitox2, during the project. Appendix A includes the list of drugs ERG evaluated under this project.

3.1 NIOSH List of Hazardous Drugs

The list of hazardous drugs presented in the NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010 comes from two evaluations. NIOSH published the evaluation that identified the majority of the drugs in a September 2004 Alert, titled Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Healthcare Settings.3 Appendix A of the Alert includes a sample list of hazardous drugs compiled from information received from the following:

 Four institutions that have generated lists of hazardous drugs for their respective facilities  The Pharmaceutical Research and Manufacturers of America (PhRMA)  The American Hospital Formulary Service Drug Information (AHFS DI) monographs (American Society of Health-System Pharmacists [ASHP]/AHFS DI, 2003)

For the 2004 Alert, drugs considered hazardous included those that exhibit one or more of the following six characteristics in humans or animals:

1. Carcinogenicity 2. Teratogenicity or other developmental toxicity 3. Reproductive toxicity 4. Organ toxicity at low doses 5. Genotoxicity 6. Structure and toxicity profiles of new drugs that mimic existing drugs determined hazardous by the above criteria.

NIOSH’s second evaluation identified an additional 21 drugs that were new drugs or existing drugs that had new warnings from 2004 to 2007. The review process for the addition of the new

2 Denileukin was listed by NIOSH, however, ERG could not locate a CASRN for it. The National Library of Medicine (NLM) and U.S. Food and Drug Administration (FDA) sources, as well as the AHFS DI monograph, listed Denileukin diftitox (173146-27-5), but not Denileukin. Therefore, ERG added Denileukin diftitox to the list of drugs. 3 NIOSH’s Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Healthcare Settings can be accessed at http://www.cdc.gov/niosh/docs/2004-165/. 3-1

listings is described in the Federal Register (74 FR 19570, April 29, 2009). NIOSH reviewed the following:

 60 new FDA-approved drugs  60 drugs that received special warnings on reported adverse effects in patients  18 drugs included in the updated National Institutes of Health (NIH) Hazardous Drug List

After expert review, scientific literature review, public comments, and stakeholder input, NIOSH identified 24 drugs4 that met the NIOSH definition of hazardous drugs. In addition, NIOSH removed one drug from the 2004 list.

3.2 OSHA List of Hazardous Drugs

The list of hazardous drugs presented in the OSHA Technical Manual Section VI: Chapter 2 – Controlling Occupational Exposure to Hazardous Drugs is not intended as an all-inclusive list. The sources for the list include the Physicians Desk Reference, Section 10:00 in the American Hospital Formulary Service Drug Information; International Agency for Research on Cancer (IARC) publications (particularly Volume 50); The Johns Hopkins Hospital; and the NIH Clinical Center Nursing Department. The list does not include investigational drugs, but the manual notes that “they should be prudently handled as hazardous drugs until adequate information becomes available to exclude them” (OSHA, 1999).

The OSHA Technical Manual provides criteria for classifying drugs as hazardous and cites the ASHP hazardous drug definition. The manual lists two ways to classify drugs as hazardous: 1) based on characteristic; or 2) based on pharmacology/toxicology. The manual defines the four drug characteristics, each of which could be considered hazardous, as the following:

 Carcinogenicity  Teratogenicity or fertility impairment  Serious organ or other toxic manifestation at low doses in experimental animals or treated patients  Genotoxicity

The manual includes the following major considerations by professionals trained in pharmacology/toxicology in designating drugs as hazardous:

 Is the drug designated as Therapeutic Category 10:00 (Antineoplastic Agent) in the AHFS DI?  Does the manufacturer suggest the use of special isolation techniques in its handling, administration, or disposal?  Is the drug known to be a human mutagen, carcinogen, teratogen, or reproductive toxicant?

4 The 2010 document stated that only 21 drugs were added; this may have been based on information received by NIOSH following the 2009 notice. 3-2

 Is the drug known to be carcinogenic or teratogenic in animals (drugs known to be mutagenic in multiple bacterial systems or animals should also be considered hazardous)?  Is the drug known to be acutely toxic to an organ system?

3.3 Proposed Additions and Deletions to the NIOSH Hazardous Drug List

In July 2011, NIOSH requested comments on proposed additions and deletions to its list of hazardous drugs to be included in the NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012 (NIOSH, 2011). To identify potential new drugs to add to the list, NIOSH looked at the 48 new drugs that received FDA approval between June 2007 and December 2009 and 115 drugs that received special warnings (usually black box warnings) based on reported adverse effects in patients. NIOSH identified 45 drugs from the list of 169 drugs as candidate hazardous drugs. Seven of these drugs had safe handling instructions from its manufacturers, and NIOSH decided to add these seven drugs without further review. NIOSH asked a panel of peer reviewers and stakeholders to review and comment on the remaining 38 candidate hazardous drugs. After receiving the panel recommendations, NIOSH decided to add 24 drugs in addition to the 7 drugs with manufacturer’s warnings. NIOSH determined that these 24 drugs have one or more characteristic of a hazardous drug.

As part of its update to the list of hazardous drugs, NIOSH proposed to delete 15 drugs from its 2010 list and requested its panel members to comment on the deletions. The proposed deletions include the following:

 Four drugs reclassified as not meeting the criteria for a hazardous drug: Alemtuzumab, Interferon alfa 2a, Interferon alfa 2b, and Interferon alfa n3 (all antineoplastic agents).  Two radio-pharmaceuticals with specific handling regulations set by the Nuclear Regulatory Commission: Ibritumomab tiuxetan and Tositumomab (both antineoplastic agents).  Nine others currently not available in the United States: Dienestrol and Trimetrexate glucuronate (not antineoplastic agents) and Interferon alfa n1, Perphosphamide, Piritrexim isethionate, Plicamycin, Prednumustine, Raltitrexed, and Vindesine (antineoplastic agents) (NIOSH, 2011b).

3.4 Collection of Toxicity Data

ERG collected formulary and toxicity information for the 204drugs listed in Appendix A of this document. ERG compiled the data into the Microsoft Excel™ spreadsheet, ORCR Drug Data.xlsx, and included the spreadsheet as Appendix B of this report. The following subsections of this report describe the data sources ERG used for the toxicity data collection, the approach ERG used to collect the data, and ERG’s design of the ORCR drug data spreadsheet.

3.4.1 Data Sources

ERG searched for formulary information, lethal doses, and toxicity information for each drug. Table 3-1 presents the data sources ERG used to identify formulary data. In addition, ERG

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reviewed the 2011 AHFS DI catalog to supplement formulary information (use, route, form, strength, brand name) when information was not available in the data sources below.

Table 3-1. Sources of Formulary Information

Source Formulary Information Website NLM ChemIDplus  CASRN http://chem.sis.nlm.nih.gov/chemidplus/ chemidlite.jsp FDA Drugs@FDA  Generic name http://www.accessdata.fda.gov/scripts/c  Proprietary/brand name der/drugsatfda/index.cfm  Active ingredient  Strengths or concentrations  Dose form and route  Marketing status NLM MedlinePlus  Drug use http://www.nlm.nih.gov/medlineplus/dr  Use route uginformation.html  Brand name

In consideration of the definitional requirements for determining “hazardous” as it relates to RCRA §261.11, ERG specifically searched for human and animal lethal dose data in the sources identified in Table 3-2. All sources provide the toxicity value type, species, route of exposure, dose, and primary source of the data (reference listed by the secondary source). ERG also captured the secondary source (i.e., Hazardous Substances Data Bank [HSDB], ChemIDplus, Registry of Toxic Effects of Chemical Substances [RTECS]) for each toxicity value. The primary sources are listed for reference purposes; ERG did not obtain and review the primary sources to ensure accuracy of the information presented in the secondary sources.

Table 3-2. Sources of Lethal Dose Data

Source Website NLM HSDB http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB NLM ChemIDplus http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp NIOSH RTECS Through ERG’s Dialog subscription

To supplement the lethal toxicity data, ERG searched data sources listed in Table 3-3 for additional non-lethal toxicity information.

Table 3-3. Sources of Toxicity Information

Source Toxicity Benchmark Value Website NIOSH 2010 List of  AHFS pharmacologic-therapeutic http://www.cdc.gov/niosh/docs/2010- Antineoplastic and Other classification 167/ Hazardous Drugs in Healthcare Settings

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Table 3-3. Sources of Toxicity Information

Source Toxicity Benchmark Value Website EPA, Distributed Structure-  Therapeutic category http://www.epa.gov/ncct/dsstox/sdf_fda Searchable Toxicity  Maximum Recommended Daily mdd.html (DSSTox) Dose (MRDD) FDA  Maximum Recommended http://www.fda.gov/aboutfda/centersoffi Therapeutic Dose (MRTD) ces/cder/ucm092199.htm IARC  Cancer classification http://monographs.iarc.fr/ENG/Classific ation/index.php National Toxicology  Cancer assessment http://ntp.niehs.nih.gov/index.cfm?objec Program (NTP) 12th Report tid=03C9AF75-E1BF-FF40- on Carcinogens (RoC) DBA9EC0928DF8B15

University of California,  Tumorigenic dose (TD50) for rats http://potency.berkeley.edu/chemnamein Berkeley Lab Carcinogenic  TD50 for mice dex.html Potency Database (CPDB)  TD50 for rhesus monkeys  TD50 for cynomulgus monkeys  TD50 for hamsters RTECS  Compound class (tumorigen, Through ERG’s Dialog subscription mutagen, primary irritant, reproductive effector)  Substance name EPA, National Center for  Reference Dose (RfD) http://www.epa.gov/iris/ Environmental Assessment  Reference Concentration (RfC) (NCEA), Integrated Risk  Cancer slope factor (CSF) Information System (IRIS)  Inhalation unit risk (IUR)  Cancer classification EPA Office of Water (OW)  Maximum Contaminant Level http://www.epa.gov/safewater/mcl.html (MCL)  1-day/10-day Health Advisories http://www.epa.gov/waterscience/drinki (HA) ng/standards/dwstandards.pdf  Drinking Water Equivalent Level (DWEL)  Lifetime Health Advisory (LTHA) NIOSH  Immediately Dangerous To Life or http://www.cdc.gov/niosh/idlh/intridl4.h Health Concentration (IDLH) tml  Recommended Exposure Limit (REL) http://www.cdc.gov/niosh/npg/ OSHA  Permissible Exposure Limit (PEL) http://www.osha.gov/SLTC/pel/ American Conference of  Threshold Limit Value (TLV) ACGIH: 2011 TLVs and Biological Government Industrial Exposure Indices (BEIs) Hygienists (ACGIH)

As part of EPA OW development of the contaminant candidate list 3 (CCL3) chemicals, EPA collected toxicity and benchmark data. ERG reviewed the EPA OW data and found benchmarks for 13 of the drugs reviewed (U.S. EPA, 2007). These benchmarks, from the California Office of Environmental Health Hazard Assessment (OEHHA), are also included in the ORCR drug data spreadsheet developed for this project.

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3.4.2 Data Collection Approach

ERG searched each data source by the drug name (i.e., generic name), CASRN, and brand name. ERG specifically searched for lethal doses in humans and animals that meet the specific criteria set forth in §261.11 for acute toxicity (e.g., oral LD50, dermal LD50, and inhalation LC50). When available, ERG also captured other lethal doses (e.g., lowest dose causing lethality, [LDL0]).

3.4.3 Design of Hazardous Drugs Toxicity Data Spreadsheet

ERG collected and managed the data in a Microsoft Excel™ spreadsheet ORCR Drug Data.xlsx (see Appendix B). The ORCR drug data spreadsheet includes the following worksheets:

 Data Dictionary – explains the data captured in each worksheet  Formulary Information – captures formulary information for the drugs  Toxicity Information – captures non-lethal toxicity information for the drugs  Lethal Doses – captures lethal dose data  Drug Tiers – contains the tier assignment for each drug (see Section 3.4)  OW OEHHA – contains the OEHHA benchmarks as captured by EPA OW

3.5 Review of Lethal Toxicity Data

Following the collection of lethality data, ERG categorized each drug into one of the following EPA-defined tiers.

Tier 1: Drugs on the NIOSH or OSHA lists of hazardous drugs with evidence of a low lethal dose in humans or lethal doses that meet the specific criteria set forth in §261.11 for acute toxicity, i.e., oral LD50 (rat), dermal LD50 (rabbit), or inhalation LC50 (rat).

ERG assigned Tier 1 to any drug found to have lethal animal toxicity data that meets the following criteria:

 An oral LD50 in rats less than 50 mg/kg  An inhalation LC50 in rats less than 2 mg/L  A dermal LD50 in rabbits less than 200 mg/kg

ERG identified 11 drugs as Tier 1. Three of these drugs are already included on the federal RCRA list of hazardous chemicals (U list):

 Carmustine (154-93-8)  Mitomycin (50-07-7) – EPA Waste  Cisplatin (15663-27-1) Code U010  Colchicine (64-86-8)  Mitoxantrone HCl (70476-82-3)  Dactinomycin (50-76-0)  Oxytocin (50-56-6)  Mechlorethamine (51-75-2)  Thiotepa (52-24-4)  Melphalan (148-82-3) – EPA  Uracil mustard (66-75-1) – EPA Waste Code U150 Waste Code U237

Tier 2: Drugs on the NIOSH or OSHA lists that do not meet the specific criteria in §261.11 for acute toxicity, but have lethal doses for other animals comparable to criteria in §261.11 or evidence for documented toxicity in humans at “low” doses for carcinogenicity, 3-6

teratogenicity or other developmental toxicity, reproductive toxicity, or specific organ toxicity.

ERG assigned Tier 2 to any non-Tier 1 drug found to have lethal animal or human toxicity data outside the criteria set forth in §261.11. NIOSH already determined that all drugs on its 2010 List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings exhibit one or more of the following six characteristics in humans or animals:

1. Carcinogenicity 2. Teratogenicity or other developmental toxicity 3. Reproductive toxicity 4. Organ toxicity at low doses 5. Genotoxicity 6. Structure and toxicity profiles of new drugs that mimic existing drugs determined hazardous by the above criteria

The drugs on OSHA’s list are considered hazardous by the following criteria:

1. Genotoxicity; 2. Carcinogenicity; 3. Teratogenicity or fertility impairment; or 4. Serious organ or other toxic manifestation at low doses in experimental animals or treated patients

Therefore, documented evidence of toxicity exists for the drugs investigated for this project. ERG identified 114 drugs as Tier 2 (see Appendix B). Two of the 114 drugs (Docetaxel and Mycophenolic acid) were categorized as Tier 2 drugs based on one of the CASRNs; the drugs fall into the Tier 3 category based on the other CASRN. Seventeen of the 114 Tier 2 drugs have very little lethality data (borderline Tier 3). One of the 114 Tier 2 drugs almost meets the Tier 1 criteria (Podofilox [518-28-5]).

Tier 3: Drugs on the NIOSH or OSHA lists that have limited human or animal data for the classes of toxicities noted above.

ERG assigned Tier 3 to any drug that does not have lethality data. ERG identified 79 drugs as Tier 3 (see Appendix B). Two additional drugs (Docetaxel and Mycophenolic acid) were categorized as Tier 3 drugs based on one of the CASRNs; but were categorized as Tier 2 drugs based on the other CASRN. Denileukin diftitox (173146-27- 5) was not originally included on either the NIOSH or OSHA list; however, no lethality data were available for the drug, and, therefore, ERG categorized it as a Tier 3 drug.

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4. EXTENT OF DRUG USE AND CURRENT DISPOSAL PRACTICES

ERG performed a cursory review of publicly available information (secondary data) to gather data on the extent of drug use for the 204 drugs included in Appendix A. A more exhaustive literature search might produce more detailed and thorough results. This section of the report presents the data ERG found on the extent of use for the drugs and an overview of current drug disposal practices at healthcare facilities.

4.1 Extent of Drug Use

ERG reviewed two lists of commonly prescribed drugs (top 300 in 2005 and top 200 in 2009) and production data from the Chemical Update System/Inventory Update Rule (CUS/IUR) to determine if any of the 204 reviewed drugs were commonly prescribed or manufactured. Table 4-1 lists the Appendix A drugs that were also commonly prescribed in 2005 and 2009 (RX List, Inc., 2011 and Pharmacy Times, 2010). Four drugs fall on both lists and none are antineoplastic agents: Estrogens, conjugated (12126-59-9), Ethinyl estradiol (57-63-6), Risperidone (106266- 06-2), and Divalproex Na (76584-70-8). In 2005, only one antineoplastic agent was on the list; however in 2009, 12 antineoplastic agents made the top 200 brand names prescribed.

Table 4-2 lists the production volume reported in the 2006 CUS/IUR database for four drugs reviewed by ERG (U.S. EPA, 2006). Because some of the drugs reviewed for this project are more recently developed drugs, the majority did not have production data reported in the CUS/IUR database. In addition, drugs may be manufactured outside the United States and imported for use.

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Table 4-1. Commonly Prescribed Drugs in 2005 and 2009

Appendix A Drugs in the Top 200 Drugs Prescribed in 2009 Appendix A Drugs in the Top 300 Drugs Prescribed in 2005 Drug (Brand) Name CASRN Drug (Brand) Name CASRN Antineoplastic Agents Antineoplastic Agents Anastrozole (Arimidex®) 120511-73-1 Tamoxifen (NA) 10540-29-1 Bortezomib (Velcade®) 179324-69-7 Capecitabine (Xeloda®) 154361-50-9 Non-Antineoplastic Agents Docetaxel (Taxotere®) 148408-66-6; 114977- Colchicine (NA) 64-86-8 28-5 Gemcitabine (Gemzar®) 95058-81-4 Estradiol (Vivelle-DOT®) 50-28-2 Imatinib mesylate (Gleevec®) 220127-57-1 Estrogens, conjugated (Premarin®) 12126-59-9 Letrozole (Femara®) 112809-51-5 Oxaliplatin (Eloxatin®) 61825-94-3 Estrogens, conjugated & 12126-59-9 Paclitaxel (Abraxane®) 33069-62-4 Medroxyprogesterone acetate (Prempro®) & Pemetrexed (Alimta®) 137281-23-3 71-58-9 Sunitinib malate (Sutent®) 341031-54-7 Ethinyl estradiol, with Norgestimate and 57-63-6 Norethindrone Temozolomide (Temodar®) 85622-93-1 Finasteride (Proscar®) 98319-26-7 Medroxyprogesterone (NA) 520-85-4 Non-Antineoplastic Agents Paroxetine HCl (Paxil CR®) 78246-49-8 Dutasteride (Avodart®) 164656-23-9 Progesterone (Prometrium®) 57-83-0 Estrogens, conjugated (Premarin®) 12126-59-9 Risperidone (Risperdal®) 106266-06-2 Ethinyl estradiol, with Norgestimate 57-63-6 Carbamazepine 298-46-4 (Ortho Tri Cy Lo 28®) Risperidone (Risperdal Consta®) 106266-06-2 Clonazepam 1622-61-3 Tacrolimus (Prograf®) 109581-93-3; Oxcarbazepine 28721-07-5 104987-11-3 Testosterone (Androgel® 1%) 58-22-0 Simvastatin 79902-63-9 Divalproex Na (Depakote ER® and Divalproex Sodium 76584-70-8 Divalproex Na 76584-70-8 ER®) Zoledronic acid (Reclast® and Zometa®) 118072-93-8 Source: RX List, Inc., 2011; Pharmacy Times, 2010 NA – not applicable

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Table 4-2. U.S. Production Ranges for Appendix A Drugs

U.S. Production Range Appendix A Drugs Less than 500,000 pounds (lbs) Estradiol (50-28-2) Ethinyl estradiol (57-63-6) 1 to less than 10 million lbs Mercaptopurine (50-44-2; 6112-76-1) 1 billion lbs and greater Fluoxymesterone (76-43-7) Source: U.S. EPA, 2006

ERG did not perform a separate data search to determine if the drugs are commonly combined with other active ingredients or compounds. However, from the data collected, there are a few examples in which drugs are commonly combined with other active ingredients or compounds. As noted in Table 4-1, Ethinyl estradiol may be combined with Norgestimate, Norethindrone, or Norgestral and the brand name Prempro® contains Estrogens, conjugated and Medroxyprogesterone acetate. The formulary data in Appendix B also lists whether the drug is present in medications with other active ingredients.

4.2 Current Drug Disposal Practices

Current drug disposal practices at healthcare facilities depend on multiple factors, including type of facility (large facilities such as pharmacies or hospitals versus small facilities such as long- term care facilities or medical offices), form of the drug (e.g., liquid or solid), and current regulations. The primary disposal practices for drug wastes include: reverse distribution, collection with municipal trash or collection by waste hauler, and down the drain (U.S. EPA, 2008c). Table 4-3 provides a brief description of these disposal practices and factors that affect how facilities select which disposal practice to use.

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Table 4-3. Current Drug Disposal Practices at Healthcare Facilities

Disposal Type of Drug Regulations Affecting Practice Description (U.S. EPA, 2008b) Type of Facilities (ERG, 2009) Disposal Practice Reverse Method used by healthcare facilities to Larger facilities: Pharmacies and Typically solid dose Controlled Substances Act Distribution receive credit from the pharmaceutical hospitals forms or unopened (CSA) – limits transfer of manufacturer prior to disposal. The reverse containers (e.g., past controlled substances between distributor determines which medications Most, if not all, large hospitals use expiration date). Drug Enforcement can receive credit from the manufacturer reverse distribution for unused Administration (DEA)- and then arranges for disposal of the drug pharmaceuticals that are potentially registrants. waste. The drug is then disposed of via creditable (U.S. EPA, 2009). incineration or landfill (see below discussion of solid waste disposal). Solid Waste Solid waste disposal includes collection of Larger facilities, such as hospitals, May be liquids in Collection and disposal must Disposal everyday trash from healthcare facilities pharmacies, and large medical addition to solids meet RCRA (or state) and collection of drug and other medical clinics are more likely to have a hazardous requirements for waste by a waste hauler. The solid waste is drug waste management program listed drugs. either disposed in a landfill or incinerated. and a contract with a waste hauler who specializes in drug waste (U.S. CSA limits transfer of Facilities may also include drug waste in EPA, 2008b). controlled substances between their biohazardous (red bag) waste which is DEA-registrants; if not a DEA- either sterilized and landfilled or Smaller facilities may choose to registrant, the controlled incinerated. dispose of solid dose drug wastes in substance must be rendered the regular trash (noncontrolled irretrievable to prevent substance). To prevent disposal diversion control. down the drain, smaller facilities might mix controlled substances Chemotherapy wastes also have with coffee grounds, kitty litter, etc. special requirements. to render irretrievable. Down the Disposal down the drain is easy to do and a This method is very common at Liquids, such as Drain disposal also meets the Drain low cost way to dispose of drug waste. smaller healthcare facilities (ERG, partially-used DEA requirements for 2009). intravenous (IV) controlled substances (U.S. Following disposal down the train, the drugs, are commonly EPA, 2008c). wastewater may be treated in a septic tank disposed down the or other onsite treatment system; however, drain, as are solid Local wastewater treatment this is not common. doses for diversion systems (e.g., in California) control. may have practices in place to Wastewater from most healthcare facilities limit or ban disposal of drug is collected in a sewer system and waste down the drain (e.g., transported via pipes to a municipal obtaining permission from wastewater treatment system. POTW prior to discharge) (U.S. EPA, 2008b).

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4.2.1 Regulations Affecting Drug Disposal Practices

Regulations that affect drug disposal practices include RCRA and CSA. Under CSA, controlled substances can only be transferred between DEA-registrants and must be destroyed to prevent diversion. Smaller healthcare facilities typically do not have DEA registrations and must dispose of controlled substances onsite (DEA, 2011).

The DEA divides controlled substances into five schedules (21 CFR Sections 1308.11 through 1308.15). DEA places a controlled substance in its respective schedule based on whether it has a currently accepted medical use in treatment in the United States and its relative abuse potential and likelihood of causing dependence. The definition of the substances in the five schedules includes the following (DEA, 2011b):

 Schedule I Controlled Substances have a high potential for abuse, have no currently accepted medical use in treatment in the United States, and there is a lack of accepted safety for use of the drug or other substance under medical supervision.  Schedule II Controlled Substances have a high potential for abuse which may lead to severe psychological or physical dependence. Examples of single entity schedule II narcotics include morphine and opium.  Schedule III Controlled Substances have a potential for abuse less than substances in schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence.  Schedule IV Controlled Substances have a low potential for abuse relative to substances in schedule III.  Schedule V Controlled Substances have a low potential for abuse relative to substances listed in schedule IV and consist primarily of preparations containing limited quantities of certain narcotics.

Appendix C includes a list of all controlled substances by schedule for reference purposes. For this project, ERG collected toxicity data for five controlled substances. Fluoxymesterone (76-43- 7), Methyltestosterone (58-18-4), Testolactone (968-93-4), and Testosterone (58-22-0) are Schedule III controlled substances. Clonazepam (1622-61-3) is a Schedule IV controlled substance.

Drugs that are RCRA or state hazardous drugs must meet transportation and disposal requirements protective of the environment and public health. Eight of the drugs in Appendix A are included on the federal RCRA U list (U.S. EPA, 2008):

 U035: Chlorambucil (305-03-3)  U058: Cyclophosphamide (50-18-0; 6055-19-2)  U059: Daunorubicin (as Daunomycin) (20830-81-3)  U089: Diethylstilbestrol (56-53-1)  U150: Melphalan (148-82-3)  U010: Mitomycin (as Mitomycin C) (50-07-7)  U206: Streptozocin (18883-66-4)  U237: Uracil mustard (66-75-1)

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All of these drugs, except Diethylstilbestrol, are antineoplastic agents (i.e., chemotherapy drugs). In addition to federal regulations, ERG reviewed hazardous waste lists for three states, including California, Florida, and North Carolina. California and North Carolina did not list any additional Appendix A drugs in their list or summary of RCRA regulations (McGurk, 2002; NCDENR, 2011). Florida identified three drugs in Appendix A as being hazardous based on meeting the ignitability criteria (Waste Code D001): Carmustine (154-93-8), Etoposide (33419-42-0) and Paclitaxel (33069-62-4). In addition, Idarubicin (58957-92-9) was listed as “Idarubicin/Idamycin” with an EPA waste code of U059 (FLDEP, 2007). All of these drugs are also antineoplastic agents. One other antineoplastic agent included on Florida’s list (and the federal U list), but not included in Appendix A, is Chlornaphazin (494-03-1), EPA Waste Code U026.

4.2.2 Federal Drug Administration’s Recommendations for Flushing Unused Drugs

The FDA published recommendations to consumers on when to flush unused drugs down the drain in its document Disposal of Unused Medicines: What You Should Know (FDA, 2010). FDA recommends flushing of these drugs due to potential harm to someone from taking the drug when not prescribed to them. Table 4-4 includes a list of the drugs recommended for flushing by FDA. None of these drugs are currently included on the federal RCRA hazardous waste list and ERG did not collect toxicity data for the 14 drugs in Table 4-4.

Table 4-4. Drugs Recommended for Disposal By Flushing

Active Ingredient Active Ingredient Drug/Brand Name CASRN Acetaminophen/Oxycodone 103-90-2/124-90-3 Percocet Hydrochloride Aspirin/Oxycodone Hydrochloride 50-78-2/124-90-3 Percodan Diazepam (a) 439-14-5 Diastat/Diastat AcuDial Fentanyl (a) 437-38-7 Duragesic Fentanyl Citrate 990-73-8 Actiq; Fentora; Onsolis Hydromorphone Hydrochloride 71-68-1 Dilaudid; Exalgo Meperidine Hydrochloride 50-13-5 Demerol Methadone Hydrochloride 1095-90-5 Dolophine Hydrochloride; Methadose Methylphenidate (a) 113-45-1 Daytrana Morphine Sulfate 64-31-3; 6211-15-0 Avinza; Kadian; MS Contin; Oramorph SR Morphine Sulfate/Naltrexone 64-31-3; 6211-15-0/ Embeda Hydrochloride 16676-29-2 Oxycodone Hydrochloride 124-90-3 Oxycontin Oxymorphone Hydrochloride 357-07-3 Opana; Opana ER Sodium Oxybate 502-85-2 Xyrem Source: FDA, 2010. Disposal of Unused Medicines: What You Should Know. March. a – Drug is a controlled substance.

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5. REFERENCES

1. DEA (Drug Enforcement Administration). 2011. Controlled Substances: Alphabetical Order. January 18. Available online at: http://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf. 2. DEA.2011b. Controlled Substance Schedules (website). Accessed online September2011 at: http://www.deadiversion.usdoj.gov/schedules/index.html# Office of Diversion Control. 3. Eastern Research Group (ERG). 2009. Management Practices and Control Technologies for Unused Pharmaceuticals at Health Care Facilities – Final, Document Control Number 06570. October 8. Available at www.regulation.gov: EPA-HQ-OW-2008-0517-0517 4. FDA (Food and Drug Administration). 2010. Disposal of Unused Medicines: What You Should Know. March. Available online at: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/E nsuringSafeUseofMedicine/SafeDisposalofMedicines/ucm186187.htm 5. FLDEP (Florida Department of Environmental Protection). 2007. List of Pharmaceuticals that are Potentially Hazardous Wastes When Discarded. Hazardous Waste Regulation Section. December 3. Available online at: http://www.dep.state.fl.us/waste/quick_topics/publications/shw/hazardous/WastePharmLi stLetter12_07.pdf. 6. Mcgurk, Jack. 2002. Management of Pharmaceutical Medical Waste. California Department of Health and Services. October 15. Available online at: http://www.cwea.org/p3s/documents/DHS%20Guidance%20Pharmacy%20Waste%20fro m%20Hospitals.pdf. 7. NIOSH (National Institute for Occupational Safety and Health). 2010. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2010. Available online at: http://www.cdc.gov/niosh/docs/2010-167/. 8. NIOSH. 2011. Notice of Draft Document Available for Public Comment. Available online at:http://www.cdc.gov/niosh/docket/review/docket190/pdfs/FRNFinal07192011.pdf. 9. NIOSH. 2011b. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012: Proposed Additions and Deletions to the NIOSH Hazardous Drug List. Available online at: http://www.cdc.gov/niosh/docket/review/docket190/pdfs/Proposedchanges07112011.pdf 10. North Carolina Department of the Environment and Natural Resources (DENR). 2011. Part 261: Identification and List of Hazardous Wastes. Retrieved July 2011 from: http://wastenot.enr.state.nc.us/hwhome/webrules/pdf/0106_1.pdf. 11. OSHA (Occupational Safety and Health Administration).1999. OSHA Technical Manual – Effective Date: 1/20/1999; Directive Number: TED 01-00-015. Available online at: http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html. 12. Pharmacy Times. 2010. Top 200 Products in the U.S. Market by Sales, 2009. May, p35. Available online at: http://www.pharmacytimes.com/media/pdf/PHTM_35.pdf.

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13. RX List, Inc. 2011. Top 300 Prescriptions for 2005. Retrieved June 2011from: http://www.rxlist.com/script/main/art.asp?articlekey=79509. 14. U.S. EPA (U.S. Environmental Protection Agency). 2006. Non-confidential 2006 IUR Company/Chemical Records. Available online at: http://cfpub.epa.gov/iursearch/index.cfm. 15. U.S. EPA. 2007. Microsoft Excel™ spreadsheet: APIUniverse_MRDD_CombinedListing_v3.xls. Office of Water. 16. U.S. EPA. 2008. Hazardous Waste Listings: A User-Friendly Reference Document (Draft). Available online at: http://www.epa.gov/wastes/hazard/wastetypes/pdfs/listing- ref.pdf. 17. U.S. EPA. 2008b. Health Services Industry Study: Management and Disposal of Unused Pharmaceuticals (Interim Technical Report). August. Available at www.regulation.gov: EPA-HQ-OW-2006-0771-1694. 18. U.S. EPA. 2008c. Unused Pharmaceuticals in the Health Care Industry: Interim Report (EPA-821-R-08-010). August. Available online at: http://water.epa.gov/scitech/swguidance/ppcp/upload/2010_1_11_ppcp_hcioutreach.pdf. 19. U.S. EPA. 2009. Memorandum: Health Care Industry Study - Meeting with Stericycle, July 23, 2009. Office of Water, August 4, 2009. Available at www.regulation.gov: EPA- HQ-OW-2008-0517-0333.

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Appendix A LIST OF HAZARDOUS DRUGS REVIEWED BY ERG

Table A-1. List of Drugs Reviewed by ERG and Tier Assignments

Drug CASRN Source Tier Notes 1 Acitretin 55079-83-9 NIOSH 2011 2 Very little lethality data, borderline Tier 3. NIOSH proposed as an addition to its List of Hazardous Drugs. 2 Aldesleukin 110942-02-4 NIOSH 2010 3 3 Alefacept 222535-22-0 NIOSH 2010 3 4 Alemtuzumab 216503-57-0; NIOSH 2010 3 NIOSH proposed deletion from 126775-97-1 List of Hazardous Drugs. 5 Alitretinoin 5300-03-8 NIOSH 2010 3 6 Altretamine 645-05-6 NIOSH 2010/OSHA 2 7 Ambrisentan 177036-94-1 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 8 Aminoglutethimide 125-84-8 OSHA 2 9 Amsacrine 51264-14-3 NIOSH 2010 2 10 Anastrozole 120511-73-1 NIOSH 2010 3 NA Arsenic trioxide 1327-53-3 NIOSH 2010 NA Already included on the P list of hazardous wastes. No toxicity data collected. 11 Asparaginase 9015-68-3 NIOSH 2010/OSHA 2 12 Azacitidine 320-67-2 NIOSH 2010 2 13 Azathioprine 446-86-6 NIOSH 2010/OSHA 2 14 Bacillus Calmette- D001500000 NIOSH 2010 3 Guerin (BCG) 15 Bendamustine HCl 3543-75-7 NIOSH 2011 2 NIOSH proposed as an addition to its List of Hazardous Drugs. 16 Bexarotene 153559-49-0 NIOSH 2010 3 17 Bicalutamide 90357-06-5 NIOSH 2010 2 18 Bleomycin 11056-06-7 NIOSH 2010/OSHA 2 19 Bortezomib 179324-69-7 NIOSH 2010 2 20 Bosentan 147536-97-8 NIOSH 2010 3 21 Busulfan 55-98-1 NIOSH 2010/OSHA 2 22 Cabergoline 81409-90-7 NIOSH 2011 2 Very little lethality data, borderline Tier 3. NIOSH proposed as an addition to its List of Hazardous Drugs. 23 Capecitabine 154361-50-9 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 24 Carbamazepine 298-46-4 NIOSH 2011 2 NIOSH proposed as an addition to its List of Hazardous Drugs. 25 Carboplatin 41575-94-4 NIOSH 2010/OSHA 2 26 Carmustine 154-93-8 NIOSH 2010/OSHA 1 27 Cetrorelix acetate 145672-81-7 NIOSH 2010 3 28 Chlorambucil 305-03-3 NIOSH 2010/OSHA 2 Already included on the U list of hazardous wastes (U035). 29 Chloramphenicol 56-75-7 NIOSH 2010/OSHA 2 30 Chlorotrianisene 569-57-3 OSHA 3 31 Chlorozotocin 54749-90-5 OSHA 2 32 Choriogonadotropin 177073-44-8 NIOSH 2010 3 alfa 33 Cidofovir 149394-66-1; NIOSH 2010 3 113852-37-2 34 Cisplatin 15663-27-1 NIOSH 2010/OSHA 1 35 Cladribine 4291-63-8 NIOSH 2010 2 A-1

Table A-1. List of Drugs Reviewed by ERG and Tier Assignments

Drug CASRN Source Tier Notes 36 Clofarabine 123318-82-1 NIOSH 2010 3 37 Clonazepam 1622-61-3 NIOSH 2011 2 NIOSH proposed as an addition to its List of Hazardous Drugs. 38 Colchicine 64-86-8 NIOSH 2010 1 39 Cyclophosphamide 50-18-0; NIOSH 2010/OSHA 2 Already included on the U list 6055-19-2 of hazardous wastes (U058). 40 Cyclosporin 79217-60-0; NIOSH 2010/OSHA 2 Different data were found for 59865-13-3 the CASRN and alternate CASRN. 41 Cytarabine 147-94-4 NIOSH 2010/OSHA 2 42 Dacarbazine 4342-03-4 NIOSH 2010/OSHA 2 43 Dactinomycin 50-76-0 NIOSH 2010/OSHA 1 44 Dasatinib 302962-49-8; NIOSH 2010 3 863127-77-9 45 Daunorubicin 20830-81-3 OSHA 2 Already included on the U list of hazardous wastes (U059). 46 Daunorubicin HCl 23541-50-6 NIOSH 2010 2 47 Decitabine 2353-33-5 NIOSH 2010 2 48 Degarelix 214766-78-6 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 49 Denileukin See NIOSH 2010 3 ERG could not locate a Denileukin CASRN for Denileukin. The diftitox NLM and FDA sources as well 50 Denileukin diftitox 173146-27-5 AHFS 3 as the AHFS DI monograph listed Denileukin diftitox, but not Denileukin. Therefore, ERG added Denileukin diftitox to the list of drugs. 51 Dienestrol 84-17-3 NIOSH 2010 3 NIOSH proposed deletion from List of Hazardous Drugs. 52 Diethylstilbestrol 56-53-1 NIOSH 2010/OSHA 2 Already included on the U list of hazardous wastes (U089). 53 Dinoprostone 363-24-6 NIOSH 2010 2 54 Divalproex Na 76584-70-8 NIOSH 2011 3 NIOSH listed “Valproic acid/Divalproex Na”; however, since each drug has a unique CASRN, ERG captured information for them individually. NIOSH proposed as an addition to its List of Hazardous Drugs. 55 Docetaxel 148408-66-6; NIOSH 2010 3, 2 Different data were found for 114977-28-5 the CASRN and alternate CASRN, resulting in a different tier for each (148408-66-6 = Tier 3; 114977-28-5 = Tier 2). 56 Doxorubicin 23214-92-8 NIOSH 2010/OSHA 2 57 Dronedarone HCl 141625-93-6 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 58 Dutasteride 164656-23-9 NIOSH 2010 3 59 Efavirenz 154598-52-4 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 60 Entecavir 142217-69-4 NIOSH 2010 3 A-2

Table A-1. List of Drugs Reviewed by ERG and Tier Assignments

Drug CASRN Source Tier Notes 61 Epirubicin 56420-45-2 NIOSH 2010 2 62 Ergonovine 60-79-7 NIOSH 2010 2 NIOSH listed “Ergonovine/ Methylergonovine”; however, since each drug has a unique CASRN, ERG captured information for them individually. 63 Estradiol 50-28-2 NIOSH 2010/OSHA 2 Very little lethality data, borderline Tier 3. 64 Estramustine 2998-57-4 OSHA 3 65 Estramustine phosphate 4891-15-0 NIOSH 2010 3 66 Estrogen-progestin NIOSH 2010 3 combinations 67 Estrogens, conjugated 12126-59-9 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 68 Estrogens, esterified D042724000 NIOSH 2010 3 69 Estrone 53-16-7 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 70 Estropipate 7280-37-7 NIOSH 2010 3 71 Ethinyl Estradiol 57-63-6 OSHA 2 72 Etoposide 33419-42-0 NIOSH 2010/OSHA 2 73 Everolimus 159351-69-6 NIOSH 2011 2 Very little lethality data, borderline Tier 3. NIOSH proposed as an addition to its List of Hazardous Drugs. 74 Exemestane 107868-30-4 NIOSH 2010 3 75 Finasteride 98319-26-7 NIOSH 2010 2 76 Floxuridine 50-91-9 NIOSH 2010/OSHA 2 77 Fludarabine 21679-14-1 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 78 Fluorouracil 51-21-8 NIOSH 2010/OSHA 2 79 Fluoxymesterone 76-43-7 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 80 Flutamide 13311-84-7 NIOSH 2010/OSHA 2 81 Fulvestrant 129453-61-8 NIOSH 2010 3 82 Ganciclovir 82410-32-0 NIOSH 2010/OSHA 2 83 Ganirelix acetate 129311-55-3 NIOSH 2010 3 84 Gemcitabine 95058-81-4 NIOSH 2010 3 85 Gemtuzumab 220578-59-6 NIOSH 2010 3 ozogamicin 86 Gonadotropin, 9002-61-3 NIOSH 2010 3 chorionic 87 Goserelin 65807-02-5 NIOSH 2010 3 88 Hydroxyurea 127-07-1 NIOSH 2010/OSHA 2 89 Ibritumomab tiuxetan 206181-63-7 NIOSH 2010 3 NIOSH proposed deletion from List of Hazardous Drugs. 90 Idarubicin 58957-92-9 NIOSH 2010/OSHA 2 91 Ifosfamide 3778-73-2; NIOSH 2010/OSHA 2 84711-20-6 92 Imatinib mesylate 220127-57-1 NIOSH 2010 3

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Table A-1. List of Drugs Reviewed by ERG and Tier Assignments

Drug CASRN Source Tier Notes 93 Interferon alfa-2a 76543-88-9; NIOSH 2010 2 Different data were found on 77907-69-8 HSDB for the alternate CASRN. NIOSH proposed deletion from List of Hazardous Drugs. 94 Interferon alfa-2b 99210-65-8; NIOSH 2010 2 NIOSH proposed deletion from 98530-12-2 List of Hazardous Drugs. 95 Interferon alfa-n1 308067-63-2 NIOSH 2010 3 NIOSH proposed deletion from List of Hazardous Drugs. 96 Interferon alfa-n3 NIOSH 2010 3 NIOSH proposed deletion from List of Hazardous Drugs. 97 Interferon-A OSHA 3 98 Irinotecan HCl 100286-90-6; NIOSH 2010 2 136572-09-3 99 Isotretinoin 4759-48-2 OSHA 2 100 Ixabepilone 219989-84-1 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 101 Leflunomide 75706-12-6 NIOSH 2010 2 102 Lenalidomide 191732-72-6 NIOSH 2010 3 103 Letrozole 112809-51-5 NIOSH 2010 3 104 Leuprolide 53714-56-0 OSHA 3 105 Leuprolide acetate 74381-53-6 NIOSH 2010 2 106 Levamisole 14769-73-4 OSHA 2 107 Lomustine 13010-47-4 NIOSH 2010/OSHA 2 108 Mechlorethamine 51-75-2 NIOSH 2010/OSHA 1 109 Medroxyprogesterone 520-85-4 OSHA 3 110 Medroxyprogesterone 71-58-9 NIOSH 2010 2 acetate 111 Megestrol 3562-63-8 NIOSH 2010/OSHA 3 112 Melphalan 148-82-3 NIOSH 2010/OSHA 1 Already included on the U list of hazardous wastes (U150). 113 Menotropins 9002-68-0; NIOSH 2010 2 61489-71-2 114 Mercaptopurine 50-44-2; NIOSH 2010/OSHA 2 Different data were found for 6112-76-1 the CASRN and alternate CASRN. 115 Methotrexate 59-05-2 NIOSH 2010/OSHA 2 116 Methylergonovine 113-42-8 NIOSH 2010 2 NIOSH listed “ergonovine/ methylergonovine”; however, since each drug has a unique CASRN, ERG captured information for them individually. 117 Methyltestosterone 58-18-4 NIOSH 2010 2 118 Mifepristone 84371-65-3 NIOSH 2010 3 119 Mitomycin 50-07-7 NIOSH 2010/OSHA 1 Already included on the U list of hazardous wastes (U010). 120 Mitotane 53-19-0 NIOSH 2010/OSHA 2 121 Mitoxantrone 65271-80-9 OSHA 2 122 Mitoxantrone HCl 70476-82-3 NIOSH 2010 1

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Table A-1. List of Drugs Reviewed by ERG and Tier Assignments

Drug CASRN Source Tier Notes 123 Mometasone furoate 83919-23-7 NIOSH 2011 2 Very little lethality data, borderline Tier 3. NIOSH proposed as an addition to its List of Hazardous Drugs. 124 Mycophenolate mofetil 128794-94-5 NIOSH 2010 3 125 Mycophenolic acid 24280-93-1; NIOSH 2011 2,3 Different data were found for 483-60-3 the CASRN and alternate CASRN, resulting in a different tier for each (24280-93-1 = Tier 2; 483-60-3 = Tier 3). NIOSH proposed as an addition to its List of Hazardous Drugs. 126 Nafarelin 76932-56-4 NIOSH 2010/OSHA 3 127 Nelarabine 121032-29-9 NIOSH 2010 3 128 Nilotinib 641571-10-0 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 129 Nilutamide 63612-50-0 NIOSH 2010 2 130 Oxaliplatin 61825-94-3 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 131 Oxcarbazepine 28721-07-5 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 132 Oxytocin 50-56-6 NIOSH 2010 1 133 Paclitaxel 33069-62-4 NIOSH 2010 2 134 Palifermin 162394-19-6 NIOSH 2010 3 135 Paroxetine HCl 78246-49-8 NIOSH 2010 2 136 Paroxetine mesylate 217797-14-3 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 137 Pazopanib HCl 635702-64-6 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 138 Pegaspargase 130167-69-0 NIOSH 2010 3 139 Pemetrexed 137281-23-3 NIOSH 2010 3 140 Pentamidine isethionate 140-64-7 NIOSH 2010 2 141 Pentetate calcium 12111-24-9 NIOSH 2010 2 trisodium 142 Pentostatin 53910-25-1 NIOSH 2010 2 143 Perphosfamide 62435-42-1 NIOSH 2010 3 NIOSH proposed deletion from List of Hazardous Drugs. 144 Phenoxybenzamine HCl 63-92-3 NIOSH 2011 2 NIOSH proposed as an addition to its List of Hazardous Drugs. 145 Pipobroman 54-91-1 NIOSH 2010/OSHA 2 146 Piritrexim isethionate 79483-69-5 NIOSH 2010 3 NIOSH proposed deletion from List of Hazardous Drugs. 147 Pitavastatin Ca 147526-32-7 NIOSH 2011 2 Very little lethality data, borderline Tier 3. NIOSH proposed as an addition to its List of Hazardous Drugs. 148 Plerixafor 110078-46-1 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 149 Plicamycin 18378-89-7 NIOSH 2010/OSHA 2 NIOSH proposed deletion from List of Hazardous Drugs. 150 Podofilox 518-28-5 NIOSH 2010 2 Has a dermal LD50 in rabbits of 200 mg/kg, borderline Tier 1. 151 Podophyllum resin 9000-55-9 NIOSH 2010 2 A-5

Table A-1. List of Drugs Reviewed by ERG and Tier Assignments

Drug CASRN Source Tier Notes 152 Pralatrexate 146464-95-1 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 153 Prednimustine 29069-24-7 NIOSH 2010 2 NIOSH proposed deletion from List of Hazardous Drugs. 154 Procarbazine 671-16-9 NIOSH 2010/OSHA 2 155 Progesterone 57-83-0 NIOSH 2010 2 156 Progestins P097000000 NIOSH 2010 3 157 Raloxifene 84449-90-1 NIOSH 2010 3 158 Raltitrexed 112887-68-0 NIOSH 2010 3 NIOSH proposed deletion from List of Hazardous Drugs. 159 Rasagiline mesylate 161735-79-1 NIOSH 2010 3 160 Ribavirin 36791-04-5 NIOSH 2010/OSHA 2 161 Risperidone 106266-06-2 NIOSH 2010 2 162 Romidepsin 128517-07-7 NIOSH 2011 2 Very little lethality data, borderline Tier 3. NIOSH proposed as an addition to its List of Hazardous Drugs. 163 Rufinamide 106308-44-5 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 164 Simvastatin 79902-63-9 NIOSH 2011 2 NIOSH proposed as an addition to its List of Hazardous Drugs. 165 Sirolimus 53123-88-9 NIOSH 2010 2 166 Sorafenib 284461-73-0 NIOSH 2010 3 167 Streptozocin 18883-66-4 NIOSH 2010/OSHA 2 Already included on the U list of hazardous wastes (U206). 168 Sunitinib malate 341031-54-7 NIOSH 2010 3 169 Tacrolimus 109581-93-3; NIOSH 2010 2 104987-11-3 170 Tamoxifen 10540-29-1 NIOSH 2010/OSHA 2 171 Telavancin HCl 560130-42-9 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 172 Temsirolimus 162635-04-3 NIOSH 2011 3 NIOSH proposed as an addition to its List of Hazardous Drugs. 173 Temozolomide 85622-93-1 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 174 Teniposide 29767-20-2 NIOSH 2010 2 175 Testolactone 968-93-4 NIOSH 2010/OSHA 3 176 Testosterone 58-22-0 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 177 Tetracycline 64-75-5 NIOSH 2011 2 NIOSH proposed as an addition hydrochloride to its List of Hazardous Drugs. 178 Thalidomide 50-35-1 NIOSH 2010 2 179 Thioguanine 154-42-7 NIOSH 2010/OSHA 2 180 Thiotepa 52-24-4 NIOSH 2010/OSHA 1 181 Topotecan 123948-87-8 NIOSH 2010 3 182 Toremifene citrate 89778-27-8 NIOSH 2010 2 183 Tositumomab 192391-48-3; NIOSH 2010 3 NIOSH proposed deletion from 208921-02-2 List of Hazardous Drugs. 184 Tretinoin 302-79-4 NIOSH 2010 2 185 Trifluridine 70-00-8 NIOSH 2010 2 186 Trimetrexate 82952-64-5 NIOSH 2010 2 NIOSH proposed deletion from glucuronate List of Hazardous Drugs. 187 Triptorelin 57773-63-4 NIOSH 2010 3 A-6

Table A-1. List of Drugs Reviewed by ERG and Tier Assignments

Drug CASRN Source Tier Notes 188 Uracil mustard 66-75-1 NIOSH 2010/OSHA 1 Already included on the U list of hazardous wastes (U237). 189 Valganciclovir 175865-60-8 NIOSH 2010 3 190 Valproic acid 99-66-1 NIOSH 2011 2 NIOSH listed “Valproic acid/Divalproex Na”; however, since each drug has a unique CASRN, ERG captured information for them individually. NIOSH proposed as an addition to its List of Hazardous Drugs. 191 Valrubicin 56124-62-0 NIOSH 2010 2 Very little lethality data, borderline Tier 3. 192 Vidarabine 24356-66-9; NIOSH 2010/OSHA 2 5536-17-4 193 Vigabatrin 60643-86-9 NIOSH 2011 2 NIOSH proposed as an addition to its List of Hazardous Drugs. 194 Vinblastine 865-21-4 OSHA 2 195 Vinblastine sulfate 143-67-9 NIOSH 2010 2 196 Vincristine 57-22-7 OSHA 2 197 Vincristine sulfate 2068-78-2 NIOSH 2010 2 198 Vindesine 53643-48-4 NIOSH 2010 2 NIOSH proposed deletion from List of Hazardous Drugs. 199 Vinorelbine tartrate 125317-39-7 NIOSH 2010 3 200 Vorinostat 149647-78-9 NIOSH 2010 3 201 Zidovudine 30516-87-1 NIOSH 2010/OSHA 2 202 Ziprasidone HCl 122883-93-6; NIOSH 2011 3 NIOSH proposed as an addition 138982-67-9 to its List of Hazardous Drugs. 203 Zoledronic acid 118072-93-8 NIOSH 2011 2 Very little lethality data, borderline Tier 3. NIOSH proposed as an addition to its List of Hazardous Drugs. 204 Zonisamide 68291-97-4 NIOSH 2010 2

A-7

Appendix B TOXICITY DATA

(See separate Excel file: ORCR Drug Data.xlsx)

B-1

Appendix C LIST OF CONTROLLED SUBSTANCES BY DEA SCHEDULE

C-1

Table C-1. Schedule I Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES 1-(1-Phenylcyclohexyl)pyrrolidine 7458 I N PCPy, PHP, rolicyclidine 1-(2-Phenylethyl)-4-phenyl-4- 9663 I Y PEPAP, synthetic heroin acetoxypiperidine 1-[1-(2- 7470 I N TCP, tenocyclidine Thienyl)cyclohexyl]piperidine 1-[1-(2- 7473 I N TCPy Thienyl)cyclohexyl]pyrrolidine 1-Methyl-4-phenyl-4- 9661 I Y MPPP, synthetic heroin propionoxypiperidine 2,5-Dimethoxy-4-(n)- 7348 I N 2C-T-7 propylthiophenethylamine 2,5-Dimethoxy-4-ethylamphetamine 7399 I N DOET 2,5-Dimethoxyamphetamine 7396 I N DMA, 2,5-DMA 3,4,5-Trimethoxyamphetamine 7390 I N TMA 3,4-Methylenedioxyamphetamine 7400 I N MDA, Love Drug 3,4- 7405 I N MDMA, Ecstasy, XTC Methylenedioxymethamphetamine 3,4-Methylenedioxy-N- 7404 I N N-ethyl MDA, MDE, MDEA ethylamphetamine 3-Methylfentanyl 9813 I Y China White, fentanyl 3-Methylthiofentanyl 9833 I Y Chine White, fentanyl 4-Bromo-2,5- 7391 I N DOB, 4-bromo-DMA dimethoxyamphetamine 4-Bromo-2,5- 2C-B, Nexus, has been sold as 7392 I N dimethoxyphenethylamine Ecstasy, i.e. MDMA 4-Methoxyamphetamine 7411 I N PMA 4-Methyl-2,5- 7395 I N DOM, STP dimethoxyamphetamine 4-Methylaminorex (cis isomer) 1590 I N U4Euh, McN-422 5-Methoxy-3,4- 7401 I N MMDA methylenedioxyamphetamine 5-Methoxy-N,N- 7439 I N 5-MeO-DIPT diisopropyltryptamine 5-Methoxy-N-N-dimethyltryptamine 7431 I N 5-MeO-DMT Acetorphine 9319 I Y Acetyl-alpha-methylfentanyl 9815 I Y Acetyldihydrocodeine 9051 I Y Acetylcodone Acetylmethadol 9601 I Y Methadyl acetate Allylprodine 9602 I Y Alphacetylmethadol except levo- 9603 I Y alphacetylmethadol Alpha-ethyltryptamine 7249 I N ET, Trip Alphameprodine 9604 I Y Alphamethadol 9605 I Y Alpha-methylfentanyl 9814 I Y China White, fentanyl

C-1

Table C-1. Schedule I Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Alpha-methylthiofentanyl 9832 I Y China White, fentanyl Alpha-methyltryptamine 7432 I N AMT Aminorex 1585 I N has been sold as methamphetamine Benzethidine 9606 I Y Benzylmorphine 9052 I Y Betacetylmethadol 9607 I Y Beta-hydroxy-3-methylfentanyl 9831 I Y China White, fentanyl Beta-hydroxyfentanyl 9830 I Y China White, fentanyl Betameprodine 9608 I Y Betamethadol 9609 I Y Betaprodine 9611 I Y Bufotenine 7433 I N Mappine, N,N-dimethylserotonin Cathinone 1235 I N Constituent of "Khat" plant Clonitazene 9612 I Y Codeine methylbromide 9070 I Y Codeine-N-oxide 9053 I Y 5-(1,1-Dimethylheptyl)-2-[(1R,3S)-3- CP-47497 7297 I N hydroxycyclohexyl phenol 5-(1,1-Dimethyloctyl)-2-[(1R,3S)3- CP-47497 C8 Homologue 7298 I N hydroxycyclohexyl phenol Cyprenorphine 9054 I Y Desomorphine 9055 I Y Dextromoramide 9613 I Y Palfium, Jetrium, Narcolo Diampromide 9615 I Y Diethylthiambutene 9616 I Y Diethyltryptamine 7434 I N DET Difenoxin 9168 I Y Lyspafen Dihydromorphine 9145 I Y Dimenoxadol 9617 I Y Dimepheptanol 9618 I Y Dimethylthiambutene 9619 I Y Dimethyltryptamine 7435 I N DMT Dioxaphetyl butyrate 9621 I Y Dipipan, phenylpiperone HCl, Dipipanone 9622 I Y Diconal, Wellconal Drotebanol 9335 I Y Metebanyl, oxymethebanol Ethylmethylthiambutene 9623 I Y Etonitazene 9624 I Y Etorphine (except HCl) 9056 I Y

C-2

Table C-1. Schedule I Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Etoxeridine 9625 I Y Captagon,amfetyline,ethyltheophylline Fenethylline 1503 I N amphetamine Furethidine 9626 I Y GHB, gamma hydroxybutyrate, Gamma Hydroxybutyric Acid 2010 I N sodium oxybate Heroin 9200 I Y Diacetylmorphine, diamorphine Hydromorphinol 9301 I Y Hydroxypethidine 9627 I Y Constituent of "Tabernanthe iboga" Ibogaine 7260 I N plant JWH-018 (also known as AM678) 7118 I N 1-Pentyl-3-(1-naphthoyl)indole JWH-073 7173 I N 1-Butyl-3-(1-naphthoyl)indole 1-[2-(4-Morpholinyl)ethyl]-3-(1- JWH-200 7200 I N naphthoyl)indole Ketobemidone 9628 I Y Cliradon Levomoramide 9629 I Y Levophenacylmorphan 9631 I Y Lysergic acid diethylamide 7315 I N LSD, lysergide Marihuana 7360 I N Cannabis, marijuana Mecloqualone 2572 I N Nubarene Mescaline 7381 I N Constituent of "Peyote" cacti Quaalude, Parest, Somnafac, Opitimil, Methaqualone 2565 I N Mandrax Methcathinone 1237 I N N-Methylcathinone, "cat" Methyldesorphine 9302 I Y Methyldihydromorphine 9304 I Y Morpheridine 9632 I Y Morphine methylbromide 9305 I Y Morphine methylsulfonate 9306 I Y Morphine-N-oxide 9307 I Y Myrophine 9308 I Y N,N-Dimethylamphetamine 1480 I N N-Benzylpiperazine 7493 I N BZP, 1-benzylpiperazine N-Ethyl-1-phenylcyclohexylamine 7455 I N PCE N-Ethyl-3-piperidyl benzilate 7482 I N JB 323 N-Ethylamphetamine 1475 I N NEA N-Hydroxy-3,4- 7402 I N N-hydroxy MDA methylenedioxyamphetamine Nicocodeine 9309 I Y Nicomorphine 9312 I Y Vilan C-3

Table C-1. Schedule I Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES N-Methyl-3-piperidyl benzilate 7484 I N JB 336 Noracymethadol 9633 I Y Norlevorphanol 9634 I Y Normethadone 9635 I Y Phenyldimazone Normorphine 9313 I Y Norpipanone 9636 I Y Para-Fluorofentanyl 9812 I Y China White, fentanyl Parahexyl 7374 I N Synhexyl, Peyote 7415 I N Cactus which contains mescaline Phenadoxone 9637 I Y Phenampromide 9638 I Y Phenomorphan 9647 I Y Phenoperidine 9641 I Y Operidine, Lealgin Copholco, Adaphol, Codisol, Lantuss, Pholcodine 9314 I Y Pholcolin Piritramide 9642 I Y Piridolan Proheptazine 9643 I Y Properidine 9644 I Y Propiram 9649 I Y Algeril Psilocybin 7437 I N Constituent of "Magic mushrooms" Psilocin, constituent of "Magic Psilocyn 7438 I N mushrooms" Racemoramide 9645 I Y THC, Delta-8 THC, Delta-9 THC, Tetrahydrocannabinols 7370 I N dronabinol and others Acetylhydrocodone, Acedicon, Thebacon 9315 I Y Thebacetyl Thiofentanyl 9835 I Y Chine white, fentanyl Tilidine 9750 I Y Tilidate, Valoron, Kitadol, Lak, Tilsa Trimeperidine 9646 I Y Promedolum NARC - Narcotic

Table C-2. Schedule II Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES 1-Phenylcyclohexylamine 7460 II N PCP precursor 1-Piperidinocyclohexanecarbonitrile 8603 II N PCC, PCP precursor 4-Anilino-N-phenethyl-4-piperidine 8333 II N ANPP (ANPP) Alfentanil 9737 II Y Alfenta Alphaprodine 9010 II Y Nisentil C-4

Table C-2. Schedule II Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Amobarbital 2125 II N Amytal, Tuinal Amphetamine 1100 II N Dexedrine, Adderall, Obetrol Anileridine 9020 II Y Leritine Benzoylecgonine 9180 II Y Cocaine metabolite Bezitramide 9800 II Y Burgodin Carfentanil 9743 II Y Wildnil Coca Leaves 9040 II Y Cocaine 9041 II Y Methyl benzoylecgonine, Crack Morphine methyl ester, methyl Codeine 9050 II Y morphine Dextropropoxyphene, bulk (non-dosage 9273 II Y Propoxyphene forms) Dihydrocodeine 9120 II Y Didrate, Parzone Dihydroetorphine 9334 II Y DHE Diphenoxylate 9170 II Y Ecgonine 9180 II Y Cocaine precursor, in Coca leaves Ethylmorphine 9190 II Y Dionin Etorphine HCl 9059 II Y M 99 Duragesic, Oralet, Actiq, Fentanyl 9801 II Y Sublimaze, Innovar Glutethimide 2550 II N Doriden, Dorimide Hydrocodone 9193 II Y dihydrocodeinone Hydromorphone 9150 II Y Dilaudid, dihydromorphinone Isomethadone 9226 II Y Isoamidone LAAM, long acting methadone, Levo-alphacetylmethadol 9648 II Y levomethadyl acetate Levomethorphan 9210 II Y Levorphanol 9220 II Y Levo-Dromoran Lisdexamfetamine 1205 II N Vyvanse Meperidine 9230 II Y Demerol, Mepergan, pethidine Meperidine intermediate-A 9232 II Y Meperidine precursor Meperidine precursor, Meperidine intermediate-B 9233 II Y normeperidine Meperidine intermediate-C 9234 II Y Meperidine precursor Metazocine 9240 II Y Methadone 9250 II Y Dolophine, Methadose, Amidone Methadone intermediate 9254 II Y Methadone precursor Desoxyn, D-desoxyephedrine, Methamphetamine 1105 II N ICE, Crank, Speed Methylphenidate 1724 II N Concerta, Ritalin, Methylin Metopon 9260 II Y C-5

Table C-2. Schedule II Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Moramide-intermediate 9802 II Y MS Contin, Roxanol, Oramorph, Morphine 9300 II Y RMS, MSIR Nabilone 7379 II N Cesamet Opium extracts 9610 II Y Opium fluid extract 9620 II Y Opium poppy 9650 II Y Papaver somniferum Opium tincture 9630 II Y Laudanum Opium, granulated 9640 II Y Granulated opium Opium, powdered 9639 II Y Powdered opium Opium, raw 9600 II Y Raw opium, gum opium Oripavine 9330 II Y OxyContin, Percocet, Endocet, Oxycodone 9143 II Y Roxicodone, Roxicet, Oxymorphone 9652 II Y Numorphan Pentobarbital 2270 II N Nembutal Phenazocine 9715 II Y Narphen, Prinadol Phencyclidine 7471 II N PCP, Sernylan Phenmetrazine 1631 II N Preludin P2P, phenyl-2-propanone, benzyl Phenylacetone 8501 II N methyl ketone Piminodine 9730 II Y Opium poppy capsules, poppy Poppy Straw 9650 II Y heads Poppy Straw Concentrate 9670 II Y Concentrate of Poppy Straw, CPS Racemethorphan 9732 II Y Racemorphan 9733 II Y Dromoran Remifentanil 9739 II Y Ultiva Secobarbital 2315 II N Seconal, Tuinal Sufentanil 9740 II Y Sufenta Tapentadol 9780 II Y Thebaine 9333 II Y Precursor of many narcotics NARC - Narcotic

Table C-3. Schedule III Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES 13Beta-ethyl-17beta-hydroxygon-4-en-3- 4000 III N one 17Alpha-methyl-3alpha,17beta-dihydroxy- 4000 III N 5alpha- androstane

C-6

Table C-3. Schedule III Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES 17Alpha-methyl-3beta,17beta-dihydroxy- 4000 III N 5alpha- androstane 17Alpha-methyl-3beta,17beta- 4000 III N dihydroxyandrost-4-ene 17Alpha-methyl-4-hydroxynandrolone (17alpha-methyl 4-hydroxy-17beta- 4000 III N hydroxyestr-4-en-3-one) 17Alpha-methyl-delta1- dihydrotestosterone (17beta hydroxy- 4000 III N 17-Alpha-methyl-1-testosterone 17alpha-methyl-5alpha-androst-1-en-3- one) 19-Nor-4,9(10)-androstadienedione 4000 III N 19-Nor-4-androstenediol (3beta,17beta- dihydroxyestr-4 ene; 3alpha,17beta- 4000 III N dihydroxyestr-4-ene) 19-Nor-4-androstenedione (estr-4-en-3,17- 4000 III N dione) 19-Nor-5-androstenediol (3beta,17beta- dihydroxyestr-5 ene; 3alpha,17beta- 4000 III N dihydroxyestr-5-ene) 19-Nor-5-androstenedione (estr-5-en-3,17- 4000 III N dione) 1-Androstenediol (3beta,17beta- dihydroxy-5alpha androst-1-ene; 4000 III N 3alpha,17beta-dihydroxy-5alpha androst- 1-ene) 1-Androstenedione (5alpha-androst-1-en- 4000 III N 3,17-dione) 3Alpha,17beta-dihydroxy-5alpha- 4000 III N androstane 3Beta,17beta-dihydroxy-5alpha- 4000 III N androstane 4-Androstenediol (3beta,17beta- 4000 III N 4-AD dihydroxy-androst-4 ene) 4-Androstenedione (androst-4-en-3,17- 4000 III N dione) 4-Dihydrotestosterone (17beta- Anabolex, Andractim, Pesomax, 4000 III N hydroxyandrostan-3 one) Stanolone 4-Hydroxy-19-nortestosterone (4,17beta- 4000 III N dihydroxyestr 4-en-3-one) 4-Hydroxytestosterone (4,17beta- 4000 III N dihydroxyandrost-4 en-3-one) 5-Androstenediol (3beta,17beta- 4000 III N dihydroxy-androst-5 ene) 5-Androstenedione (androst-5-en-3,17- 4000 III N dione) Amobarbital & noncontrolled active 2126 III N ingred. Amobarbital suppository dosage form 2126 III N Anabolic steroids 4000 III N "Body Building" drugs Androstanedione (5alpha-androstan-3,17- 4000 III N dione) C-7

Table C-3. Schedule III Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Aprobarbital 2100 III N Alurate Barbituric acid derivative 2100 III N Barbiturates not specifically listed Benzphetamine 1228 III N Didrex, Inapetyl Bolasterone (7alpha,17alpha-dimethyl- 4000 III N 17beta hydroxyandrost-4-en-3-one) Boldenone (17beta-hydroxyandrost-1,4- Equipoise, Parenabol, Vebonol, 4000 III N diene-3-one) dehydrotestosterone Boldione 4000 III N Buprenex, Temgesic, Subutex, Buprenorphine 9064 III Y Suboxone Butabarbital (secbutabarbital) 2100 III N Butisol, Butibel Butalbital 2100 III N Fiorinal, Butalbital with aspirin Butobarbital (butethal) 2100 III N Soneryl (UK) Calusterone (7beta,17alpha-dimethyl- 4000 III N Methosarb 17beta hydroxyandrost-4-en-3-one) Mechloral, Mecoral, Medodorm, Chlorhexadol 2510 III N Chloralodol Pre-Sate, Lucofen, Apsedon, Chlorphentermine 1645 III N Desopimon Clortermine 1647 III N Voranil Clostebol (4-chloro-17beta- Alfa-Trofodermin, Clostene, 4- 4000 III N hydroxyandrost-4-en-3-one) chlorotestosterone Codeine with papaverine or Codeine & isoquinoline alkaloid 90 mg/du 9803 III Y noscapine Empirin,Fiorinal,Tylenol,ASA or Codeine combination product 90 mg/du 9804 III Y APAP w/codeine Dehydrochloromethyltestosterone (4- chloro-17beta hydroxy-17alpha- 4000 III N Oral-Turinabol methylandrost-1,4-dien-3-one) Delta1-dihydrotestosterone (17beta- 4000 III N 1-Testosterone hydroxy-5alpha androst-1-en-3-one) Desoxymethyltestosterone 4000 III N Dihydrocodeine combination product 90 9807 III Y Synalgos-DC, Compal mg/du Marinol, synthetic THC in sesame Dronabinol (synthetic) in sesame oil in 7369 III N oil/soft gelatin as approved by soft gelatin capsule as approved by FDA FDA Drostanolone (17beta-hydroxy-2alpha- 4000 III N Drolban, Masterid, Permastril methyl-5alpha androstan-3-one) Embutramide 2020 III N Tributane Ethylestrenol (17alpha-ethyl-17beta- Maxibolin, Orabolin, Durabolin-O, 4000 III N hydroxyestr-4-ene) Duraboral Ethylmorphine combination product 15 9808 III Y mg/du Fluoxymesterone (9-fluoro-17alpha- Anadroid-F, Halotestin, Ora- methyl11beta,17beta-dihydroxyandrost-4- 4000 III N Testryl en-3-one) Formebolone (2-formyl-17alpha-methyl- 11alpha,17beta-dihydroxyandrost-1,4- 4000 III N Esiclene, Hubernol dien-3-one) Furazabol (17alpha-methyl-17beta- 4000 III N Frazalon, Miotolon, Qu Zhi Shu hydroxyandrostano[2,3-c]-furazan) C-8

Table C-3. Schedule III Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Gamma Hydroxybutyric Acid preparations 2012 III N Xyrem Hydrocodone & isoquinoline alkaloid <15 Dihydrocodeinone+papaverine or 9805 III Y mg/du noscapine Hydrocodone combination product <15 Lorcet, Lortab,Vicodin, 9806 III Y mg/du Vicoprofen,Tussionex, Norco Ketamine 7285 III N Ketaset, Ketalar, Special K, K Lysergic acid 7300 III N LSD precursor Lysergic acid amide 7310 III N LSD precursor Mestanolone (17alpha-methyl-17beta- Assimil, Ermalone, Methybol, 4000 III N hydroxy-5alphaandrostan-3-one) Tantarone Mesterolone (1alpha-methyl-17beta- 4000 III N Androviron, Proviron, Testiwop hydroxy-5alphaandrostan-3-one) Methandienone (17alpha-methyl-17beta- Dianabol, Metabolina, Nerobol, 4000 III N hydroxyandrost-1,4-diene-3-one) Perbolin Methandriol (17alpha-methyl- 4000 III N Sinesex, Stenediol, Troformone 3beta,17betadihydroxyandrost-5-ene) Methenolone (1-methyl-17beta-hydroxy- Primobolan, Primobolan Depot, 4000 III N 5alpha-androst1-en-3-one) Primobolan S Methyldienolone (17alpha-methyl-17beta- 4000 III N hydroxyestr4,9(10)-dien-3-one) Methyltestosterone (17alpha-methyl- 4000 III N Android, Oreton, Testred, Virilon 17betahydroxyandrost-4-en-3-one) Methyltrienolone (17alpha-methyl-17beta- 4000 III N Metribolone hydroxyestr4,9,11-trien-3-one) Methyprylon 2575 III N Noludar Mibolerone (7alpha,17alpha-dimethyl- 4000 III N Cheque, Matenon 17betahydroxyestr-4-en-3-one) Morphine combination product/50 mg/100 9810 III Y ml or gm Nalorphine 9400 III Y Nalline Nandrolone (17beta-hydroxyestr-4-en-3- Deca-Durabolin, Durabolin, 4000 III N one) Durabolin-50 Norbolethone (13beta,17alpha-diethyl- 4000 III N Genabol 17betahydroxygon-4-en-3-one) Norclostebol (4-chloro-17beta- 4000 III N Anabol-4-19, Lentabol hydroxyestr-4-en-3-one Norethandrolone (17alpha-ethyl-17beta- 4000 III N Nilevar, Pronabol, Solevar hydroxyestr-4en-3-one) Normethandrolone (17alpha-methyl- 4000 III N Lutenin, Matronal, Orgasteron 17betahydroxyestr-4-en-3-one) Paregoric, other combination Opium combination product 25 mg/du 9809 III Y products Oxandrolone (17alpha-methyl-17beta- Anavar, Lonavar, Oxandrin, 4000 III N hydroxy-2-oxa5alpha-androstan-3-one) Provitar, Vasorome Oxymesterone (17alpha-methyl-4,17beta Anamidol, Balnimax, Oranabol, 4000 III N dihydroxyandrost-4-en-3-one) Oranabol 10 Oxymetholone (17alpha-methyl-2- Anadrol-50, Adroyd, Anapolon, hydroxymethylene 17beta-hydroxy- 4000 III N Anasteron, Pardroyd 5alpha-androstan-3-one) Pentobarbital & noncontrolled active 2271 III N FP-3 ingred. Pentobarbital suppository dosage form 2271 III N WANS C-9

Table C-3. Schedule III Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Plegine, Prelu-2, Bontril, Melfiat, Phendimetrazine 1615 III N Statobex Secobarbital & noncontrolled active 2316 III N ingred Secobarbital suppository dosage form 2316 III N Stanozolol (17alpha-methyl-17beta- hydroxy-5alpha androst-2-eno[3,2-c]- 4000 III N Winstrol, Winstrol-V pyrazole) Stenbolone (17beta-hydroxy-2-methyl-- 4000 III N 5alpha-androst 1-en-3-one) Stimulant compounds previously excepted 1405 III N Mediatric Sulfondiethylmethane 2600 III N Sulfonethylmethane 2605 III N Sulfonmethane 2610 III N Talbutal 2100 III N Lotusate Testolactone (13-hydroxy-3-oxo-13,17- 4000 III N Teolit, Teslac secoandrosta 1,4-dien-17-oic acid lactone) Testosterone (17beta-hydroxyandrost-4- Android-T, Androlan, Depotest, 4000 III N en-3-one) Delatestryl Tetrahydrogestrinone (13beta,17alpha- diethyl-17beta hydroxygon-4,9,11-trien-3- 4000 III N THG one) Thiamylal 2100 III N Surital Thiopental 2100 III N Pentothal Tiletamine & Zolazepam Combination 7295 III N Telazol Product Trenbolone (17beta-hydroxyestr-4,9,11- 4000 III N Finaplix-S, Finajet, Parabolan trien-3-one) Vinbarbital 2100 III N Delvinal, vinbarbitone NARC - Narcotic

Table C-4. Schedule IV Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Alprazolam 2882 IV N Xanax Barbital 2145 IV N Veronal, Plexonal, barbitone Bromazepam 2748 IV N Lexotan, Lexatin, Lexotanil Stadol, Stadol NS, Torbugesic, Butorphanol 9720 IV N Torbutrol Camazepam 2749 IV N Albego, Limpidon, Paxor Constituent of "Khat" plant, (+)- Cathine 1230 IV N norpseudoephedrine Chloral betaine 2460 IV N Beta Chlor Chloral hydrate 2465 IV N Noctec Chlordiazepoxide 2744 IV N Librium, Libritabs, Limbitrol, SK-Lygen Clobazam 2751 IV N Urbadan, Urbanyl Clonazepam 2737 IV N Klonopin, Clonopin Clorazepate 2768 IV N Tranxene Clotiazepam 2752 IV N Trecalmo, Rize, Clozan, Veratran Cloxazolam 2753 IV N Akton, Lubalix, Olcadil, Sepazon C-10

Table C-4. Schedule IV Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Delorazepam 2754 IV N Dexfenfluramine 1670 IV N Redux Dextropropoxyphene dosage Darvon, propoxyphene, Darvocet, 9278 IV Y forms Propacet Diazepam 2765 IV N Valium, Diastat Dichloralphenazone 2467 IV N Midrin, dichloralantipyrine Diethylpropion 1610 IV N Tenuate, Tepanil Difenoxin 1 mg/25 ug 9167 IV Y Motofen AtSO4/du Estazolam 2756 IV N ProSom, Domnamid, Eurodin, Nuctalon Ethchlorvynol 2540 IV N Placidyl Ethinamate 2545 IV N Valmid, Valamin Ethyl loflazepate 2758 IV N Fencamfamin 1760 IV N Reactivan Fenfluramine 1670 IV N Pondimin, Ponderal Fenproporex 1575 IV N Gacilin, Solvolip Fludiazepam 2759 IV N Flunitrazepam 2763 IV N Rohypnol, Narcozep, Darkene, Roipnol Flurazepam 2767 IV N Dalmane Fospropofol 2138 IV N Lusedra Halazepam 2762 IV N Paxipam Haloxazolam 2771 IV N Ketazolam 2772 IV N Anxon, Loftran, Solatran, Contamex Loprazolam 2773 IV N Lorazepam 2885 IV N Ativan Lormetazepam 2774 IV N Noctamid Mazindol 1605 IV N Sanorex, Mazanor Mebutamate 2800 IV N Capla Medazepam 2836 IV N Nobrium Mefenorex 1580 IV N Anorexic, Amexate, Doracil, Pondinil Miltown, Equanil, Micrainin, Equagesic, Meprobamate 2820 IV N Meprospan Methohexital 2264 IV N Brevital Methylphenobarbital 2250 IV N Mebaral, mephobarbital (mephobarbital) Midazolam 2884 IV N Versed Modafinil 1680 IV N Provigil Nimetazepam 2837 IV N Erimin Nitrazepam 2834 IV N Mogadon Nordiazepam 2838 IV N Nordazepam, Demadar, Madar Oxazepam 2835 IV N Serax, Serenid-D Oxazolam 2839 IV N Serenal, Convertal Paraldehyde 2585 IV N Paral Pemoline 1530 IV N Cylert Talwin, Talwin NX, Talacen, Talwin Pentazocine 9709 IV N Compound Petrichloral 2591 IV N Pentaerythritol chloral, Periclor Phenobarbital 2285 IV N Luminal, Donnatal, Bellergal-S Ionamin, Fastin, Adipex-P, Obe-Nix, Phentermine 1640 IV N Zantryl Pinazepam 2883 IV N Domar C-11

Table C-4. Schedule IV Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Pipradrol 1750 IV N Detaril, Stimolag Fortis Prazepam 2764 IV N Centrax Quazepam 2881 IV N Doral Sibutramine 1675 IV N Meridia 1-dimethylamino-1,2-diphenylethane, SPA 1635 IV N Lefetamine Temazepam 2925 IV N Restoril Tetrazepam 2886 IV N Myolastan, Musaril Triazolam 2887 IV N Halcion Zaleplon 2781 IV N Sonata Zolpidem 2783 IV N Ambien, Ivadal, Stilnoct, Stilnox Zopiclone 2784 IV N Lunesta NARC - Narcotic

Table C-5. Schedule V Controlled Substances

DEA CSA SUBSTANCE NUMBER SCH NARC OTHER NAMES Codeine preparations - 200 mg/100 ml or 100 Cosanyl,Robitussin A- V Y gm C,Cheracol,Cerose,Pediacof Difenoxin preparations - 0.5 mg/25 ug V Y Motofen AtSO4/du Dihydrocodeine preparations 10 mg/100 ml or V Y Cophene-S, various others 100 gm Diphenoxylate preparations 2.5 mg/25 ug V Y Lomotil, Logen AtSO4 Ethylmorphine preparations 100 mg/100 ml or V Y 100 gm Lacosamide 2746 V N Vimpat Opium preparations - 100 mg/100 ml or /100 Parepectolin, Kapectolin PG, V Y gm Kaolin Pectin P.G. Pregabalin 2782 V N Lyrica Pyrovalerone 1485 V N Centroton, Thymergix NARC - Narcotic

C-12