United States Office of Pollution EPA 744-R-97-003
Environmental Protection Prevention and Toxics March 1997
Agency (7406)
vvEPA Chemistry Assistance
Manual for
Premanufacture
Notification
Submitters
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TABLE OF CONTENTS
PREFACE 1
LIST OF TABLES 3
LIST OF FIGURES 4
THE PREMANUFACTURE NOTIFICATION (PMN) REVIEW PROCESS 5
1.1 Introduction 5
1.2 The PMN Review Process 6
1.2.1 Receipt of the PMN 11
1.3 Chemistry Review Phase 12
1.3.1 Initial Chemistry Review 13
1.3.2 Inventory Review 15
1.3.3 Preparation of the Chemistry Report 16
1.3.4 Chemical Review and Search Strategy (CRSS) Meeting 24
1.4 Hazard Evaluation 27
1.4.1 Human and Ecological Hazard Identification 27
1.4.2 Environmental Fate 31
1.4.3 Structure-Activity Team Meeting 32
1.5 Exposure Evaluation 33
1.6 Risk Assessment/Risk Management Phase 35
1.6.1 Focus Meeting 35
1.6.2 Standard Review 38
References for Chapter 1 40
List of Selected Readings for Chapter 1 42
CHEMICAL INFORMATION NEEDED FOR RISK ASSESSMENT 44
2.1 Introduction 44
2.2 Important Chemical Information 45
2.2.1 Melting Point 45
2.2.2 Octanol/Water Partition Coefficient (Kow, P) 49
2.2.3 Water Solubility 59
2.2.4 Soil/Sediment Adsorption Coefficient 62
2.2.5 Henry's Law Constant 63
2.2.6 Boiling Point 65
2.2.7 Vapor Pressure 66
2.2.8 Reactivity 68
2.2.9 Hydrolysis 69
2.2.10 Spectral Data 70
2.2.11 Photolysis (Direct/Indirect) 70
2.2.12 Other Chemical Information 72
2.3 Use of Chemical Information in Assessment of PMN Chemicals 74
2.4 How EPA Obtains Physicochemical Information 74
2.4.1 General Approach 74
ii
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2.4.2 Methods of Searching for Measured Physicochemical Properties 78
2.4.3 Methods For Estimating Physicochemical Properties From
Structural Analogs 80
2.4.4 Methods For Estimating Physicochemical Properties Using Computer Estimation Programs ..81
References for Chapter 2 83
List of Selected Readings for Chapter 2 90
POLLUTION PREVENTION AND PREMANUFACTURE NOTIFICATIONS 95
3.1 Introduction: Pollution Prevention 95
3.2 Pollution Prevention Initiatives within EPA's PMN Program 97
3.2.1 Optional Pollution Prevention Information (page 11 of the PMN form) 97
3.2.2 Synthetic Method Assessment for Reduction Techniques (SMART) Review
98
3.3 Considerations in Implementing Pollution Prevention Practices Prior to Submission of PMN Substances 100
References for Chapter 3 103
List of Selected Readings for Chapter 3 104
THE TOXIC SUBSTANCES CONTROL ACT: HISTORY AND IMPLEMENTATION 105
A.I Introduction 105
A.2 The Premanufacture Provisions of TSCA 108
A.2.1 Definition of "Chemical Substance" Under TSCA 109
A.2.2 Definition of "New" Chemical Substance 109
A.2.3 Section 5: Manufacturing and Processing Notices 109
A.2.4 Other Sections of TSCA Related to Section 5 112
A.2.4.1 Section 4. Testing of Chemical Substances and Mixtures 112
A.2.4.2 Section 6. Regulation of Hazardous Chemical Substances and Mixtures 112
A.2.4.3 Section 7. Imminent Hazards 113
A.2.4.4 Section 8. Reporting and Retention of Information 113
A.2.4.5 Section 12. Exports 113
A.2.4.6 Section 13. Entry into Customs Territory of the
United States 113
A.2.4.7 Section 14. Disclosure of Data 114
A.3 Implementation of TSCA 114
A.3.1 The TSCA Inventory 114
A.3.2 Inventory Update Rule 116
A.3.3 Premanufacture Notification Rule and Form 116
A.3.4 Biotechnology 117
A.3.5 Exemptions 117
A.3.5.1 Test Market Exemptions 117
A.3.5.2 5(h)(3) Exemption for Research and Development 118
A.3.5.3 5(h)(4) Exemptions 118
A.3.5.4 Instant Film Exemption 118
A.3.5.5 Low Volume Exemption 118
A.3.5.6 Low Release and Exposure Exemption 119
A.3.5.7 Polymer Exemption 119
A.3.6 TSCA Section 5(e) Consent Orders and Significant New Use Rules 120
A.3.7 Polymers: The Two Percent Rule 121
iii
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A.3.8 Importing Chemical Substances 121
A.3.9 Addendum to Appendix: Inventory Reporting Regulations 121
References for Appendix 124
List of Selected Readings for Appendix 129
Index 132
IV
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PREFACE
Since the passage of the Toxic Substances
Control Act (TSCA) in 1976, the Environmental
Protection Agency (EPA) has received and reviewed
nearly 30,000 Premanufacture Notifications (PMNs)
for new chemical substances. During this period, the
Agency has developed both a review process to
estimate the risk attributable to a new chemical
substance and a decision process to determine whether
an unreasonable risk may occur if the substance is
commercialized.
The information included in the PMN
submissions constitutes the basis of the Agency's risk
assessments. Careful consideration is given to all
submitted physicochemical, environmental, and health-
related data. If the PMN does not contain chemical
properties or other information needed for assessment,
the Agency scientists often must estimate the missing
values. This leads to less accurate risk assessments
than might be desirable, and may lead to regulation of
substances that would not have been regulated if data
had been available.
The purpose of this book is to assist submitters
in the technical aspects of PMN preparation. EPA's
hope is that, with this information, submitters will be
able to develop more physicochemical property data
and other technical information for their new
substances so that the Agency's ability to perform
accurate risk assessments will increase. Chapter 1
provides a discussion of the PMN review process,
emphasizing its scientific aspects. Chapter 2, the heart
of the book, reviews the most important
physicochemical properties, including methods for
measurement and estimation, and describes how EPA
uses these properties to assess the risks of PMN
substances. Chapter 3 discusses the Agency's pollution
prevention program as it relates to the PMN program,
emphasizing factors that submitters should consider in
the development of new chemical substances and in
their preparation of PMNs. Both references and a list
of selected reading materials containing additional
information are included at the end of each chapter.
Also included is an Appendix, which provides an
historical overview of the factors and events leading to
the passage of TSCA, a summary of the
premanufacture provisions of TSCA, and a review of
the Agency's implementation of TSCA.
This book is intended primarily for people in the
chemical industry who are involved with the design and
development of new chemical substances, and the
submission of PMNs. This book is also intended for a
broader audience of other individuals such as technical
managers, risk assessors, and risk managers who are
involved with evaluating chemical substances for
potential risks. We feel that the information contained
in this book will help these individuals make better risk
assessment and risk management decisions.
Stephen C. DeVito, Ph.D.
Carol A. Farris, Ph.D.
Exposure, Economics, and Technology Division
Office of Pollution Prevention and Toxics U.S.
Environmental Protection Agency
Washington, DC 20460
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Acknowledgment Disclaimer
The authors gratefully acknowledge the support This publication has been reviewed and approved for
and encouragement of our many EPA colleagues who publication as an EPA document. Mention of trade
rigorously reviewed this book or provided helpful names, commercial products, or computer programs
comments or assistance during its preparation: does not constitute Agency endorsement or
recommendation for use.
Frank S. Amato
(Eastman Kodak Company,
Rochester, NY)
Kent E. Anapolle, Ph.D.
Paul T. Anastas, Ph.D.
Charles M. Auer
Robert S. Boethling, Ph.D.
Anna C. Coutlakis
Mary E. Cushmac, Ph.D.
Gregory L. Fritz, Ph.D.
Roger L. Garrett, Ph.D.
Steven M. Hassur, Ph.D.
Carol L. Hetfield
Rebecca A. Jones
Leonard Keifer, Ph.D
Raymond J. Kent, Ph.D.
Doyoung Lee, Ph.D
Robert J. Lenahan.
C-T. Daniel Lin, Ph.D.
Robert L. Lipnick, Ph.D.
Gregory J. Macek
Nhan T. Nguyen
Breeda M. Reilly
William A. Silagi
Jay Tunkel, Ph.D.
(Syracuse Research Corporation,
Syracuse, NY)
Caroline D. Weeks, Ph.D.
Tracy C. Williamson, Ph.D.
Maurice G. Zeeman, Ph.D.
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LIST OF TABLES
Table 1-1 Types of Submissions and Their Designators 7
Table 1-2 Acronym List: Organizational and Meeting Acronyms 8
Table 1-3 Test Data Submitted with PMNs (1979-1985) 10
Table 1-4 Technical Problems Frequently Encountered in PMN Submissions 17-21
Table 1-5 Notations Used for CRSS Meeting Notes 26
Table 1-6 The Role of Pharmacokinetics in Predicting Health Hazards 30
Table 1-7 Possible Outcomes of Focus Meeting 37
Table 2-1 Methods of Measuring Octanol/Water Partition Coefficient (Kow) 54
Table 2-2 Methods of Estimating Octanol/Water Partition Coefficient (Kow) 56
Table A-l Sources of Office of Pollution Prevention
and Toxics Information 131
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LIST OF FIGURES
Figure 1-1 Office of Pollution Prevention and Toxics New Chemical (PMN)
Review Process 9
Figure 2-1 Important Physicochemical Properties, Their
Interrelationships, and Their Uses in Risk Assessment 46
Figure 2-2 Use of Octanol-Water Partition Coefficient (Log Kow) in
Risk Assessment 51
Figure 2-3 Methods for Obtaining Measured Physicochemical Property Values on
Exact Structures 75-76
Figure 2-4 Methods for Identifying Analogs of PMN Substances and Their
Physicochemical Properties 77
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Chapter 1
THE PREMANUFACTURE NOTIFICATION (PMN) REVIEW PROCESS
1.1 Introduction
Prior to the promulgation of the
Toxic Substances Control Act (TSCA) in
1976 (TSCA 1976), there was no statutory
requirement that required either risk
assessment of new chemical substances prior
to their commercial introduction or testing
of substances suspected of being harmful.
Unlike other federal statutes that regulate
risk after a chemical is in commerce, TSCA
requires the Environmental Protection
Agency (EPA) to assess and regulate risks to
human health and the environment before a
new chemical substance is introduced into
commerce. Section 5 of TSCA requires
manufacturers and importers to notify the
Agency before manufacturing or importing a
new chemical substance.1 EPA then
performs a risk assessment2 on the new
chemical substance to determine if an
unreasonable risk may or will be presented
by any aspect of the new substance. Finally,
EPA must make risk management decisions
and take action to control any unreasonable
risks posed by new chemical substances.
TSCA implies that EPA will develop
a review process for evaluating chemicals
before they enter the marketplace. Other
Acts, such as the Federal Food, Drug, and
Cosmetic Act (FFDCA 1982) and the
Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA 1972), have led to
the development of similar processes within
the FDA's New Drug Application Program
and EPA's Pesticide Registration Program,
respectively.
TSCA, however, departs from FDCA
and FIFRA in several significant ways in its
treatment of new substances. First, under
TSCA, the Agency only receives the data
that are available (if any) and must then
determine whether there may be an
unreasonable risk associated with the
chemical. Second, TSCA does not require
toxicity testing of a new chemical substance
prior to submission of a Premanufacture
Notification (PMN) to EPA. Third, under
1. As discussed in the Appendix, these provisions apply to substances that are either manufactured
within the U.S. or imported into the U.S. In the following discussion, the words manufacture or
manufacturer include import or importer.
2. Risk assessment is the characterization of the potential for adverse health or ecological effects
resulting from exposure to a chemical substance. Risk management is the weighing of policy alternatives
and selecting the most appropriate regulatory (or non-regulatory) action after integration of risk
assessment with social and economic considerations. Risk, in either case, is the probability that a
substance will produce harm under specified conditions, and is a function of the intrinsic toxicity of a
substance and the expected or known exposure to the substance. In practical situations, the critical factor
is not the intrinsic toxicity of a substance, but the risk associated with its use.
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TSCA, EPA is allowed only 90 days to
review each substance (extendable to 180
days under certain conditions; see
Appendix).
Currently, the EPA receives
approximately 2,500 PMNs annually. The
Agency must assess the risks posed by each
of these new substances, regardless of the
quantity or quality of data submitted or
available. Charged with the difficult task of
rapidly forecasting the environmental
behavior and toxicity of chemical substances
for which very little or nothing is known,
EPA has developed the PMN Review
Process. This process utilizes several
general approaches to fill in data gaps so that
the Agency can make rapid risk assessment
and risk management decisions for new
chemicals as prescribed by TSCA.
The PMN review process is used for
"standard" PMNs as well as PMN
exemption notifications (Appendix; USEPA
1986a; USEPA 1995b; USEPA 1995c). In
this chapter, the terms "PMN submission" or
"PMN" refer to all new substance
submissions, unless one type of submission
is mentioned explicitly. The types of
submissions and their respective review
periods are shown in Table 1-1.
Numerous acronyms are used to
describe Divisions or Branches within the
Office of Pollution Prevention and Toxics
(OPPT) as well as to identify scheduled
meetings and types of scientific reviews.
Table 1-2 contains a list of frequently-used
acronyms. This list is current as of
December 1996. OPPT is scheduled to be
reorganized in 1997 and some of these
acronyms will change. The PMN review
process, however, will remain essentially the
same.
1.2 The PMN Review Process
The PMN Review Process consists
of four distinct, successive technical phases:
the chemistry review phase, the hazard
(toxicity) evaluation phase, the exposure
evaluation phase and the risk
assessment/risk management phase. These
phases are structured to "drop" substances of
low-risk from review and to focus more
sharply on, and explore more deeply, those
substances of greater risk as the review
progresses. Thus, the resource-intensive
efforts of the later review phases are
conserved by eliminating many PMN
chemicals from consideration early in the
process and by focusing only on those
specific aspects of a few PMN substances
for which there is the greatest concern. It is
important to note that although a chemical
substance may drop from review because of
low risk, the 90-day review period still
applies.
The PMN Review Process is designed to
accommodate the large number of PMNs
received, to assess the risks posed by each
substance adequately within the strict
timeframe prescribed by TSCA (whether or
not toxicity data are available), and to
maximize the efficiency of staff resources.
Figure 1-1 provides an overview of the
process as it exists today. Although some
changes have taken place over the years, the
process illustrated in Figure 1-1 is quite
similar to the original PMN review process
that began in 1979.
Table 1-3 contains historical
information on the amount of test data
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Table 1-1. Types of Submissions and Their Designators
Submission
Type
Review
Period
Designator
Reference: TSCA
Section
PMN and Exemption
Submissions:
Standard Premanufacture
Notification (PMN) 90 days
Low Volume
Exemption (LVE) 30 days
Low Release and
Exposure Exemption
(LoRex) 30 days
Test Market
Exemption (TME) 45 days
Polymer Exemption1 None
Non-PMN Submissions:
Correction Case2' varies
Enforcement Case3 varies
X
T
Formerly Y
C
I
5(h)(4)
5(h)(4)
5(h)(4)
N/A
N/A
1 Polymers meeting the conditions of the Agency's most recent Polymer Exemption Rule no
longer need to be submitted to the Agency (USEPA 1995a). See text for details.
2 Those correction cases that go through the PMN review process arise from requests by industry
to revise a previous PMN chemical name. Inventory corrections, which are requests to correct
chemical identity in initial Inventory reporting forms, do not go through the PMN review
process.
Enforcement cases arise from EPA investigations into potential TSCA violations.
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Table 1-2. Acronym List: Organizational and Meeting Acronyms
Organizational Acronyms*:
Office of Pollution Prevention and Toxics OPPT
Economics, Exposure, and Technology Division EETD
Industrial Chemistry Branch ICB
Chemical Engineering Branch CEB
Exposure Assessment Branch EAB
Regulatory Impacts Branch RIB
Health and Environmental Review Division HERD
Health Effects Branch HEB
Environmental Effects Branch EEB
Information Management Division IMD
TSCA Information Management Branch TIME
Confidential Business Information Center CBIC
Chemical Control Division CCD
New Chemicals Branch NCB
Chemical Screening and Risk Assessment Division CSRAD
Analysis and Information Management Branch AEVIB
Meeting Acronyms:
Chemical Review and Search Strategy CRSS
Structure-Activity Team SAT
*This list is current as of December 1996. OPPT is scheduled to be reorganized in 1997 and some
of these acronyms will change.
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Figure 1-1.
Office of Pollution Prevention and Toxics New Chemical (PMN) Review Process1
PMNs: Drop or Drop/Follow-up
[Including non-5(e) SNUR2 and
Letter of Concern]
Test Market Exemptions
Grant or Deny
Drop Polymers that Meet Select Criteria
Days 15-19
Days 9-13
Drop or Drop/Follow-up
Drop or Risk Management and Regulatory Action
1 See Appendix for additional information on EPA's authority under TSCA.
3 SNUR stands for Significant New Use Rule.
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Table 1-3. Test Data Submitted with PMNs (1979-1985)
1,2
Percent of PMNs Containing the Specified Data
Type of Data ... AT _ . _ .
All Non-Polymers Polymers
Toxicologic data (some)
Acute Toxicity (oral)
Acute Toxicity (dermal)
Acute Skin/Eye Irritation
Mutagenicity
Sensitization
Other
Ecotoxicological data (some)
Acute Toxicity (vertebrate)
Acute Toxicity (invertebrate)
Environmental fate data (some)
Biodegradation
LogP
No Test Data
44
38
21
34
13
8
8
9
6
3
9
6
3
54
55
50
27
45
18
12
11
11
9
3
11
8
5
41
28
22
13
21
6
5
O
5
O
2
5
2
1
70
1 These data are based on the receipt of approximately 5,500 PMNs. Current trends in test
data submissions are similar. See text for additional details and references.
2 Source: DiCarlo et al. 1986.
10
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submitted with PMNs; although the
information is several years old, the amount
of data submitted has not changed
significantly. From Table 1-3, it is apparent
that over half of all submitted PMNs have
not contained any hazard or fate test data.
More recent studies show that: less than 5%
of PMN submissions contain ecotoxicity
data (Zeeman et al. 1993); less than 4%
contain at least one measured
physicochemical property value (Lynch et al.
1991); and less than 1% contain
biodegradation data (Boethling and Sabljic
1989).
For the vast majority of PMN
substances, the Agency is unable to reach a
decision based on the submitted data alone.
The Agency utilizes a number of technical
approaches to overcome the lack of data
during risk assessment. These approaches
include, for example, chemistry review,
analysis of structure-activity relationships
(SARs), analysis of quantitative structure-
activity relationships (QSARs), and the use
of physicochemical properties to assess the
likelihood of absorption in exposed
individuals; the various approaches are
discussed in greater detail in this chapter and
in Chapter 2. The remainder of this chapter
discusses the PMN Review Process,
including the purpose and function of each
phase, with particular focus on the technical
approaches used by the Agency to assess the
risks of new chemical substances. Other
Agency publications are available to assist
the reader in understanding the general PMN
review process (USEPA 1986a) and in filing
aPMN(USEPA1991).3
1.2.1 Receipt of the PMN (Day 1)
PMN submissions are received at the
Confidential Business Information Center
(CBIC) where they are time- and date-
stamped. Here, appropriate security
management of any submissions containing
TSCA Confidential Business Information
(CBI) is initiated. The TSCA Information
Management Branch (TEVIB) performs an
administrative review of each submission to
verify that all of the required information,
other than specific chemical information, is
present in the PMN. This review includes
submitter and chemical information, generic
chemical name and use (if chemical name
and use information are claimed as CBI),
projected production volume, and the
presence of any submitted health or
environmental hazard studies in the
sanitized version (i.e., the version that does
not contain CBI). The submissions must
also contain the English translations for any
submitted studies originally written in a
foreign language. Next, TEVIB checks the
user tracking sheets received from EPA's
Financial Management Division to confirm
that the appropriate fees have been paid.
The submission is then forwarded to the
Industrial Chemistry Branch (ICB) of the
Exposure, Economics, and Technology
Division (EETD) where chemists check the
adequacy of the submitted chemical name,
molecular formula, and chemical structure
diagram to describe the new substance. As
of the effective date (May 30, 1995) of the
Revisions to PMN Regulations (USEPA
1995c), EPA requires the submission of a
correct Chemical Abstracts (CA) name that
3. These, and other useful documents for PMN submitters, are available through the TSCA
Assistance Information Service at (202) 554-1404.
11
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is consistent with listings of chemical names
for similar substances already on the TSCA
Inventory. A correct molecular formula and
chemical structure diagram, where
appropriate, are also required.
If the name is determined by EPA to be
inadequate or incorrect, the Agency will
declare the notice incomplete unless the
submitter used Method 1 (USEPA 1995c) to
determine chemical identification and
submitted exactly the same substance
information to EPA and the Chemical
Abstracts Service (CAS) Inventory Expert
Service. Only in this situation will EPA
allow the PMN review period to continue
while the problem is resolved. If the
submitter did not use the CAS Inventory
Expert Service (which solely constitutes
Method 1) the Agency will not begin the
review period until the problem is resolved
by the submitter. (See USEPA 1995c for
details.)
If no problems are identified during the
administrative and nomenclature
prescreening reviews, the first day of the
90-day clock4 for PMN review is the day
that the PMN submission was received at
EPA Headquarters. If very minor problems
are identified that would not constitute an
incomplete notice, and the information is
believed to be readily available, the
submitter is contacted for this information
by telephone. If the notice is incomplete, the
submitter is given a list of the problems in
writing so that the submitter will know what
is needed to complete the notice and start the
review period. If the submitter has not
responded to EPA's request for additional
information within 30 days, EPA terminates
the notice and returns the PMN user fee.
When all required additional information is
received from the submitter, the first day of
the review period is assigned as the day EPA
receives this information.
Following the resolution of any minor
problems with administrative information
and chemical identification, the CBIC staff
assign a case number to the PMN. Case
numbers are assigned in sequential order
using a one-letter designator to indicate the
type of submission (see Table 1-1). The
CBIC staff assign document control
numbers and log each submission (and copy)
into a computerized document tracking
system designed for TSCA CBI documents.
Using established procedures to protect CBI
(USEPA 1993), the CBIC staff forward
copies of each case to technical staff in
EETD and the Health and Environmental
Review Division (HERD) as well as to
program management staff in the Chemical
Control Division (CCD) for their respective
reviews.
1.3 Chemistry Review Phase (Days 2-12)
The first technical phase of PMN review
by EPA scientists is the chemistry review
phase, which is performed by the Industrial
Chemistry Branch (ICB). This phase
establishes a chemistry profile for each new
substance and establishes the essential
foundation for the review by other OPPT
4. The phrase "90-day clock" refers to standard PMN submissions. In the interest of brevity, the
reader should note that this phrase will be used for the amount of time in which the Agency must
complete its review; the actual time for exemption notices is less than 90 days, as indicated in
Table 1-1.
12
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scientists in subsequent phases of PMN
review. The chemistry review phase has
four components: initial review, preparation
of the Chemistry Report, Inventory review,
and discussion at the Chemical Review and
Search Strategy (CRSS)5 meeting.
1.3.1 Initial Chemistry Review (Day 2)
The initial chemistry review is a rapid
assessment by ICB chemists of each new
chemical submission. The first step is to
establish the technical completeness of the
submission. The chemists check the
reported Chemical Abstracts (CA) name,
molecular formula, and chemical structure
against the reactants and feedstocks used in
its manufacture to determine quickly
whether the PMN substance is identified
correctly, as well as consistently, and check
the generic chemical name (if provided) to
verify that it is appropriate.
If the submission is an exemption
notice, the chemist checks for compliance
with the exemption guidelines.6 For all
submissions, an in-house electronic database
is searched to establish if an identical
substance has been submitted previously.7
This check for previous exemptions is a
rapid screening process, not to be confused
with the definitive determination performed
during the Inventory review (see below).
Based on its experience during the
review of thousands of new chemical
substances, EPA has identified a group of
polymers (see below) that it believes poses
no unreasonable risk of harm to human
health or the environment. When a PMN
substance in initial chemistry review falls
within this group, the ICB chemist labels the
case a "pre-CRSS drop" and the Agency
performs no further review. As a general
practice, the Agency does not notify the
submitter that a PMN submission has been
dropped from further review; by law,
manufacture of a new substance cannot
commence before the normal review period
has expired, even for PMN cases that have
been dropped from further Agency review.
For a polymer to be considered a pre-
CRSS drop, it must satisfy all six of the
following criteria:
(1) It must belong to one of twelve (12)
acceptable polymer classes:
polyesters, polyamides and
polyimides, polyacrylates,
polyurethanes and polyureas,
polyolefms, aromatic polysulfones,
polyethers, polysiloxanes,
polyketones, aromatic polythioethers,
polymeric hydrocarbons, and phenol-
formaldehyde copolymers;
5. The CRSS meeting is the first meeting of the PMN review process.
6. Since the effective date of the Agency's revised Polymer Exemption Rule (USEPA 1995a), no
notifications have been required for exempt polymers. Manufacturers must, however, follow the
Agency's requirements for all polymers exempt under this rule.
7. In a change from the previous low volume exemption regulation, more than one low volume
exemption may now be granted for any substance (USEPA 1995b), but the Agency will assess
the risk of the total production volume if there is more than one exemption notification for the
same substance.
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(2) The levels of oligomer present in the
polymer must be less than or equal to
(a) 10 weight percent of polymer
molecules with molecular weight less
than 500 daltons and (b) 25 weight
percent of polymer molecules with
molecular weight less than 1,000
daltons;
(3) It must have no more than the level of
ionic character permitted by the
polymer exemption rule (generally a
functional group equivalent weight
for ionic groups greater than or equal
to 5,000);
(4) It must have (a) no reactive
functional groups, (b) only reactive
functional groups specifically
excluded based on OPPT's risk
assessment experience (e.g., blocked
isocyanates), or (c) a reactive
functional group equivalent weight
no less than a defined threshold (e.g.,
for pendant methacrylates, the
equivalent weight threshold is 5,000);
(5) The lowest number-average
molecular weight of the polymer
must be less than 65,000 daltons but
greater than 1,000 daltons; and
(6) the polymer must not swell in water.
These criteria have been developed for use
by EPA, although they can by useful to
submitters interested in developing low risk
polymers. These criteria should not be
confused with the criteria stated in the
Polymer Exemption Rule (USEPA 1995a),
which specifically exempt certain polymers
from PMN submission. (The above criteria
were used, however, in the development of
the Polymer Exemption Rule).
It has been the Agency's experience
that polymers meeting these criteria have a
low risk for causing adverse environmental
and human health effects. Both the group of
acceptable polymer classes and the reactive
functional group criteria are being updated
and expanded as OPPT's experience in risk
identification and assessment continues to
grow. The actual figure varies from time to
time, but, in general, many of the PMNs for
polymers meet these criteria and are dropped
from further review. (Many of these
polymers also qualify for exemption and
need not be reported at all.)
Another important function of the
initial chemistry review is to identify PMN
cases for which pollution prevention
opportunities may exist. For example, ICB
has developed a PMN screening
methodology known as the Synthetic
Method Assessment for Reduction
Techniques (SMART). The purpose of the
SMART review is to identify pollution
prevention opportunities (e.g., alternative
syntheses, in-process recycling, etc.) and to
encourage the PMN submitters to take
advantage of these opportunities, if possible,
during production of their new chemical
substances. The SMART review of PMN
cases takes place simultaneously with the
chemistry review. PMN cases that are
judged appropriate candidates for SMART
review are assigned to staff chemists with
expertise in identifying pollution prevention
opportunities as they relate to the
manufacture of the substance (see Chapter 3
and USEPA 1995e).
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The next step of the initial chemistry
review is to assign each PMN case (except
those already dropped) to a chemist for
preparation of a Chemistry Report.
Generally, each PMN is assigned to a staff
member with particular expertise in that
chemical class. For example, a submission
for a new dye would be assigned to an
organic chemist with experience reviewing
this class of substances. Substances
submitted simultaneously that are closely
related or that comprise a synthetic pathway
are typically assigned as a group to an
individual chemist for review.8
At this stage, the senior chemist also
assigns each PMN case for presentation at a
specific CRSS meeting. The CRSS
meetings are held twice a week, on Monday
and Thursday mornings. A routine CRSS
meeting has between 10 and 30 PMN cases;
frequently, some of the cases are grouped for
review and are presented together. This
twice-weekly bundling of cases for review
greatly increases the efficiency of the PMN
review process. Unless any unforeseen
problems delay the review of individual
cases, the cases bundled for review at this
point will go through the review process
together.
1.3.2 Inventory Review (Days 3-11)
The Inventory review is an extremely
important component of the PMN review
process, from both legal and technical
standpoints. The Inventory review,
performed by chemists within ICB, has two
major functions. The first is to establish a
complete and accurate chemical name for
the new substance. The chemist compares
the chemical structure, molecular formula,
the reactants, and the reaction scheme for
consistency with the CAS name submitted in
the PMN; if a CAS Registry Number is
provided, the chemist verifies it as well.
The name must be consistent with CAS
nomenclature policies and with how similar
substances have been named previously for
the TSCA Inventory. If inconsistencies are
found, the chemist declares the notice
incomplete, and review of the notice is
terminated, unless the submitter used
Method 1 to develop the name (See USEPA
1995c for details).
The second function of the Inventory
review is to determine definitively that the
new chemical substance is not (or is) on the
TSCA Chemical Substance Inventory. For
this search, the Agency uses the continually
updated computer database of the Inventory,
known as the Master confidential and non-
confidential listings. The Agency maintains
a separate list of low volume and LoREX
exemptions on the Master Inventory File, in
light of the special status of exempt
substances.
If the Inventory review establishes
that a PMN substance is currently on the
TSCA Inventory or the intended use of the
substance is a non-TSCA use (e.g.,
pesticide, pharmaceutical, pharmaceutical
8. PMNs for closely-related new chemical substances submitted at the same time by one
manufacturer are frequently grouped into what is called a consolidated submission. Each new
substance gets a unique case number, however. A consolidated submission must have prior
approval by the EPA. See USEPA 1991.
15
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intermediate), the substance is excluded
from PMN reporting.9 If the review
establishes that the same manufacturer had
submitted the identical substance in an
earlier PMN and that this submission was
not withdrawn, the new notice is declared
not valid. In either circumstance, Agency
staff terminate the review and notify the
submitter.
1.3.3 Preparation of the Chemistry
Report (Days 3-11)
It is essential that all of the chemical
aspects of PMN substances are thoroughly
explored and understood, because the
Agency's hazard and risk assessments are
based largely on the chemistry of these
substances. The chemistry information is
summarized in the Chemistry Report,
prepared for each PMN. In preparing the
Chemistry Report, the chemist verifies the
chemical identity information, researches the
chemistry of the PMN substance, and
examines and/or estimates the
physicochemical properties that are critical
for Agency risk assessment.10
Chemists frequently contact the PMN
submitter to clarify information submitted or
to discuss an apparent error. Most such
problems are resolved over the telephone (at
the submitter's discretion and with
confidentiality preserved, as appropriate),
allowing the PMN review to continue on its
normal schedule. The manufacturer is
required, however, to submit correction
pages for the Agency's records. EPA may
request a suspension of the 90-day clock
from the submitter if obtaining the necessary
information from the submitter is expected
to be delayed. Examples of frequent
chemistry problems with PMN submissions
are given in Table 1-4 (helpful advice
regarding these issues is also included). For
answers to questions about procedural,
technical, or regulatory requirements prior to
submitting a PMN, submitters are invited to
telephone a PMN Prenotice Coordinator at
(202) 260-1745, (202) 260-3937, or (202)
260-8994.
OPPT utilizes an electronic database
on its own local area network (LAN) that
captures and rapidly disseminates
information on the PMN case to the various
staff participating in the PMN review
process. This database, as well as the LAN,
is designed to protect CBI data. A portion of
this electronic database contains the
Chemistry Report data.
In establishing the chemical structure,
EPA recognizes two classes of chemical
substances (USEPA 1986b; USEPA 1991).
Class 1 substances are single compounds
composed of molecules with particular
atoms arranged in a definite, known
structure. Class 2 substances typically have
9. If the substance is already on the Inventory, the submitter is free to manufacture it, subject to
any SNUR, section 4 test rule, or other rule that the Agency may have promulgated for that
substance.
10. Many of EPA's risk assessments of PMN substances are based on the physicochemical
properties of these substances. A detailed discussion of the use of physicochemical properties
during risk assessment of PMN substances is provided in Chapter 2.
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Table 1-4. Technical Problems Frequently Encountered
in PMN Submissions
Page of Description of Problem
PMN Form
Chemical Identity Problems
Chemical name and structure do not agree because:
(1) degree of specificity is different in name vs.
structure, (e.g., the name indicates no specific isomer,
but the structure is specific for a particular isomer);
(2) submitter incorrectly drew the structure (i.e., the number of
bonds or atoms is incorrect; the location of bonds or
atoms is incorrect);
(3) submitter did not draw a representative or partial
structure of a complex/variable/multi-component PMN
substance (e.g., the appropriate form of a sulfur dye:
leuco or oxidized).
CAS Registry Number (CASRN) and chemical name or structure do not
agree because:
(1) submitter made a typographical error, or
(2) submitter is trying to cover a choice of alternative
counterions with one PMN (e.g., using either Na or Li or Mg),
or
(3) submitter is trying inappropriately to cover multiple, class 1 chemicals
with one PMN. The EPA allows a single PMN to cover multi-
components if submitter is making only one product. For multi-
component submissions, each unique substance should be drawn within
a single PMN.
CASRN and reactant name(s) do not agree, for the same reasons.
Chemical name and molecular formula do not agree, for the same reasons.
Reporting two or more substances as a mixture when they should be
considered collectively as a Class 2 substance.
Molecular weight values
The lowest number-average (NAVG) molecular weight is supposed to be
measured for the complete polymer mixture from a series of reactions or an
17
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Table 1-4. Technical Problems Frequently Encountered
in PMN Submissions (continued)
Page of Description of Problem
PMN Form
Molecular weight values (continued)
average of multiple analyses of a particular reaction; often it is submitted as
the lowest peak in an individual run.1
Although submitters are not required to report values for typical number-
average molecular weights for their polymers, this would be useful,
especially if the typical and lowest molecular weights are far apart.
For polymers that cannot be analyzed by GPC (these polymers typically are
high molecular weight and are solvent-insoluble), the molecular weight (in
grams/mole) can be estimated using Avagadro's number (6.02 x 1023)
multiplied by the mass of a typical particle.
Molecular weight values given as "greater than" some number are not helpful
unless the base number is fairly close to the actual molecular weight. For
example, MW > 10,000 is often listed; it might be more accurate, for
example, to list MW > 30,000 or > 100,000 or > 1,000,000.
Monomer composition of polymers
If the submitter does not know the identity of one or more monomers because
the identity is the proprietary information of a supplier, a letter of support
from the supplier of the proprietary monomer(s) is required to complete the
chemical identity information. The notice submitter must ensure that the
supplier sends the letter of support directly to EPA, referencing the PMN
submitter and the PMN user fee number. Often, these letters are missing.
Structural diagram of polymers
The structural diagram for polymers often fails to show at least the most
likely bond types (i.e., the chemical bonds of the polymer) expected to be
present, or a representative arrangement of monomers and other reactants in
the polymer. Submitters are expected to provide as much structural
information as known to or reasonably ascertainable by them.
1 See Chapter 2 for methodology and discussion.
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Table 1-4. Technical Problems Frequently Encountered
in PMN Submissions (continued)
Page of Description of Problem
PMN Form
Impurities and byproducts
Unreacted feedstocks and reactants are not listed when they should be. The
description of impurities and byproducts/coproducts is incomplete.
Generic names
Submitted generic names often are much more general than they should be,
and are sometimes improperly deceiving. The degree of masking of specific
parts of a name should be minimal, just enough to hide true proprietary
details. (For guidance, see USEPA 1986c.)
Synonyms and generic names
Both of these need to be consistent with the chemical structure. For example,
since polyethylene terephthalate is an aromatic polyester, it should not be
described as an aliphatic or olefmic polyester.
Use information
At least one use must be reported that is covered under TSCA. For example,
a substance used for coatings on eyeglasses would be excluded from TSCA
reporting, as it is part of a medical device covered under another statute, but
the same substance used also for telescope lens coatings would be subject to
reporting.
For substances with both TSCA and non-TSCA uses, submitters need to
specify the percentage of each use. The production volume to be reported is
the total amount manufactured for all uses.
If the use is given as "chemical intermediate," it would be useful to know the
ultimate use of the final product. The ultimate use may determine whether
the intermediate is even subject to TSCA. Further, unreacted chemical
intermediate remaining in the final product may present risk issues.
19
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Table 1-4. Technical Problems Frequently Encountered
in PMN Submissions (continued)
Page of Description of Problem
PMN Form
8 Process description
Weights of reactants and other starting materials charged and of product
formed are often missing.
A simple diagram showing only the reaction vessel and a list of reactants and
other starting materials doesn't reflect critical intermediate steps and
separations. For example, a simple process flow diagram for polyurethane
condensation polymers may show an alcohol in the reagent list as if the
alcohol were capping the polymer; however, it could be a solvent in the
formulated product.
Sometimes the diagram shows that both the free acid and its salt are formed
and isolated, but the PMN reports only one of these. Both may be separately
subject to reporting under TSCA.
Submitters who are planning to import a chemical(s), but contemplating
domestic manufacture should provide a prospective manufacturing process
diagram. They should know and describe how the substance is made or how
they plan to make it. A diagram of the processing or formulation of the PMN
substance after import should not be substituted for the manufacturing
process diagram.
Releases of non-PMN substances, such as solvents, from the chemical
reaction should be indicated. Mass or weight balance information would be
helpful to tie in with pollution prevention information on page 11.
13 Physical and Chemical Properties
The physical form of the neat substance would be very helpful and often is
not stated.
Physicochemical properties should be measured and reported for the neat
substance, whenever possible. If data are available for mixtures, solutions,
20
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Table 1-4. Technical Problems Frequently Encountered
in PMN Submissions (concluded)
Page of Description of Problem
PMN Form
13 Physical and Chemical Properties (continued)
or formulations containing the PMN substance, the percent of the individual
components should be specified. (Note that MSDS sheets, by law, reflect the
formulated product, whereas the PMN physicochemical property sheet should
reflect the neat substance.)
Upon occasion, physicochemical properties that exist in the literature are
inconsistent with those measured by the submitter.
Physicochemical properties are used by Agency toxicologists; toxicologists
usually consider water solubility or vapor pressure to be significant at lower
levels than do submitter chemists. For example, vapor pressures given in
PMNs as "<0.1 torr" are often significant for Agency reviews and should be
measured more exactly. Further, estimated values expected to be less than
0.01 torr, for example, should be reported as <0.01 torr and not simply <0.1
torr. The terms "negligible" and "soluble" are not useful.
For all submitted test data, the Agency requires submission of copies of the
actual data; a summary of the data is not considered to meet this requirement.
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variable or unknown compositions or are
composed of complex combinations of
different molecules and, hence, do not meet
the criteria for Class 1 substances.
For Class 1 substances, there is only
one molecular entity to review. For Class 2
substances, however, the chemist usually
identifies a representative molecule(s) for
review purposes. For example, a PMN
substance may be the reaction product of an
alcohol with a fatty acid feedstock having a
carbon chain length ranging from 2 to 18
atoms. The various esters in this reaction
product will differ somewhat in their
physicochemical properties and will likely
differ in potential health hazard, ecological
hazard, and/or exposure. The chemist is
responsible for deciding how this substance
is best represented for Agency review.
Once a Class 2 substance is placed
on the TSCA Inventory, the manufacturer
may have some limited compositional
freedom in the make-up of the substance.
Given this freedom, the Agency concentrates
its review on the composition with the
greatest potential for harm to health or the
environment (i.e., the worst case).
Typically, the chemist chooses the
component that is the lowest molecular
weight, the most water soluble, the most
volatile, or the most prevalent to represent
the whole Class 2 substance, although all
reasonable components are identified during
the chemistry review. Thus, the review is
representative of a very complex substance,
but focuses on the worst-case scenarios.
The chemist next considers the
synthesis of the PMN substance. He or she
reviews the feedstocks to establish that they
are identified correctly, that the PMN
substance can be synthesized from them, and
that they are individually listed on the TSCA
Inventory.11 This aspect of the chemistry
review is critical. One of the most frequent
errors in PMN submissions is that the named
PMN substances cannot be synthesized from
the listed feedstocks; either the feedstocks
or the PMN substances are not identified
correctly. For example, a straight-chain
octyl group is frequently listed in PMNs,
whereas a 2-ethylhexyl group is the actual
feedstock moiety. Although each group
contains eight carbons and there are not
large differences in physicochemical
properties, there may be significant
differences in toxicity. The Agency
anticipates that the most recent PMN rule
revision (USEPA 1995c) will decrease the
number of problems in this area through the
requirement of CAS nomenclature for
naming PMN substances. Regardless of the
effect of the rule, however, careful review
will remain an important function of Agency
chemists.
Chemists also review the chemical
synthesis to identify (or confirm) impurities
or byproducts that may be present in the
PMN substance. If present in substantial
quantities, impurities may pose even greater
risks than those of the PMN substance itself.
Chemists review the uses, production
volumes, and manufacturing methods of the
PMN substance. They determine whether
the chemical nature of the PMN substance is
consistent with its intended use and also
identify other potential commercial and
11. This is a quick check of the Inventory; more definitive searches of the Inventory are done as
required.
22
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consumer uses to be included in Agency
assessments of potential exposure to the
PMN substance from these other uses.12
During the chemistry review of a
PMN substance, chemists frequently identify
closely-related or congeneric substances for
which physicochemical and toxicity data are
available. These structural analogs are used
as surrogates for risk assessment of the PMN
substance. EPA chemists also identify
previous PMN cases with chemical
structures analogous to the case under
review (structural analogs). This allows
EPA staff to compare the current
assessments with earlier ones, promoting
consistency and aiding in relative risk
comparisons.
Chemists also identify "use analogs,"
which are other substances that have been or
are known to be used for the same purpose
as the intended use of the PMN substance.
Use analogs allow the Agency to compare
the risk of the PMN substance to that of
other commercial substances intended for
the same use.
Those physicochemical properties of
the PMN substance that are important to risk
assessment are also determined during the
chemistry review. These typically include
molecular weight, physical state, melting
point, boiling point, water solubility, vapor
pressure, and octanol/water partition
coefficient. Chemists develop a value for
each of these properties for every PMN in
the review process at this point; they may
also add values for other properties as
warranted by the specific PMN substance.
Chemists confirm submitted values (if
provided), locate experimental values from
the literature, or derive estimated values
using appropriate techniques. Chapter 2
provides a detailed discussion of
physicochemical properties, their
measurement or estimation, and their
subsequent use in risk assessment.
Most PMNs contain few
physicochemical data. Consequently, the
majority of physicochemical properties used
for risk assessment of PMN substances are
obtained by EPA scientists, usually by
estimation. Any chemical estimation
technique possesses some degree of
uncertainty. In the absence of data, it is the
practice of the Agency to select the
estimation method that, within reasonable
limits, maximizes the exposure or hazard
potential. The Agency's aim is to estimate
physicochemical properties to result in
somewhat higher exposure and risk, so that a
margin of safety results. Therefore, actual
exposures and risks will not be under-
estimated due to lack of data. For this
reason, it is in the submitter's best interest to
provide reliable experimental values in the
PMN, if these can be measured. Even
accurately measured (reliable) values for
close analogs of a PMN substance are likely
to be helpful for accurate estimation of
exposure and risk. A more detailed
discussion of the importance of accurate
physicochemical property data in the risk
assessment of PMN substances is provided
in Chapter 2.
12. The exposure to a chemical substance that has more than one use can vary substantially from
one use to the next. Thus, depending upon use, the overall risk of such a chemical can vary
substantially. If there are known uses (i.e., in the case of an imported substance, commercial
uses outside of the U.S.) or potential new uses that would be of concern for unreasonable risk,
the Agency may choose to develop a SNUR. See Appendix. 23
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For polymers, EPA chemists review
additional data, including the number-
average molecular weight of the polymer,
how it was determined, and what
percentages of the molecules in the polymer
have a molecular mass of less than 500
daltons and 1,000 daltons (USEPA 1995d).
This is a result of the Agency's findings that
lower weight oligomers may pose a greater
degree of risk than their corresponding
higher weight polymers, all else being equal.
Finally, chemists determine the equivalent
weight of any reactive functional group(s)
and charged species.
In rare cases, the chemist may
determine, during the more thorough
chemistry review, that a polymer fulfills the
requirements for a pre-CRSS drop (even
though the initial chemistry review did not
reach that conclusion). When this occurs,
the Agency drops the PMN from further
review.
1.3.4 Chemical Review and Search
Strategy (CRSS) Meeting (Days 8-12)
As stated earlier, the Agency's ability
to assess the potential hazards and risks of a
given PMN substance is based largely on the
chemistry of the substance. The chemistry
of each PMN substance, summarized in the
form of a Chemistry Report, is presented at
the CRSS meeting. The CRSS meeting is
thus an extremely important meeting within
the PMN process: it is at this meeting that
the chemistry needed for subsequent hazard
and risk assessments is discussed and
evaluated. The CRSS meeting is chaired by
one of the senior chemists in ICB and
attended by approximately 20 Ph.D.-level
scientists. The key participants are ICB
chemists, but representatives of most other
groups involved in the PMN review process
also attend. Typically, these include
toxicologists, chemical engineers, and
chemists from other branches in OPPT.
The CRSS chairman follows a
defined agenda to initiate discussion of each
new chemical submission that is in active
review at that point. (Pre-CRSS drops,
invalid, delayed, withdrawn, or incomplete
submissions are not discussed.) Cases that
previously had been delayed while the
submitter resolved problems are presented
first. Second are low volume cases.13
Finally, all test market exemptions and
regular PMN and SNUN cases are discussed
in the order in which they were received at
EPA headquarters. Occasionally,
corrections to PMN or exemption notices are
discussed at CRSS meetings, as are
enforcement cases. (Those enforcement
cases discussed at CRSS meetings are
usually PMN submissions for substances
already in commerce in violation of TSCA.)
The chemist who performed the
review presents the PMN case at the CRSS
meeting rapidly, but comprehensively, using
standardized visual aids to facilitate
understanding. He or she starts with the
case number (which indicates the
submission type), chemical name,
manufacturer, production volume, and
method of manufacture, then continues with
specific uses of the substance, focusing on
the structure and functional group(s) that
impart the characteristics of the PMN
13. Polymer exemption cases had been discussed here as well; however, under the revised
polymer exemption rule, the Agency no longer reviews polymer exemption notifications.
24
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substance. Next, the chemist discusses the
values of the physicochemical properties,
along with the methods used for their
estimation or, in the case of measured
values, the literature sources and
measurement methods used. These values
are closely scrutinized by meeting attendees,
as they form a basis for subsequent risk
assessments. The chemist compares and
contrasts any structure or use analogs from
previous PMN cases to the new submission.
Chemists also scrutinize PMN
submissions for pollution prevention
opportunities. This is discussed in detail in
Chapter 3. When applicable, the chemist
will discuss known or potential alternative
syntheses that appear to offer greater
pollution prevention opportunities than the
synthesis intended to be used by the PMN
submitter. If a Synthetic Method Assessment
for Reduction Techniques (SMART) review
(see Chapter 3, section 2.2) was undertaken,
the chemist presents these results,
concentrating on any less polluting
alternative syntheses that he or she may have
identified.
Finally, the chemist initiates a
discussion of any unique, interesting, or
important information regarding the new
chemical substance. These additional
comments may range from the curious (e.g.,
an unexpected shade of red displayed by a
new dye) to the serious (e.g., it appears that
the synthesis will form a particularly toxic
byproduct that was not identified in the
PMN), and may include information needed
by others in the PMN review process. The
chemist may discuss other potential uses of
the new substances (based on use data of
analogs or the substance itself) and the
anticipated production volumes.
Following the Chemistry Report
presentation, another ICB chemist presents
the proper chemical name for the PMN
substance; he or she also states whether it is
present on the TSCA Inventory. This
chemist further identifies any feedstocks or
other reagents that are not on the Inventory.
If the PMN substance is declared to be on
the TSCA Inventory, all review stops, as the
chemical is excluded from reporting.
Typically, during the presentation of
a case, attending staff members ask
questions and provide comments in
informal, round-table peer review. These
discussions draw on the combined
experience (both academic and industrial)
and scientific expertise of all participants to
evaluate the chemistry of the PMN
substance. Attendees also suggest ways to
resolve any problems that have arisen. If,
following all this discussion, the CRSS
meeting participants feel they do not have
sufficient information to be comfortable
with the technical quality and reliability of
the chemistry for the PMN substance, they
will delay further Agency review of the case
until additional information can be gathered.
The vast majority of cases, however,
proceed to the next step.
After the case is presented, ensuing
discussions are completed, and a consensus
is reached, the meeting chairman records the
status of each case using one or more
identifiers (shown in Table 1-5). The case
number, the chemist responsible for the
case, and the identifier(s) are entered into the
CRSS meeting notes. These notes are
physically posted in a central location and on
the CBI LAN. The CRSS notes are used by
subsequent reviewers for scheduling
purposes.
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Table 1-5. Notations Used For CRSS Meeting Notes
Notation Description
BT Biotechnology Case: The PMN substance is a biotechnology case.
CP Consolidation Problem: The different substances contained in a consolidated submission are not sufficiently
similar in nature or use.
DE Delayed: Indicates that the case could not be discussed at its initially-scheduled CRSS meeting and will be
delayed to the next meeting. Typically due to missing, ambiguous, inconsistent, or incorrect information that
could not be obtained, clarified, or corrected prior to the meeting. The review period clock (between 30 and
90 days) does not stop for delayed cases.
DR Dropped: Indicates a polymer that was dropped from further review, i.e., a pre-CRSS drop or a drop
decision made during the CRSS Meeting.
ER Excluded from Reporting: Indicates a substance that is specifically excluded from TSCA § 5 reporting
requirements (i.e., the chemical substance is listed on the TSCA Inventory, is not subject to TSCA reporting,
or does not meet the definition of "chemical substance" under TSCA).
EL Eligible: The new chemical meets the requirements for exemption. Only substances submitted as PMN
exemptions may be declared eligible.
1C Incomplete: The submission does not contain mandated information.
ID Chemical Identity: The correct identity of the new chemical substance is not accurately described or cannot
be ascertained.
MC Multi-component case: A reaction product combination reported in one submission (one PMN case number)
that is represented as a mixture under TSCA Inventory policy.
MX Mixture: The substance is a mixture of chemical substances and thus is excluded as a whole entity under
TSCA; the individual substances are, however, subject to PMN notification if they are not already on the
Inventory.
NE Not Eligible: The PMN substance is not eligible for the type of exemption filed.
NV Not Valid: The submission is identical to an earlier one submitted by the same manufacturer. (Previously,
only one low volume exemption was allowed per substance and any subsequent exemption requests were
declared not valid; see the revised exemption, USEPA 1995b.)
NX Not Exposure-based: The substance is a polymer produced at greater than 100,000 kg/yr that does not meet
certain criteria for inhalation toxicity. It is exempted from a human and environmental exposure review.
SP Suspended: Review of the substance is suspended at the submitter's request, although this process is usually
initiated by EPA phoning the submitter; the review clock stops.
SR Suspension Requested: A significant problem affecting the review of the case was found; the suspension
request is transmitted to the CCD manager who contacts the submitter to request a suspension.
LTF User Fee: A problem with the fee payment must be resolved before the review (and the review clock) can be
started.
WD Withdrawn: The submitter withdrew the submission.
YX Exposure-based: The new chemical substance is produced at greater than 100,000 kg/yr, is not a polymer
(unless it meets certain criteria for inhalation toxicity) and is, therefore, subject to a section 5(e) exposure
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Following the CRSS meeting, the
chemist who presented a specific case makes
any necessary changes to his or her
Chemistry Report and files the report
electronically on the CBI LAN and in hard
copy in the CBIC. Subsequent reviewers at
EPA use this report as a source of validated
chemical information for the next steps in
the PMN process: hazard identification and
risk assessment. The report is especially
critical to the hazard determinations
performed by the Structure-Activity Team
(SAT); correct structure, presence of
impurities, and physicochemical properties
identified during the chemistry review are
key to the accuracy of the SARs used by the
Agency to predict human and environmental
hazard, especially in the absence of
toxicological test data.
1.4 Hazard Evaluation
The second phase of the PMN
review process is the hazard evaluation
phase. The term "hazard," in the vernacular
of PMN review, is synonymous with
toxicity. The purpose of this phase, as the
name implies, is the identification of
possible hazards (toxic properties) of PMN
substances to human health and the
environment; this phase includes analyses of
the likelihood of absorption and metabolism
in humans, human toxicity, toxicity to
environmental organisms, and
environmental fate. During this phase,
OPPT convenes a team of scientists who
specialize in organic chemistry,
biochemistry, medicinal chemistry,
pharmacokinetics, metabolism, toxicology,
genetics, oncology, environmental
toxicology, and environmental fate. It is the
responsibility of this multidisciplinary team
to assess the potential hazards and risks of
each new substance within the narrow time
constraints of TSCA, using the sparse data
available for most of the substances. During
the hazard identification phase, these EPA
scientists strive to elucidate the probable
human toxicity, environmental fate, and
environmental hazards posed by each new
chemical substance. The hazard
identification phase begins at approximately
the same time as the Inventory review and
preparation of the chemistry report and
continues after the CRSS meeting.
1.4.1 Human and Ecological Hazard
Identification (Days 2-12)
For any case that is not a pre-CRSS
drop, scientific staff from the EAB, the
Health Effects Branch (HEB), and the
Environmental Effects Branch (EEB) of
HERD initiate reviews in the areas of
environmental fate, human toxicity, and
ecological effects, respectively, at
approximately the same time as the
Chemistry Report is being prepared by the
ICB. The first step is to evaluate submitted
test data and to search the scientific
literature for published information on the
PMN substance. As previously stated,
however, PMNs seldom contain enough
measured toxicity data to perform a
complete hazard assessment (see Table 1-3).
In addition, because PMN substances are
"new" substances, there are seldom any data
available on them in the scientific literature.
The paucity of human, animal, and
aquatic toxicity data for most PMN
substances has led OPPT scientists to use
several different approaches for hazard
identification. These approaches include:
consideration of the likelihood of absorption
from the lung, gastrointestinal tract, and
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skin; consideration of the expected products
of metabolism and their toxicity; structure-
activity relationships (SARs); and
consideration of the presence of structural
groups or substituents that are known to
bestow toxicity. SARs are the comparison
of the substance under review with
structurally analogous substances for which
data are available.14 In SARs, a series of
structurally similar chemicals for which a
measured toxicological or environmental
endpoint (the "activity") is available is used
as a basis for qualitative estimation of the
same endpoint for an untested chemical of
the same structural class. The underlying
assumption in using SARs is that the
toxicological properties of substances
belonging to the same chemical class are
related or attributable to the general structure
(or some particular portion thereof) of the
class. Logically, any substance that has the
same general structure is likely to have the
same toxicological properties. Using SARs,
for example, one can be alerted to the
possibility of a new, untested chemical
sharing the same toxic effect(s) with
structurally similar chemicals that are known
to produce the effect(s). On the other hand,
SARs can be used to mitigate a health
concern for a substance if an analog is
identified with data showing that the analog
is nontoxic.
HEB scientists qualitatively estimate
human acute and chronic toxicity of PMN
substances, including: oncogenicity;
mutagenicity; developmental toxicity;
neurotoxicity; reproductive toxicity; and
systemic toxicity, irritability, and
sensitization. Again, the Agency's findings
of the likelihood of these effects occurring in
humans are seldom based on measured
animal data on the PMN substance. Rather,
they are usually based on structural
comparison of the PMN substance with
closely-related substances for which toxicity
data are available (SARs). To use SARs
during PMN review, OPPT scientists try to
identify structural analogs of PMN
substances from the literature or from in-
house sources, including PMN structural
databases, TSCA section 8(e) toxicity
databases, and other in-house substructure-
searchable databases of substances for which
toxicity data are available.
Subtle differences in molecular
structure within a congeneric series of
substances can greatly change the relative
toxicity. Knowledge of the biochemical
mechanisms of toxicity can help to explain
why such structural differences affect
toxicity. OPPT scientists utilize their
knowledge of toxic mechanisms, whenever
possible, to improve the predictive quality of
SARs. In cases where analogs closely
related to the PMN substance are equally
good but vary greatly in toxicity and for
which mechanistic data on the chemical
class are unknown to EPA, it is the general
practice of EPA to assume that the PMN
substance is as toxic as the most toxic
analog. If, however, mechanistic data are
available and such data lead OPPT scientists
to believe that the PMN substance is less
toxic than other analogs, then EPA will
assume that the PMN substance is less toxic.
Although not required under TSCA, it
14. For most chemical substances, toxicity data are almost always derived from animal studies.
It is the policy of the EPA to assume that chemicals that are capable of causing toxic effects in
animals will cause the same toxic effects in humans.
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would be extremely helpful if PMN
submitters would provide analogs of the
PMN substance for which toxicity data are
available in their PMN submissions,
particularly if mechanistic data for the
chemical class are known to the submitter.
Such information would greatly enhance
EPA's ability to make more accurate hazard
assessments of PMN substances and lessen
the likelihood that OPPT scientists will
over-estimate the toxicity of PMN
substances.
HEB scientists also estimate the
probable human pharmacokinetics of the
PMN substance, evaluating absorption,
distribution and redistribution, metabolism
(biotransformation), and excretion of the
substance. Special attention is given to the
possible formation of toxic metabolites.
(The role of pharmacokinetics in predicting
health hazards is illustrated in Table 1-6 and
described further in DiCarlo 1986.)
Estimation of absorption is a particularly
important component of hazard
identification in that a PMN substance may
appear toxic (based on SARs), but it may
have other characteristics that will lead HEB
scientists to believe that the substance will
not be significantly absorbed through the
gastrointestinal tract, skin, or lungs of
humans. A human toxicity concern for a
PMN substance derived by SARs may be
mitigated by EPA's belief that the substance
will be poorly absorbed.
Although SARs are useful in
estimating toxicity, the likelihood of
absorption of a PMN substance through the
skin, lung, and gastrointestinal tract may not
be inferred easily from the structure without
careful consideration of the physicochemical
properties of the substance. The relationship
between the physicochemical properties of a
substance and its absorption is discussed in
greater detail in Chapter 2. OPPT scientists
use physicochemical properties extensively
to predict the likelihood of absorption of a
PMN substance.
Another approach used by EPA to
identify the likely toxicity of PMN
substances is quantitative structure-activity
relationships (QSARs), which combine
physicochemical properties with SARs. In
QSARs, a particular biological
(lexicological) or environmental property of
a series of structurally analogous chemicals
is mathematically correlated with one or
more physicochemical properties of the
chemicals using a regression equation. The
goal of QSAR is to delineate a particular
property or activity more precisely than is
possible by intuition or SAR alone. Using
QSARs, one can predict, for example, the
acute toxicity (LD50) value of an untested
substance directly from a physicochemical
property of that substance.
EEB scientists use QSARs to
estimate chronic and acute toxicity values
for fish (vertebrates), daphnids
(invertebrates), and algae (plants) (USEPA
1994). Based on these values, EEB
scientists determine a concentration of
concern, the minimum concentration at
which Agency scientists have concern about
harm to these aquatic species. These
QSARs most frequently utilize
octanol/water partition coefficient as the
physicochemical descriptor of toxicity.
Some other physicochemical properties used
by EEB scientists in QSARs include melting
point, dissociation constant, and water
solubility.
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Table 1-6. The Role of Pharmacokinetics in Predicting Health Hazards
Metabolic Process
Role in Human Health Risk Assessment
Absorption
Di stributi on/Redi stributi on
Biotransformation
Excretion
If a substance is not absorbed, its toxic expression is limited
to topical effects such as skin and eye irritation, and to
unfavorable effects on nose, mouth, respiratory tract, and
gastrointestinal tract membranes. Qualitative estimation of
the rate and extent of absorption is based on lipophilicity and
water solubility. The susceptibility of the substance to (and
the likely products of) degradation by microorganisms in the
gastrointestinal tract is important for assessing absorption
following oral exposure.
Tissue distribution and redistribution determine the potential
for a substance to reach a site where toxicity can be
expressed. These assessments require knowledge of blood
flow rates, the octanol/water partition coefficient, and the
dissociation constant of the PMN substance.
The rate of degradation as well as the nature and reactivity of
the metabolites are required for this assessment. Although
the body frequently uses biotransformation to detoxify
absorbed xenobiotics, in some cases toxic metabolites are
created.
If a compound is absorbed, its capability to express a
biological effect is generally limited by the amount of time it
remains in the body. Thus, a rapid rate of excretion will limit
the potential for an adverse effect.
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1.4.2 Environmental Fate
The environmental fate of PMN
substances is assessed by EAB scientists.
Environmental fate is a very important
component of hazard identification; it
predicts where a chemical will partition in
the environment, which is useful in
determining environmental and human
exposure and, ultimately, long-term health
and environmental effects of a substance.
Information on the partitioning and
environmental lifetime of a substance is
important in determining levels, routes, and
the likelihood of both human and
environmental exposure. Environmental
fate assessment includes the consideration
of: relative rates of environmental
biodegradation, hydrolysis, and photolysis;
adsorption to soils and sediments;
treatability (generally in publicly-owned
treatment works (POTWs)); and half-lives in
the atmosphere, surface waters, soils, and
sediments.
Because fewer than 10% of
submitted PMNs contain environmental fate
data, EAB scientists typically must estimate
the environmental fate of new substances.
EAB scientists estimate the environmental
fate of a new chemical substance utilizing
the substance's water solubility,
octanol/water partition coefficient, soil
adsorption coefficient, vapor pressure,
Henry's Law constant, absorption spectra,
and bioconcentration factor (BCF).
Utilizing the physicochemical properties
obtained not only from the Chemistry
Report, but also from their own preliminary
review, EAB scientists estimate the potential
for a substance to adsorb onto soils and
sediments, pass into streams, rivers, and
groundwaters, and to volatilize into the
atmosphere. EAB scientists also estimate
the environmental lifetime of a PMN
substance by determining the percentage of
the substance removed by wastewater
treatment plants and the speed of hydrolysis,
primary and ultimate biodegradation, and
destruction by sunlight (photolysis) or
atmospheric oxidants.
It is readily apparent from the
preceding paragraphs of this section that
physicochemical properties play an
important role in estimating the likelihood of
human exposure and absorption,
environmental fate, ecological toxicity, and
thus, risk of chemical substances. A more
comprehensive discussion of
physicochemical properties, including their
measurement, estimation, and use in
estimating absorption, environmental fate,
QSARs, and exposure is provided in
Chapter 2. It is important to stress here,
however, that when PMN submitters do not
submit accurately-measured
physicochemical property data to EPA,
OPPT scientists will estimate such data if
they are unavailable from the literature or
other sources. The estimated values may not
always be accurate and may vary greatly
from one estimation method to another
because of the limitations of the estimation
methods. As a general practice during
physicochemical property estimation, OPPT
scientists will use those estimated values
that indicate significant exposure,
absorption, or toxicity. The importance of
OPPT possessing, and consequently
utilizing, accurately-measured
physicochemical property data for hazard
identification cannot be overstated.
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1.4.3 Structure-Activity Team Meeting
(Days 9-13)
Because of the strict time constraints
imposed by TSCA for PMN review, the
OPPT scientists involved with assessing the
potential hazards posed by PMN substances
must have their hazard and environmental
fate evaluations completed by the time the
PMN substances are to be discussed at the
designated SAT meetings. For most PMN
substances, this allows only two weeks or
less for the chemistry review, environmental
fate, and hazard evaluation by OPPT
scientists.
The SAT is a multidisciplinary team
composed of approximately twenty OPPT
scientists who specialize in disciplines that
include organic chemistry, biochemistry,
medicinal chemistry, pharmacokinetics,
general toxicology, neurotoxicology,
reproductive and developmental toxicology,
genetics, oncology, aquatic toxicology, and
environmental fate. These scientists are the
same scientists who perform the hazard
identification for PMN substances. The
purpose of the SAT meeting is for these
scientists to make a critical judgement on the
likely hazard(s) posed by each PMN
substance to human health and the
environment, so that subsequent risk
assessments and risk management decisions
regarding these substances can be made.
The SAT meetings are held twice a
week, on Tuesday and Friday mornings. In
general, the PMN cases discussed at the
CRSS meeting the day before (Monday or
Thursday, respectively) are discussed at the
SAT meeting. Exceptions are those cases
for which technical problems at CRSS delay
the review or those cases dropped from
review at CRSS. Each PMN substance is
discussed separately, and each SAT member
individually discusses his or her findings
and opinions, as well as the scientific basis
for those opinions.
The discussion of a PMN submission
begins with a summary of the chemistry of
the substance by the CRSS chairperson,
including: synthesis; byproducts or products
from side reactions that may be present as a
result of the synthesis; intended use; and
physicochemical properties. The
environmental fate specialist then
summarizes the potential for the substance
to adsorb onto soils and sediments, pass into
streams, rivers and groundwater, and
volatilize into the atmosphere; the
percentage removed by wastewater
treatment plants; rates of hydrolysis; primary
and ultimate biodegradation; and destruction
by sunlight (photolysis) or atmospheric
oxidants. Following the environmental fate
discussion, the pharmacokinetic specialist
discusses the extent to which the substance
is expected to be absorbed through the skin,
lung, and gastrointestinal tract and the
expected metabolites of the substance
following absorption. The other SAT
members then individually discuss their
findings and judgements regarding the case
being presented. The discussion may
include, for example, the toxicity of analogs,
previous related PMN cases, the significance
of functional groups, and toxic mechanisms.
These discussions culminate in deliberations
that lead to establishing separate, overall
ratings of the level of concern for human
health effects and for ecological effects of
each PMN substance using the following
scale: low, low to moderate, moderate,
moderate to high, or high.
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1.5 Exposure Evaluation (Days 13-15)
The third phase of PMN review
involves exposure evaluation. Following
the SAT meeting, other OPPT scientists and
engineers estimate the degree of human
exposure (occupational and general
population) and environmental exposure for
those PMN substances that receive a SAT
score of at least "low to moderate" for either
health or ecological effects. Like hazard
identification, exposure evaluation is a
critical component of risk assessment; it
consists of establishing the likelihood and
magnitude of occupational, consumer,
general population, and environmental
exposure of a substance through careful
consideration of the substances's
physicochemical properties, expected
environmental releases, known commercial
or consumer use(s), potential commercial or
consumer use(s) (identified during the
chemistry review), and environmental fate.
Substances that receive "low" SAT
scores for both human health and
environmental effects may also undergo an
exposure analysis if their production
volumes are greater than 100,000 kg per
year, because high production volumes such
as these may lead to significant exposure
and risk. Substances that receive "low"
SAT scores for both human health and
environmental effects and that have
production volumes below 100,000 kg per
year are generally not reviewed further.
The initial part of an exposure
review of a PMN substance is performed by
the Chemical Engineering Branch (CEB) of
EETD, two to four days prior to the Focus
meeting where the substance will be
discussed. CEB engineers utilize the
physicochemical properties of the PMN
substance, most notably vapor pressure and
molecular weight, to establish the
importance of both dermal and inhalation
exposure. For example, volatile substances
and powder are typically evaluated for their
potential for inhalation exposure.
CEB relies on the process flow and
unit operations to identify potential release
and exposure points. Using
physicochemical property data and identified
release and exposure points, CEB evaluates
the potential for occupational exposure and
for releases to the environment expected to
result from manufacturing, processing, and
commercial or industrial use of the
substance. In addition, CEB may apply
exposure and release data available on
chemical substances analogous to the PMN
substance, that are produced or used in
similar circumstances as the PMN
substance, to further evaluate occupational
exposure and environmental release.
Using models that take into account
the physicochemical properties of the PMN
substance as well as unit operations, number
of workers performing each operation, and
industry-specific worksheets to fill
remaining gaps, CEB engineers estimate the
number of workers potentially exposed, their
activities, their duration of exposure, and
potential dose rates.
Emissions to the environment are
obtained by evaluating data contained in the
PMN and industry-specific worksheets to
establish the potential for releases from
manufacture, processing, and use of the
PMN substance. Releases may be process-
related, such as equipment vents and
container residual. For example, losses to
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waste by a component of a photoresist
pattern are expected to be relatively high
(since most of a photoresist washes away
during the developing stage), whereas those
from a site-limited synthetic intermediate are
expected to be relatively low. The
physicochemical properties of the PMN
substance may also be important at this
stage; for example, water solubility is
sometimes used along with information in
the PMN to estimate potential releases to
water, and vapor pressure could be used to
estimate emissions to air.
EAB staff then receive data
generated by CEB staff, allowing them to
estimate levels of consumer and general
population exposure as well as the resulting
environmental concentrations that arise from
emissions. For example, a component of a
new spray coating designed for the
household market might be expected to have
higher levels of consumer exposure (through
inhalation) during use than a new additive
for motor oil (through dermal contact). To
estimate exposure to the general population,
EAB scientists consider the level of
emissions into each environmental medium
and the expected rate of removal. For
releases to water, EAB will consider the
percentage removed in a POTW (using the
actual facility expected to receive that waste
as indicated in the submission), the rates of
biological and chemical degradation, and the
degree of partitioning between water and
sediment. For releases to air, EAB uses the
rates of oxidation and photolysis to
determine probable fence-line
concentrations at the manufacturing facility.
EAB uses the rates of biodegradation,
volatilization, and percolation through soils
to derive the concentration of the PMN
substance in groundwater following its
release to land (including landfills). The
concentrations derived through this process
are then compared to the ecological
concentrations of concern developed prior to
the SAT meeting to establish the potential
for ecological effects that may result from
environmental emissions. Estimations of
yearly human intake from drinking water
and fish consumption (if bioaccumulation is
expected) are used to evaluate the potential
for health effects.
As in hazard identification,
physicochemical properties play a very
important role in estimating occupational,
population, and environmental exposure to
PMN substances. The quality of these
exposure estimates is obviously dependent
on the accuracy of the physicochemical
property data. Measured data are always
preferred over estimated data because
estimation methods, even the very good
ones, do not take into account all of the
intra- and intermolecular interactions
responsible for given physicochemical
properties. Estimated physicochemical
properties, therefore, generally contain
errors, which may vary widely. Estimated
physicochemical properties that contain
significant errors obviously affect the
reliability of the exposure and hazard
estimates derived from them. In cases where
physicochemical property data are not
available to EPA, the Agency estimates such
data using several methods. It is the policy
of the Agency to use those estimated values
which lead to greater hazard and greater
exposure. It behooves PMN submitters,
therefore, to submit accurately measured
physicochemical properties whenever
possible.
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An economist from the Regulatory
Impacts Branch (RIB) assesses the validity
of the production volume data submitted in
the PMN by comparing the reported values
to the historical median for similar chemical
substances.
1.6 Risk Assessment/Risk Management
Phase (Days 15-82)
The fourth phase of the PMN review
process is the risk assessment/risk
management phase. As stated earlier in
this chapter, risk is the probability that a
substance will produce harm under specified
conditions. Risk is a function of the
inherent toxicity (hazard) of a substance and
the expected or known exposure to the
substance. Risk assessment is the
characterization of the potential for adverse
health or ecological effects resulting from
exposure to a chemical substance.
Risk management refers to the way
in which the risks posed by a chemical
substance are minimized. This involves the
weighing of policy alternatives and selecting
the most appropriate regulatory (or non-
regulatory) action after integration of risk
assessment with social and economic
considerations. It is in the risk
assessment/risk management phase of PMN
review that the results of the hazard and
exposure evaluation phases are used to
assess the risk of PMN substances and make
the necessary decisions to manage any
unreasonable risks that may be posed by
PMN substances.
1.6.1 Focus Meeting (Days 15-19)
The general purpose of the Focus
meeting is to allow EPA staff and
management to discuss the hazard and
exposure evaluations of PMN substances
and to make risk assessment and risk
management decisions. More specifically,
the purposes of the Focus meeting are to:
(1) characterize (assess) the risks posed by
each PMN substance; (2) decide which
PMN substances will not present an
unreasonable risk and drop them from
further review; (3) identify the PMN
substances that may present an unreasonable
risk but for which risk management
decisions can be made without additional
review; and (4) identify the PMN substances
that may present an unreasonable risk but
require additional review for risk
characterization.
Focus meetings are held twice
weekly, on Monday and Thursday
afternoons. Focus meetings are chaired by
representatives from CCD; they are attended
by the chairpersons of the CRSS and SAT
meetings, and representatives from the
groups that performed the economic
analysis, environmental fate, and exposure
assessments.
The discussion of a PMN substance
at the Focus meeting begins with a summary
by the CRSS chairperson of its chemistry,
intended use, potential uses identified by
EPA, and any remarkable attributes of the
substance, as claimed by the submitter or
identified by EPA. Next, the SAT
chairperson summarizes the human health
and ecological hazards identified by the
SAT. This is followed by a summary of the
occupational, population, and environmental
exposures expected to occur from the
intended or potential uses of the PMN
substances by the people who made these
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estimates. A RIB economist will discuss the
validity of the production volume estimates.
From the information presented, the
Focus meeting participants assess and
characterize the risks posed by the PMN
substance to human health and the
environment, and carefully consider these
risks along with the expected or potential
societal benefits of the substance. Often,
EPA may identify significant risks of a PMN
substance that also has significant benefits to
society (e.g., the PMN substance will
supplant an existing chemical substance that
poses a greater risk). In such instances, it is
the practice of EPA to balance these factors
in making risk management decisions
regarding the PMN substance. It is the
policy of EPA's PMN Review Program to
encourage creative thinking by chemical
manufacturers and producers to design and
produce efficacious substances, and not
make risk management decisions (e.g., over-
regulation) that stifle creativity. Almost 90
percent of the PMNs submitted to the EPA
complete the review process without being
restricted or regulated in any way (USEPA
1995f).
There are eleven possible outcomes
for a PMN substance at the Focus meeting
(Table 1-7). These range from dropping a
regular PMN from further review (or
granting an exemption) to pursuing a
regulatory ban on the production, use, or
disposal of the new substance.
Approximately 80% of all PMN
submissions are dropped between pre-CRSS
and the end of the Focus meeting.
Some of the remaining 20% fall into
one of approximately 46 Chemical
Categories (USEPA 1996b) that have been
identified to date by the New Chemicals
Program. These categories were developed
as an administrative aid to facilitate reviews
by grouping chemicals into categories with
similar hazard concerns and testing
requirements. For each Category, the
Agency has developed a standard regulatory
response, often involving a section 5(e)
order to limit chemical production (and,
thus, exposure) pending a certain pertinent
test. This categorical approach is continually
evolving as EPA's experience increases.
For PMNs outside of the Categories
that the Focus group characterizes as
possessing significant risks, the chairman of
the Focus meeting will recommend a
specific regulatory response to mitigate the
concerns of the Agency's risk assessment.
For example, the meeting chairman may
decide to pursue regulation under an
exposure-based section 5(e) order if a high
production volume substance has high
predicted levels of worker, consumer, and
environmental exposure and a long
environmental lifetime. For another
substance that is expected to be released to
the environment in moderate amounts and is
similar in structure to a substance of known
chronic aquatic toxicity, the chairman may
decide to pursue a risk-based section 5(e)
order. Finally, the chairman may decide to
drop from further review a substance
expected to be released to the environment
in moderate amounts yet expected to have a
very short environmental lifetime.
For low volume exemptions and
LoRex exemptions, the Focus meeting
usually serves as the final regulatory
decision meeting because of the short review
period for these exemptions.
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Table 1-7. Possible Outcomes of the Focus Meeting
Outcome
Description
Grant
Deny
Drop
Standard Review
Letter of Concern
Non-5 (e) SNUR
(Significant New Use
Rule)
5(e) SNUR
5(e) Consent Order
5(e) Exposure-Based
Authority
Unilateral 5(e) Order
5(f) Order
A PMN exemption is granted.
A PMN exemption is denied; the submitter is free to submit the
substance as a regular PMN.
A regular PMN case is dropped from further review.
Further review of the substance is required before a regulatory decision
can be made; this review is often targeted to answering one or more
specific questions.
A concern for harm to health or the environment exists for the substance
although the risk is relatively low due to low production, exposure, or
release. After the meeting, the Agency will send a letter to the
manufacturer explaining the expected risk and suggested (i.e.,
voluntary) controls to reduce human and environmental exposure.
Letters of concern may be appropriate for routine PMNs, exemption
cases, enforcement cases, or corrections.
EPA will begin to draft a non-5 (e) SNUR, which prohibits manufacture
of the substance for any use other than that contained in a regular PMN
submission; manufacturers who wish to use a substance for such a
prohibited use must submit a Significant New Use Notification (SNUN)
to the Agency. Non-5 (e) SNURs are used for those PMNs in which the
intended use is judged not to be an unreasonable risk, whereas uses
other than the intended use may lead to unreasonable risk.
In conjunction with a 5(e) order, EPA will begin to draft a SNUR to
restrict the uses of a routine PMN substance. This is often necessary
because 5(e) orders apply only to the original submitter, whereas
SNURs apply to all manufacturers of that specific substance.
EPA will begin to negotiate with the submitter to prepare a written
agreement under section 5(e) that specifies testing required to determine
the risk of a routine PMN substance. The negotiated 5(e) order will
restrict the production, distribution, use, or disposal of the substance
until EPA has received and acted upon the required test data. Consent
orders are used for those regular PMNs whose intended use,
manufacture, processing, etc. may lead to an unreasonable risk unless
certain conditions are met to reduce exposure.
This is not a risk-based finding. The Agency begins to prepare a 5(e)
order requiring testing based on exposure only.
The Agency begins to prepare a unilateral order restricting a PMN
substance under section 5(e) until specified tests have been carried out.
The Agency begins to prepare an action to initiate a order under section
5(f) restricting or banning a PMN substance because unreasonable risk
has been established.
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If a question concerning a PMN
arises that cannot be answered during the
meeting, but may be answered quickly with
further investigation, the chairman may
delay a regulatory decision until the next
Focus meeting. If more substantial
questions remain or if closer examination of
the chemical is deemed necessary, the
chairman may put the PMN into Standard
Review (see section 1.6.2, below).
If a Focus meeting decision on a
PMN is to pursue regulation, the Program
Manager for a PMN case (from CCD staff)
will contact the manufacturer and describe
the reasons for the Agency's concern as well
as the regulatory controls that EPA intends
to impose.15 Often, the manufacturer may
disagree with the Agency's concern, and may
ask the Agency to suspend the review period
to allow the manufacturer time to conduct
the appropriate tests16 that the manufacturer
feels will mitigate the EPA's concern and
lead the Agency to reverse its regulatory
controls. The Agency will then use these
measured data in preference to estimated
data or worst-case assumptions. In some
cases, the real data mitigate the risk
sufficiently and the Agency drops the case
(or grants the exemption, as appropriate)
without the manufacturer having to contend
with the potential effects of EPA regulation
on the substance's marketability.
Discussions of the Agency's regulatory
mandate are available elsewhere (Appendix;
USEPA 1986a).
1.6.2 Standard Review (Days 15-65)
If it is decided at the Focus meeting
that a PMN substance may present
significant risk(s), but either the hazard or
exposure information identified prior to the
meeting is inadequate to characterize the
risk fully at the Focus meeting, a more
detailed review may be necessary for
adequate risk characterization, and the PMN
submission will be put into Standard
Review. The purpose of a Standard Review
is to explore further the potential or known
hazards and exposures posed by a PMN
substance, so that an adequate risk
assessment may be made. Currently,
approximately 5% of all PMN submissions
go into Standard Review.
All of the scientists and other PMN
review personnel who have participated in
the regular review of the PMN substance
before the Focus meeting typically
participate in the Standard Review. In
Standard Reviews, individual detailed
reports on the chemistry, environmental fate
and exposure, worker and consumer
exposure, and health and ecological effects
of the PMN substance are prepared.
Considerable effort is devoted to identifying
related analogs, performing comprehensive
literature searches on these analogs, and
retrieving and analyzing toxicity data on
these analogs.
In addition, RIB staff perform an
economic assessment of the PMN substance
15. The detailed regulatory process itself is outside the scope of this document and the reader is
referred to other documents for further information (USEPA 1986a).
16. EPA is developing final test guidelines; for status, contact the TSCA Assistance Information
service at (202) 554-1404 or access the guidelines on the Internet at
http://fedbbs.access.gpo.gov/epa01.htm See also USEPA 1996a.
38
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that includes comparing the PMN substance the necessary steps to implement the risk
to other commercial products that are used management decision.
for the same purposes. The economic
analysis identifies alternative uses (if any) of
the PMN substance, evaluates the markets
for the PMN substance and their potential
for growth, and estimates the selling price of
the substance. The economist may also
perform specialized financial studies to
evaluate claims in the PMN including
market limitations due to cost of the PMN
substance and the feasibility of process and
input modifications.
These detailed, individual reports are
used by a designated technical integrator to
prepare a single report that summarizes the
findings of the Standard Review. In
addition to summarizing the findings of the
review team, the technical integrator writes a
risk characterization of the PMN chemical,
including recommendations for testing. The
information contained in this report is then
used by the review team and the senior risk
assessors of OPPT to make a more complete
risk characterization and to decide on the
most appropriate risk management option(s).
These findings are then presented at the
Division Directors' meeting for a risk
management decision. For PMN substances
that go into Standard Review, the Division
Directors' meeting is the final phase of the
PMN review process and takes place
between days 79 and 82. This meeting is
attended by the Directors of the seven
divisions participating in the PMN review
process and is chaired by the Director of
CCD, or his designee. It is the role of the
Division Directors at this meeting to discuss
the risk assessment findings and to make
risk management decisions.
Following the Division Directors'
meeting, the PMN program manager takes
39
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References for Chapter 1
Boethling RS, Sabljic A. 1989. Screening-Level Model for Aerobic Biodegradability Based on a
Survey of Expert Knowledge. Environ Sci Technol 23:672-679.
DiCarlo FJ, Bickart P, Auer CM. 1986. Structure-Metabolism Relationships (SMR) for the
Prediction of Health Hazards by the Environmental Protection Agency. I. Background for the
Practice of Predictive Toxicology. Drug Metabolism Reviews 17(1-2): 171-184.
FFDCA. 1982. The Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 301-392.
FIFRA. 1972. The Federal Insecticide, Fungicide, and Rodenticide Act, 7 U.S.C., § 136 et. seq.
Lynch DG, Tirado NF, Boethling RS, Huse GR, Thorn GC. 1991. Performance of On-Line
Chemical Property Estimation Methods with TSCA Premanufacture Notice Chemicals.
Ecotoxicol Environ Safety 22:240-249.
TSCA. 1976. The Toxic Substances Control Act, 15 U.S.C. §§ 2601-2629. (1982 & Supp. IE
1985).
USEPA. 1986a. U.S. Environmental Protection Agency. New Chemical Review Process
Manual. Washington, DC.: U.S. Environmental Protection Agency. Office of Toxic Substances.
EPA report number: EPA-560/3-86-002.
USEPA. 1986b. U.S. Environmental Protection Agency. Toxic Substances Control Act Chemical
Substance Inventory. TSCA Inventory: 1985 Edition. Volume I. Eligibility Criteria for Inclusion
of Chemical Substances on the Inventory. Washington, DC: U.S. Environmental Protection
Agency. EPA report number: EPA-560/7-85-002a.
USEPA. 1986c. U.S. Environmental Protection Agency. Toxic Substances Control Act Chemical
Substance Inventory. TSCA Inventory: 1985 Edition. Volume I. Appendix B. Generic Names for
Confidential Chemical Substance Identities. Washington, DC: U.S. Environmental Protection
Agency. EPA report number: EPA-560/7-85-002a.
USEPA. 1991. U.S. Environmental Protection Agency. Instructions Manual for Premanufacture
Notification of New Chemical Substances. Washington, DC: U.S. Environmental Protection
Agency. EPA report number: EPA/7710-25(1).
USEPA. 1993 (January). U.S. Environmental Protection Agency. TSCA Confidential Business
Information A Security Manual. Washington, DC: U.S. Environmental Protection Agency.
Office of Pollution Prevention and Toxics. Document number 7700.
40
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USEPA. 1994. U.S. Environmental Protection Agency. ECOSAR. A Computer Program for
Estimating the Ecotoxicity of Industrial Chemicals Based on Structure Activity Relationships.
User's Guide. Washington, DC: U.S. Environmental Protection Agency. Office of Pollution
Prevention and Toxics. Document number 748-R-93-002.
USEPA. 1995a (March 29). U.S. Environmental Protection Agency. Office of Pollution
Prevention and Toxics. Premanufacture Notification Exemptions; Revisions of Exemptions for
Polymers; Final Rule. (60 FR 16316-16336).
USEPA. 1995b (March 29). U.S. Environmental Protection Agency. Office of Pollution
Prevention and Toxics. Premanufacture Notification Exemption; Revision of Exemption for
Chemical Substances Manufactured in Small Quantities; Low Release and Exposure Exemption;
Final Rule. (60 FR 16336-16351).
USEPA. 1995c (March 29). U.S. Environmental Protection Agency. Office of Pollution
Prevention and Toxics. Premanufacture Notification; Revisions of Premanufacture Notification
Regulations; Final Rule. (60 FR 16298-16311).
USEPA. 1995d. U.S. Environmental Protection Agency. Office of Pollution Prevention and
Toxics. The Polymer Exemption Manual, in preparation. For Document availability, call the
Toxic Substances Control Act (TSCA) Assistance Information Service at (202) 554-1404.
USEPA. 1995e. U.S. Environmental Protection Agency. Office of Pollution Prevention and
Toxics. Pollution Prevention Technical Manual, in preparation. For Document availability, call
the Toxic Substances Control Act (TSCA) Assistance Information Service at (202) 554-1404.
USEPA. 1995f U.S. Environmental Protection Agency. Office of Pollution Prevention and
Toxics. New Chemicals Program. Washington, DC: U.S. Environmental Protection Agency.
Document number EPA-743-F-95-001.
USEPA. 1996a (April 15). U.S. Environmental Protection Agency. Proposed Testing Guidelines;
Notice of Availability and Request for Comments. (61 FR 16486-16488).
USEPA. 1996b. U.S. Environmental Protection Agency. Office of Pollution Prevention and
Toxics. TSCA New Chemicals Program (NCP). Chemical Categories. Available from the Toxic
Substances Control Act (TSCA) Assistance Information Service at (202) 554-1404.
Zeeman MZ, Nabholz JV, Clements RG. 1993. The Development of SAR/QSAR for Use Under
EPA's Toxic Substances Control Act (TSCA): An Introduction. In: Gorsuch JW, Dwyer FJ,
Ingersoll CG, LaPoint TW (eds). Environmental Toxicology and Risk Assessment, 2nd Volume;
SAR/QSAR in the Office of Pollution Prevention and Toxics. Philadelphia: American Society
for Testing and Materials, pp. 523-539.
41
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List of Selected Readings for Chapter 1
For more information on the use of Structure-Activity Relationships in predicting health and
environmental hazards see:
DiCarlo FJ, Bickart P, Auer CM. 1985. Role of Structure-Activity Team (SAT) in the
Premanufacture Notification Process. In: QSAR in Toxicology and Xenobiochemistry. Tichy M,
ed. Amsterdam: Elsevier. pp. 433-449.
DiCarlo FJ, Bickart P, Auer CM. 1986. Structure-Metabolism Relationships (SMR) for the
Prediction of Health Hazards by the Environmental Protection Agency. II. Application to
Teratogenicity and Other Toxics Effects Caused by Aliphatic Acids. Drug Metab Rev 17(3-4):
187-220.
Lipnick RL. 1990. Narcosis: Fundamental and Baseline Toxicity Mechanism for Nonelectrolyte
Organic Chemicals. In: Practical Applications of Quantitative Structure-Activity Relationships
(QSAR) in Environmental Chemistry and Toxicology. Karcher W, Devillers J, (eds). Dordrecht,
The Netherlands: Kluwer Academic Publishers, pp. 129-144.
Lipnick RL. 1995. Structure-Activity Relationships. In: Fundamentals of Aquatic Toxicology:
Effects, Environmental Fate, and Risk Assessment— 2nd Edition. Rand G, (ed). Washington,
DC: Taylor and Francis, pp. 609-655.
Lipnick RL, Pritzker CS, Bentley DL. 1987. Application of QSAR to Model the Toxicology of
Industrial Organic Chemicals to Aquatic Organisms and Mammals. In: Progress in QSAR.
Hadzi D, Jerman-Blazic, (eds). New York: Elsevier. pp. 301-306.
USEPA. 1980 (July 29). U.S. Environmental Protection Agency. Office of Pesticides and Toxic
Substances. Availability of TSCA Revised Inventory. C. Corrections to Previous Inventory
Reporting Forms. (45 FR 50544-5)
Wagner PM, Nabholz JV, Kent RJ. 1995. The new chemicals process at the Environmental
Protection Agency (EPA): Structure-activity relationships for hazard identification and risk
assessment. Toxicol Lett 79:67-73.
Woo Y-T, Lai DY, Argus MF, Arcos JC. 1995. Development of structure-activity relationship
rules for predicting carcinogenic potential of chemicals. Toxicol Lett 79:219-228.
Woo Y-T, Lai DY, Argus MF, Arcos JC. 1996. Carcinogenicity of Organophosphorous
Pesticides/Compounds: An Analysis of their Structure-Activity Relationships. Environ Carcino
& Ecotox Revs C 14(1): 1-42.
Woo Y-T, Lai DY, Argus MF, Arcos JC. 1996. Carcinogenic Potential of Organic Peroxides:
Prediction Based on Structure-Activity Relationships (SAR) and Mechanism-Based-Short-Term
42
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Tests. Environ Carcino & Ecotox Revs C14(l):63-80.
Zeeman M, Auer CM, Clements RG, Nabholz JV, Boethling RS. 1995. U.S. EPA Regulatory
Perspectives on the Use of QSAR for New and Existing Chemical Evaluations. SAR & QSAR in
Environ Res 3(3): 179-201.
For more information on the Chemical Categories see:
Moss K, Locke D, Auer C. 1996. EPA's New Chemicals Program. Chem Hlth Saf 3(1): 29-33.
43
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Chapter 2
CHEMICAL INFORMATION NEEDED FOR RISK ASSESSMENT
2.1 Introduction
EPA requests various types of
chemical information from companies
submitting PMNs, including information on
the physicochemical properties, synthesis,
purity, and use of PMN substances. EPA
receives approximately 2,000 PMN
submissions annually and many of these do
not contain all of the information necessary
for a good screening-level risk assessment of
the PMN substance (some contain no useful
information other than the chemical name
and structure). PMN submitters are required
to provide certain information whereas other
information is optional. This optional
information is, nonetheless, important in
EPA's review of chemicals, and its inclusion
in PMN submissions improves the basis for
EPA's evaluation and facilitates the review
process. Such information can also be very
helpful in avoiding misunderstandings
leading to additional but unnecessary EPA
review.
Chapter 1 addressed the process that
EPA uses in its evaluation of PMN
substances. The present chapter (Chapter 2)
discusses the chemical information
considered by EPA in its review process,
how this information is used, and EPA's
strategy when pertinent information is
omitted from PMN submissions. The
chemical information requested in a PMN
submission is very important because it
forms the underlying basis for risk
assessment and risk management decisions
made during the PMN review process.
The first section of this chapter
discusses each of the different types of
chemical information that EPA uses in its
evaluation of PMN substances and the
importance of this information to risk
assessment. Definitions of physicochemical
properties are included, and methods of
measuring or estimating properties are
described. EPA depends very heavily upon
physicochemical properties of chemical
substances for estimating their transport,
environmental fate, exposure, and toxicity to
mammalian and aquatic species. The use of
this information in risk assessment is
presented briefly graphically and is
discussed.
The final section of this chapter
describes EPA's methods for obtaining or
estimating values for physicochemical
properties essential in the review of PMN
substances, but often not included in PMN
submissions. Although accurately-derived
empirical data are preferred over estimated
data, if such data are not provided in a PMN
submission, EPA will first search the
literature for data on the PMN chemical,
then search for data on analogous
substances, and, finally, estimate the required
data. Data sources and methods used by
EPA in this process include reference books,
on-line databases, and computer estimation
programs.
44
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This chapter is intended to provide
submitters with an understanding of the basis
for EPA's requests for certain chemical
information. The solicited information is
important in EPA's review of PMN
chemicals. In all cases, EPA prefers accurate
empirical data. If such data are not provided
by the submitter and EPA is unable to find
data on the PMN chemical, it is EPA's policy
to make conservative assumptions and use
credible worst case scenarios in its
evaluations. Worst case scenarios may, in
some cases, lead to overestimating the
exposure and risk of a chemical. By
providing as much physicochemical property
data as possible in PMN submissions,
submitters can aid EPA in assessing
exposure and risk more accurately.
2.2 Important Chemical Information
To many people, properties such as
physical state, melting point, boiling point,
vapor pressure, water solubility, lipophilicity
(octanol/water partition coefficient),
molecular weight, etc., seem to have little to
do with toxicity and environmental fate,
although the relevance of some of these
properties to exposure assessment may be
clear. The main purpose of this chapter is to
show how these and other physicochemical
properties are used extensively by EPA for
risk assessment of new chemical substances
during PMN review.
Other factors such as intended use,
other uses, and synthesis as they relate to
risk assessment are also discussed. The
intent is not to describe all aspects of risk
assessment and associated physicochemical
properties. Comprehensive treatises on risk
assessment, physicochemical properties, and
their measurement, estimation, and use in
predicting environmental fate, exposure,
toxicity, and pharmacologic response are
listed under the Suggested Readings heading
at the end of this chapter.
Figure 2-1 illustrates the
physicochemical properties most commonly
used during risk assessment of PMNs. The
important lesson to be learned in this chapter
is that essentially all forms of risk assessment
of new chemical substances are largely
dependent upon physicochemical properties.
When measured physicochemical properties
of chemicals are not available, they must be
estimated. Although many reliable
estimation methods are available, in any
estimation a certain degree of error is always
present. Thus, estimation of
physicochemical properties should never
supplant actual measurement. This section
discusses the chemical data that are most
important to EPA in reviewing PMNs and
how EPA uses these data in risk
assessments.
2.2.1 Melting Point
Melting is the change from the highly
ordered arrangement of molecules within a
crystalline lattice to the more random
arrangement that characterizes a liquid.
Melting occurs when a temperature is
reached at which the thermal energy of the
molecules is great enough to overcome the
intracrystalline forces that hold them in
position in the lattice. As a solid becomes a
liquid, heat is absorbed, and the heat content
(enthalpy) increases. In other words, the
enthalpy of a substance in the liquid state is
greater than the enthalpy of the same
45
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Figure 2-1. Important Physicochemical Properties, Their Interrelationships, and Their Uses in Risk
Assessment
-------
substance in the solid state. The entropy (a
measure of the degree of molecular disorder)
also increases as substances change from
solid to liquid.
Melting point is an important
property used by EPA in the evaluation of
PMN substances. The melting point of a
pure substance is characteristic of that
substance. Melting point, therefore, can be
used in the identification of an unknown
substance (theoretically, a substance has a
single melting point value; however, several
substances can coincidentally have the same
melting point). The melting point also
provides information about the purity of a
substance. A sharp melting point or narrow
melting range is a good indication that the
substance is pure. A fairly wide melting
point range generally indicates the presence
of impurities. Some substances may
decompose or sublime rather than melt.
Decomposition and sublimation are also
characteristic properties and, hence, are
useful for identification purposes.
Melting point is a function of the
crystal lattice of a solid, which in turn is
dictated primarily by three factors: molecular
forces, molecular symmetry, and the
conformational degrees of freedom of a
molecule (Dearden 1991). Most ionic
substances have very high melting points
because the forces that hold the ions together
are extremely strong. For organic
substances, the most important force
influencing melting point is intermolecular
hydrogen bonding. A substance that has less
intermolecular hydrogen bonding and more
intramolecular hydrogen bonding will have a
lower melting point than a structural isomer
of the same substance that has more
intermolecular and less intramolecular
hydrogen bonding. Melting point also tends
to increase with molecular size, simply
because the molecular surface area available
for contact with other molecules increases,
thus increasing the intermolecular forces
(Dearden 1991).
Melting point can provide
information about the water solubility of
non-ionic organic substances. Both melting
point and water solubility of non-ionic
organics are affected by the strength of the
intermolecular forces in the substance. If the
intermolecular forces are very strong in a
solid, the melting point is likely to be high
and the solvation of the individual molecules
by water is likely to be low. The melting
point of a non-ionic solid, therefore, may be
used as an indicator of water solubility. The
water solubility of a non-ionic solid depends
largely on the temperature of the water, the
melting point, and the molar heat of fusion of
the solid (Yalkowsky and Banerjee 1992).
Abramowitz and Yalkowsky (1990) have
reported the use of melting point with total
molecular surface for the accurate,
quantitative estimation of water solubility for
a series of PCBs. Melting point has also
been used with Kow (i.e., octanol/water
partition coefficient) for an accurate,
quantitative estimate of water solubility of
liquid or crystalline organic non-electrolytes
(Yalkowsky et al. 1979, 1980). Melting
point may also be used with other
physicochemical properties to derive
quantitative estimates of water solubility for
non-ionic solids; some of these methods have
been summarized by Yalkowsky and
Banerjee (1992).
Because the melting point can
provide an indication of a substance's water
solubility, it can also serve as a tool for
47
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estimating the distribution of the substance in
aqueous media. If a chemical substance is
poorly soluble in water, its concentration in
aqueous media may be too low for
significant exposure; however, if a substance
is highly soluble in water, its concentration in
aqueous media is higher, thus increasing
exposure potential. In general, high-melting
non-ionic solids are likely to have low water
solubility and exposure, whereas low-
melting, non-ionic solids are likely to have
higher water solubility and exposure.
For non-ionic organic substances,
melting point can provide an indication of
the likelihood of human exposure to a
chemical via absorption through the skin,
lungs, or gastrointestinal tract. In general,
low-melting substances are more likely to be
absorbed than substances that melt at higher
temperatures, because, for a substance to
diffuse through biological membranes, the
molecules must be in their greatest state of
molecular disaggregation (i.e., in solution).
Non-ionic substances that melt at lower
temperatures have less energy within their
crystalline lattice, are more water soluble,
and will be absorbed more readily than
compounds that melt at higher temperatures.
Substances that are liquids at ambient
temperature are generally much better
absorbed than solids (USEPA 1992).
Although reasonably accurate
methods for the quantitative estimation of
melting point have been reported for certain
classes of substances (Abramowitz and
Yalkowsky 1990; Dearden 1992), estimation
of melting point is generally very difficult
because the property depends upon a
significant number of complex interactions
including crystal packing and symmetry,
molecular size, and hydrogen bonding
(Yalkowsky et al. 1980; Yalkowsky and
Banerjee 1992). While melting point may
be roughly estimated by analogy with other
chemicals that have similar structures, it is
well known that even subtle changes within a
homologous series of compounds can greatly
affect melting point. Accurate estimation of
a substance's melting point by comparison to
similar substances, therefore, is not always
feasible. Melting point is easily measurable
for most organic substances (Shriner et al.
1980).
EPA chemists routinely estimate
melting points if submitters do not provide
them, but measured values are preferable.
There is little justification for a PMN
submitter to omit melting points for solids
since melting point is easy and inexpensive to
measure; in many cases, the submitter's
analytical laboratory will have measured
melting points during research and
development activities. These data are
considered health and safety data and must
be submitted with the PMN. For known
substances, the melting point is often
available in the scientific literature, but
literature values, of course, have no bearing
on the purity of the submitter's chemical.
Submitters should so indicate when they use
literature values in PMN submissions.
When reviewing a PMN substance
for which the melting point has been omitted
by the submitter, EPA chemists search the
literature for an empirical (measured) value.
If an empirical melting point is not available,
it is the general policy of EPA to estimate a
more conservative, relatively low melting
point in its risk assessment for that
substance. As a consequence, EPA may
conclude that the substance may be absorbed
more readily through the skin, lung, or
48
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gastrointestinal tract than is actually the case
and, thus, may predict that the substance will
be toxic to humans. Likewise, in the absence
of data, EPA will make the assumption that
the substance has relatively high water
solubility and may be toxic to aquatic life.
These reasonable worst-case estimation
scenarios can be avoided or mitigated if the
submitter provides EPA with empirical
melting points.
2.2.2 Octanol/Water Partition Coefficient
(Kow, P)
A partition coefficient describes the
equilibrium ratio of the molar concentrations
of a chemical substance (the solute) in a
system containing two immiscible liquids (the
solvents). The partition coefficient is not
simply a comparison of the solubility of a
substance in one immiscible solvent with that
in another such solvent. The most common
partition coefficient is the octanol/water
partition coefficient, expressed as either Kow
or P, in which the two immiscible solvents
are w-octanol and water. The equation for
Kow(orP)is:
K
[chemical substance} in n octanol
[chemical substance] in water
where concentrations are in moles/liter.
For purposes of simplification, Kow is
usually reported as its common logarithm
(log Kow or log P). A large log Kow value for
a chemical (relative to other substances),
indicates that the chemical has a greater
affinity for the w-octanol phase and, hence, is
more hydrophobic (lipophilic). A low or
negative log Kow value indicates that a
chemical has a greater affinity for the water
phase, and hence, is more hydrophilic. A
chemical substance with a log Kow of 1 has
ten times the affinity for w-octanol that it has
for water, whereas a chemical substance with
a log Kow of-1 has ten times the affinity for
water that it has for w-octanol.
A chemical substance with a log Kow of 0 has
equal affinity for w-octanol and water.
Substances containing polar substituents
(e.g., -OH, -SH, -NH2, etc.) tend to have
lower log Kow values than substances that
lack such substituents.
For practically any given non-ionic
organic substance, it is possible to use the
octanol/water partition coefficient to
estimate other physicochemical properties
and, in many cases, the distribution of the
chemical within a living system or the
environment. This is why octanol/water
partition coefficients are extremely helpful
and are used extensively during risk
assessment of chemical substances.
Specifically, octanol/water partition
coefficients are often used by EPA and
others to estimate water solubility, soil and
sediment adsorption, biological absorption
(following oral, inhalation, or dermal
exposure), bioaccumulation, and toxicity.
A primary reason for the versatility of
the octanol/water partition coefficient in risk
assessment is that it serves as a model for the
distribution of a chemical substance within
both biological and non-biological systems.
Biological membranes and systems (e.g.,
organs, cell membranes, capillaries, blood-
brain barrier, skin, intestines) typically
contain various combinations of lipid and
aqueous components. For a chemical
substance to gain entry into and distribute
throughout a biological system, it must have
a certain amount of both lipid and water
solubility. The octanol and water phases of
an octanol/water system are representative of
49
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the lipid and aqueous components of
biological systems, respectively. Thus, the
octanol/water partition coefficient is an
important property influencing the biological
activity of a chemical substance (Hansch and
Dunn 1972; Hansch and Clayton 1973). For
this reason, the octanol/water partition
coefficient is used extensively by EPA and
others in the quantitative prediction of
toxicity (Blum and Speece 1990; Karcher
and Devillers 1990; Hermens and
Opperhuizen 1991; Grogan et al. 1992) and
environmental fate (Lu and Metcalf 1975;
Kenaga and Goring 1980; Swann et al.
1983). Pharmaceutical companies use the
octanol/water partition coefficient for the
quantitative prediction of pharmacological
activity of many chemical substances (Martin
1978; Yalkowsky et al. 1980). Figure 2-2
illustrates the usefulness of log Kow.
Suggested readings, including the use of
octanol/water partition coefficient in
estimating bioavailability, toxicity, and
pharmacological activity, are provided at the
end of this chapter.
Substances with high ( > 5) log Kow
values are so hydrophobic that they partition
very poorly into the aqueous components of
biological systems, remain within the lipid
components and are generally poorly
absorbed following acute exposure.
Chemical substances with high log Kow
values, although poorly absorbed, are more
likely to bioaccumulate into fat tissue,
whereas compounds with lower log Kow
values generally do not bioaccumulate
because of their lower affinity for lipids
(Lyman et al. 1982; Noegrohati and
Hammers 1992). Substances with high log
Kow values that exist in the environment at
sub-toxic levels may bioconcentrate to toxic
levels within aquatic organisms, following
sufficient exposure duration to achieve
steady state partitioning. The ability of a
very hydrophobic chemical to produce toxic
effects may be limited by high melting point,
resulting in both insufficient water and lipid
solubility to reach toxic levels at the site of
action within the aquatic organism (USEPA
1985). Generally, chemicals with good lipid
and water solubilities are likely to be
absorbed from all routes of exposure,
including the skin (Shah 1990).
Substances with high log Kow values
tend to adsorb more readily to organic
matter in soils or sediments because of their
low affinity for water. Compounds with
lower log Kow values are not as likely to
adsorb to soils or sediments because they
will be more prone to partition into any
surrounding water. Log Kow is often used, in
fact, by EPA to estimate quantitative
soil/sediment adsorption coefficients, Koc
(Lyman et al. 1982) and qualitative removal
of a substance during wastewater treatment.
Because the octanol/water partition
coefficient is an equilibrium ratio of the
molar concentrations of a chemical substance
in w-octanol and water, it is often useful in
estimating water solubility. Water solubility
is often a difficult property to estimate;
however, regression equations for the
quantitative estimation of water solubility
using log Kow have been reported for organic
chemical substances from several classes
(Yalkowsky et al. 1979; Yalkowsky et al.
1980; Yalkowsky and Valvani 1980;
Yalkowsky and Valvani 1979; and
Yalkowsky and Banerjee 1992; Bowman and
Sans 1983; Isnard and Lambert 1989;
Kenaga and Goring 1980). As a general rule
of thumb with non-ionic organic substances,
the higher the log Kow
50
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Figure 2-2. Use of Octanol-Water Partition Coefficient (Log Kow) in Risk Assessment
Use in Quantitative Structure-
Activity Relationships to
Estimate Toxicity
Estimate Water Solubility
Estimate Absorption from
G.I. Tract and Lung
L°gK0«
>.
Estimate Soil/Sediment
Adsorption Coefficient
Estimate Dermal Absorption
Estimate Bioconcentration
51
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value, the lower the water solubility.
Estimation of water solubility is discussed in
more detail later in this chapter. The EPA is
currently developing guidelines for the
selection of measured or estimated Kow data.
These will provide additional guidance to
PMN submitters.
Measuring log Km
Several methods of measuring
octanol/water partition coefficient are
described in EPA's Test Guidelines (USEPA
1996), and newer methods continue to
appear in the literature. Each of these
methods has advantages and disadvantages;
one must be very careful to select the best
method for a particular chemical in order to
obtain an accurate value. It is very
important to state the method of
measurement along with each log K,,w value,
so that the reliability of the value is apparent.
The classical method for measuring
log Kow is the "shake-flask" method. In this
method, the test chemical is mixed with an
appropriate w-octanol/water mixture and
shaken for some given period during which
equilibrium between both phases is achieved.
It is important for the w-octanol and water
phases to be mutually saturated prior to
shaking with the test chemical. After the
phases separate, the concentrations of the
test chemical in the octanol and aqueous
phases are determined. The aqueous phase
often needs to be centrifuged to remove any
small octanol droplets.
The shake-flask method is widely
used to measure the Kow accurately for many
chemicals. This method is not appropriate,
however, for substances with high partition
coefficients (log Kow > 4.5). The shake-flask
method is also inappropriate for (1)
polycyclic aromatic substances lacking polar
substituents, (2) halogenated hydrocarbons,
and (3) large, non-polar chemicals, because
large volumes of the aqueous phase are
required for analysis and, in addition, the
aqueous phase becomes contaminated with
micro-emulsions formed during shaking.
Although it may be possible to prevent or
remove the emulsions formed during the
shake-flask procedure, literature data for Kow
measured by this technique indicate that in
many cases, the formation of emulsions has
influenced the observed Kow values. This
may account for the high variance among
literature values for rather hydrophobic
chemicals whose Kow values were determined
by independent investigators using this
method (Hansch and Leo 1979; Kenaga and
Goring 1980).
Brooke and co-workers (1986) have
described a "slow-stir" method for measuring
octanol/water partition coefficients for
hydrophobic chemicals. This method is
similar to the shake-flask method, but differs
in that the octanol and water phases are
equilibrated under conditions of slow stirring
rather than vigorous shaking. By careful
stirring and rigid temperature control, the
formation of emulsions can be prevented,
and accurate partition coefficients can be
obtained relatively easily for very
hydrophobic substances. De Bruijn and co-
workers (1989) found that for substances
with log Kow values ranging from 0.9 to 4.5,
experimental data obtained by the slow-stir
method were in good agreement with
literature values based on the shake-flask
method. For substances having log Kow
values of 4.5 and higher, there was
reasonable agreement between data obtained
using the slow-stir method and data obtained
52
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using either reversed-phase high performance
liquid chromatography (HPLC) or the
generator column method. Thus, the slow-
stir method appears to be very useful for
measuring log Kow for hydrophobic as well as
hydrophilic substances. In addition, the
method is easy to use, relatively fast, and
does not require expensive equipment.
Detailed discussions of the slow-stir method
in determining Kow are available (Brooke et
al. 1986; de Bruijn et al. 1989).
Another very versatile method for
measuring log Kow is the generator column
method (USEPA 1985). In this method, a
generator column is used to partition the test
substance between the octanol and water
phases. The column is packed with a solid
support and is saturated with a fixed
concentration of the test substance in n-
octanol. The test substance is eluted from
the octanol-saturated generator column with
water. The aqueous solution exiting the
column represents the equilibrium
concentration of the test substance that has
partitioned from the octanol phase into the
water phase. The primary advantage of the
generator column method over the shake-
flask method is that the former completely
avoids the formation of micro-emulsions.
Therefore, this method is particularly useful
for measuring Kow for substances having log
Kow values over 4.5 (Doucette and Andren
1987, 1988; Shiu et al. 1988), as well as for
substances having log Kow values less than
4.5. A disadvantage of the generator column
method is that it requires sophisticated
equipment. A detailed description of the
generator column method is presented in
USEPA 1985.
EPA encourages PMN submitters to
provide accurately-measured log Kow data in
PMN submissions. For certain types of
chemical substances, however, it is not
necessary to do so. Substances that contain
several aromatic rings, lack polar
substituents, or are polyhalogenated most
likely have log K^ values greater than 7.
Similarly, chemicals that contain long-
chained (10 or more carbons) alkyl
substituents with few polar groups (e.g.,
fatty acids) are also likely to have log Kow
values above 7. Such substances are so
clearly hydrophobic that it is not necessary to
have an accurately-measured Kow value for
risk assessment purposes. In addition, it is
generally not necessary to measure Kow
values for substances that have strong
surfactant properties. Measuring Kow for
surfactants (particularly ionic surfactants) is
usually difficult because the surfactant causes
the octanol and water phases to become
miscible, preventing partitioning between the
two solvents. EPA does not generally
recommend measuring log Kow for polymers
or PMN substances that lack definite
structure (class 2 substances). For most
substances, especially class 1 compounds
(i.e., those with defined structures),
measured Kow values are very helpful for
properly and fairly characterizing risk
potential. It is also helpful to provide EPA
with the method used for measuring Kow.
Table 2-1 summarizes the methods used for
measuring octanol/water partition
coefficient.
Estimating log Km
Recognizing the importance of log
Kow in predicting absorption, biological
53
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Table 2-1. Methods of Measuring Octanol/Water Partition Coefficient (Kow)
Method
Advantages
Disadvantages
References
Shake-Flask
Easy to use. Reliable for Generally not useful
substances that have log
^owvalues<4.5.
Doesn't require
expensive equipment.
for measuring Kow
values for substances
having log Kow values
> 4.5; shaking may
form micro-emulsions,
which lead to
inaccurate
measurement.
USEPA(1985);
Kenaga and Goring
(1980).
Slow-Stir
Easy to use. Relatively
fast, doesn't require
expensive equipment.
Reliable for essentially
all substances.
Requires careful
stirring and close
temperature control to
avoid formation of
micro-emulsions.
Brooke et al. (1986);
de Bruijn et al. (1989).
Generator
Column
Reliable for essentially
all substances. Avoids
formation of micro-
emulsions.
Requires expensive
equipment.
USEPA(1985);
Doucette and Andren
(1987, 1988); Shiu et
al. (1988).
54
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properties, and environmental fate, scientists
over the years have measured and recorded
log Kow values for thousands of substances,
largely from the shake-flask method. These
empirical data sets have served as a basis for
developing techniques to estimate log Kow.
Numerous methods for estimating log Kow
accurately for many different classes of
substances are now available. Some of these
methods have recently been reviewed (Leo
1993; van de Waterbeemd and Mannhold
1996). Most of the log Kow estimation
methods are based upon one or more of the
following approaches:
• fragment or substituent additivity
(Hansch and Leo 1979; Leo 1990);
• correlations with capacity factors on
reversed-phase HPLC (Lins et al.
1982; Brent et al. 1983; Garst 1984;
Garst and Wilson 1984; USEPA
1985; Dunn et al. 1986; Minick et al.
1988; Yamagami et al. 1990);
• correlations with descriptors for
molecular volume or shape such as
molecular weight, molar refraction,
parachor, molar volume, total
molecular surface area and total
molecular volume (Dunn et al. 1986;
Doucette and Andren 1987; de Bruijn
and Hermans 1990); and
• correlations with molar volume,
solvatochromic (thermodynamic)
parameters, or charge transfer
interactions (Kamlet et al. 1988; Saski
etal. 1991; Dunn et al. 1991;
Moriguchi et al. 1992; Da et al.
1992).
A major problem in estimating log
Kow is that most methods work well for
certain classes of substances, but not for
other classes. Typically, originators of these
estimation methods are quick to point out
the shortcomings of other methods, but not
the limitations of their own methods. Before
using any method for estimating log Kow, the
user should become familiar with the
theoretical basis of the method, its
applicability, and its limitations. Estimation
methods that have not been validated (i.e.,
tested against accurately-measured log Kow
values) should not be used. The remainder
of this section briefly discusses the methods
above for estimating log Kow and attempts to
provide some guidance with respect to their
use. Table 2-2 summarizes the advantages
and disadvantages of the methods. A
detailed description of each estimation
method is beyond the scope of this text;
however, a comprehensive listing of
references describing various estimation
methods of log Kow is provided in the
Suggested Readings section at the end of this
chapter.
The foremost method used in
estimating log Kow is that of Hansch and Leo
(1979). This method uses empirically-
derived fragment constants and structural
factors to calculate log Kow from a structure.
Estimates are made from addition of
fragment constants and structural factors,
which are compiled for thousands of
structural fragments and atoms stored in a
database. The method has been validated by
many investigators. A detailed description of
how the method is used is available (Lyman
et al. 1982). Using this method, one
55
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Table 2-2. Methods of Estimating Octanol/Water Partition Coefficient (Kow)
Method
Advantages
Disadvantages
References
Fragment Constant
Additivity
Calculation of log Kovi for
many substances can be
accomplished directly from
structure. Available as a
computer program. Known
to be very accurate for
substances having log Kow
values less than 4.5
Inaccurate for substances
with log Kovf > 6. Cannot
estimate log Kow for
substances containing
substituents that are not in
the fragment constant
database (except for the
Meylan and Howard
method).
Hansch and Leo
(1979); Meylan
and Howard
(1995).
Correlation of
Reversed-Phase
HPLC Retention
Times
Known to be very accurate.
Requires a dataset of
accurately-measured log Kovf
values and HPLC retention
times of substances closely
related to the test substance.
Garst (1984);
Garst and Wilson
(1984); USEPA
(1985).
Correlation of
Molecular Surface
Area and Volume
Very accurate for certain
non-polar hydrophobic
substances.
Requires a dataset of
accurately-measured log Kovf
values and HPLC retention
times of substances closely
related to the test substance.
Only accurate for non-polar
hydrophobic substances
such as halogenated and
nonhalogenated benzenes
and biphenyls.
Yalkowski and
Valvani (1976);
Doucette and
Andren (1988);
de Bruijn and
Hermens (1990);
Brooke et al.
(1987).
"Three Dimensional"
Modeling
Calculation of log Kovf for
many substances can be
accomplished directly from
structure. May be used for
substances whose log Kovf
values cannot be calculated
by the fragment constant
additivity method (due to
missing fragment constants).
Requires knowledge of
molecular modeling.
Requires sophisticated
computer hardware and
software. Has not been
thoroughly validated.
Sasaki et al.
(1991);
Moriguchi et al.
(1992); Waller
(1994).
56
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can estimate log Kow for almost any
substance. If an accurately-measured value
of Kow is available for a structurally similar or
"parent" compound, this measured value can
be used to estimate the log Kow of the
"derivative" by adding or subtracting the
appropriate fragment constant or structural
factor. This approach is preferred whenever
a reliable measured value of a parent
compound is available because the solvent-
solute interaction terms in the parent
molecule are already accounted for. A
major advantage of the Hansch and Leo
method is that log Kow values can be
estimated (calculated) directly from structure
alone. This method is very accurate for
many classes of chemical substances, but is
known to overestimate log Kow for some
substances with log Kow values greater than
about 6 (Lyman et al. 1982). A computer
program (CLOGP) of the Hansch and Leo
method is available.17 A disadvantage of the
method is that it cannot estimate log Kow for
substances that contain substituents whose
fragment or structural factor contributions to
log Kow are unknown. Meylan and Howard
(1995) have recently reported a variation of
the Hansch and Leo fragment addition
method for estimating Kow. This variation
uses atom/fragment contribution values and
correction factors obtained from measured
Kow values of structurally diverse substances.
Using the Meylan and Howard method, the
Kow of a substance is estimated by summing
all atom/fragment contribution values and
correction factors pertaining to the structure.
The primary advantage of this method over
the Hansch and Leo method is that it can
calculate Kow for substances for which Kow
cannot be calculated using the Hansch and
Leo method. The Meylan and Howard
method is easy to use, and reported to be
very accurate. A computer program
(LOGKOW) of the method is available.18
A great deal of effort has been
directed towards estimating Kow from
retention times determined by reversed-
phase HPLC . A detailed discussion of this
method is available in USEPA 1985. In this
technique, accurately-measured log Kow
values for a set of closely related substances
are correlated to the reversed-phase HPLC
retention times of the substances, and a
regression equation is obtained. The log Kow
of a structurally similar substance can be
estimated using its retention time and the
regression equation. This method is semi-
empirical since HPLC retention time must be
measured.
The reversed-phase HPLC method is
known to be very accurate for many
chemical substances (Lins et al. 1982; Brent
et al. 1983; Garst 1984; Garst and Wilson
1984; Minick et al. 1988; Yamagami et al.
1990). Obvious disadvantages of this
method, however, are that it requires
accurately-measured log Kow values of
analogous substances, sophisticated technical
equipment, and a certain amount of technical
expertise. Another disadvantage is that the
linear regression equations cannot be
extrapolated beyond the Kow range for
17. The CLOGP computer program is available through the Pomona College Medicinal
Chemistry Project, Claremont, California, 91711.
18. The LOGKOW computer program is available from Syracuse Research Corporation,
Environmental Science Center, Merrill Lane Syracuse, NY, 13210.
57
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which the equations were derived. Also, log
Kow values for the reference chemicals are
usually determined by the shake-flask
method and, therefore, are not very reliable
for hydrophobic substances. Leo (1990) has
discussed other disadvantages to this
approach. The reversed-phase HPLC
method should only be used for chemicals
and reference compounds whose chemical
structures are similar.
Several investigators have reported
exceptional correlations between log K,,w and
molecular surface area or molecular volume
for hydrophobic aromatic substances, such as
halogenated benzenes and biphenyls
(Yalkowsky and Valvani 1976; Doucette and
Andren 1987, 1988; Brooke et all986,
1987; de Bruijn and Hermans 1990). Like
the reversed-phase HPLC method,
correlations with molecular surface area or
volume require a data set of measured Kow
values for structurally similar substances.
Molecular surface areas or molecular
volumes are calculated for each chemical in
the group and are then correlated with log
Kow to give a regression equation. Log Kow
of an analogous substance can then be
estimated using the substance's calculated
molecular surface area or volume in the
regression equation. This method is not
useful for estimating log Kow for aromatic
substances (or others) that contain polar
substituents, since it does not take into
account the effects that these substituents
have on octanol/water partitioning.
An extension of this approach uses
polarizability/dipolarity and hydrogen
bonding terms in addition to molecular
volume, and also has been found to predict
log Kow values accurately for PCBs and
polycyclic aromatic hydrocarbons (Kamlet et
al. 1988). Use of these descriptor terms in
predicting log Kow for more polar substances
is presumably under investigation. A
potentially serious drawback to this approach
is that the descriptor terms may not always
be available.
Recent advances in computer
hardware and software have made estimation
of log Kow possible through consideration of
three-dimensional intra- and intermolecular
interactions (Sasaki et al. 1991; Moriguchi
et al. 1992). This three-dimensional
approach estimates log Kow for organic
substances through correlation with
molecular surface area, electrostatic
potential, charge transfer interactions, and
other electronic and structural effects derived
from three-dimensional molecular structures.
Advantages to these methods are that log
Kow can be estimated directly from chemical
structure and for substances to which
Hansch and Leo's fragment constant
approach has not been applicable. Although
the three-dimensional methods for estimating
log Kow have not yet been completely
validated, they appear to be very useful for
rapid estimation of log Kow for a wide variety
of chemical substances. When in doubt
regarding the applicability of a particular log
Kow estimation method, one should seek
measured data on an analog and test the
estimation. Alternatively, the analog can be
used as the basis for estimation by
subtracting and adding needed small
fragments to obtain the PMN structure.
The octanol/water partition
coefficient is very important in EPA's
evaluation of PMN substances. EPA uses
either measured or estimated log Kow values
in assessing approximately 50% of all PMN
substances (which represents about 80% of
58
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all non-polymer PMN substances). As
discussed above, octanol/water partition
coefficients can be used to estimate other
properties (e.g., solubility, bioaccumulation,
toxicity); these other properties are then used
to evaluate the potential risk of a chemical to
human health and the environment. The
submission of accurately measured
octanol/water partition coefficients allows
for the reliable prediction of the effects of a
chemical on human health and the
environment. Accurately estimated log Kow
values are also useful to EPA. If an
accurately measured or estimated log Kow
value is not provided by the submitter, then
the EPA will estimate Kow using one of the
methods discussed previously. In cases
where it is not apparent to EPA as to which
estimation method will provide the most
accurate log Kow value, EPA will select the
method that provides a log Kow value that
results in the highest toxicity or exposure.
2.2.3 Water Solubility
Water solubility is defined as the
maximum amount of a substance in its finest
state of molecular subdivision that will
dissolve in a given volume of water at a
given temperature and pressure. For risk
assessment, EPA is most interested in the
water solubility of chemical substances given
at environmental temperatures
(20-30 °C). Water solubility may be
expressed in a number of units; EPA prefers
water solubility data to be given in
grams/liter (g/L). Most common organic
chemicals have water solubilities that range
anywhere from 0.001 g/L (1 part per million,
ppm) to 100 g/L (100,000 ppm) at
environmental temperatures. Solubilities for
extremely hydrophobic substances (e.g.,
dioxins) have been measured below 1 part
per billion, whereas some substances are
infinitely soluble (completely miscible) in
water.
Water solubility is one of the most
important properties affecting bioavailability
and environmental fate of chemical
substances. Chemicals that are reasonably
water soluble (that have low log Kow values)
are generally absorbed into biological
systems because most of these systems
contain a significant number of aqueous
components. Such chemicals have relatively
low adsorption coefficients for soils and
sediments, and they bioconcentrate poorly, if
at all, in aquatic species. Furthermore,
highly water soluble substances tend to
degrade more readily by processes such as
photolysis, hydrolysis, and oxidation
(Klopman et al. 1992). Water solubility also
affects specialized transport pathways such
as volatilization from solution and washout
from the atmosphere by rain (Lyman et al.
1982). Water solubility, therefore, is a key
element in the risk assessment of any
chemical substance.
Measuring water solubility
The two most common methods for
the experimental determination of water
solubility are the shake-flask and generator
column methods (Yalkowsky and Banerjee
1992; USEPA 1985; Lyman et al 1982).
Although these methods are not technically
difficult, there can be considerable variation
in the water solubility measured for the same
substance using the same method, but in
different laboratories. These discrepancies
result primarily from the large number of
experimental variables that are known to
affect solubility measurements. These
variables include properties of the water such
59
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as temperature, pH, presence of suspended
solids, salt content, and organic content, and
include properties of the chemical such as the
physical state (especially particle size of
solids), purity, and adsorption of the
chemical onto the walls of the experimental
apparatus (Kenaga and Goring 1980;
Yalkowsky and Banerjee 1992). It appears
that discrepancies increase as hydrophobicity
increases (USEPA 1979). The shake-flask
method is acceptable for determining water
solubilities for substances that have log Kow
values of 3 or lower. Disadvantages of the
shake-flask method are: (1) the method
requires considerable sample handling
between saturation and analysis steps; (2)
colloid formation may occur as result of the
shaking; and (3) the method is inaccurate for
hydrophobic substances. The generator
column method does not have the
shortcomings of the shake-flask method and,
therefore, is the preferred method for
measuring water solubility. In addition, it is
very rapid, precise, and is applicable to
substances with water solubilities ranging
from 10 parts per billion to grams per liter
(Yalkowsky and Banerjee 1992; USEPA
1985). The equipment used in the generator
column method, however, is
more sophisticated and, hence, more
expensive. PMN submitters are encouraged
to provide information on the method used
to measure water solubility, as well as an
estimate of systematic and random errors of
the reported result.
Estimating water solubility
A considerable amount of effort has
been devoted to understanding the
mechanism of aqueous solubility and
developing methods that enable accurate
estimation. A comprehensive treatise on
water solubility and methods for its
estimation has been published (Yalkowsky
and Banerjee 1992). To summarize the
contents of the text, water solubility is
governed by three major factors: (1) the
entropy of mixing; (2) the differences
between the solute-water adhesive
interaction and the sum of the solute-solute
and water-water adhesive interactions; and
(3) the additional intermolecular interactions
associated with the lattice energy of
crystalline substances (Yalkowsky and
Banerjee 1992; Klopman et al. 1992). In
estimating the water solubility of liquid
substances, only factors 1 and 2 need to be
considered, whereas in estimating the water
solubility of solids, factor 3 must be included
as well.
Most estimation methods for water
solubility consist of regression equations that
contain Kow data as descriptors of factors 1
and 2 (Lyman et al. 1982; Yalkowsky and
Banerjee 1992). Generally, if Kow data are
not available, it is difficult to estimate water
solubility accurately. Some estimation
methods also incorporate atomic fragment
constants, and have been moderately
successful for certain types of substances
(Lyman et al. 1982; Wakita et al. 1986;
Yalkowsky 1988; Klopman et al. 1992).
Methods for estimating water solubility have
been more successful for liquids than for
solids. This is largely because of the
difficulty in incorporating descriptors of
intermolecular interactions for solid
substances into the regression equations of
the estimation methods. Incorporation of
melting point, entropy of fusion, or enthalpy
of fusion as descriptors of factor 3 has met
with limited success for only certain types of
compounds and, thus, has limited
applicability (Lyman et al. 1982; Yalkowsky
60
-------
and Banerjee 1992). In short, accurate
estimation of water solubility is generally
difficult, particularly for solid substances. As
a general rule, non-ionic substances that are
liquids at room temperature are usually more
soluble than solids. Solid non-ionic
substances with higher melting points or
greater polarity tend to be less soluble than
non-ionic solids that have lower melting
points or lower polarity.
As noted earlier, when estimation of
properties is difficult, EPA uses conservative
values that ultimately tend to increase the
Agency's overall concern for the chemical.
EPA encourages the inclusion of reliably
measured water solubility data in PMN
submissions. By providing such information,
the PMN submitter both eliminates the
possibility that EPA will overestimate the
water solubility of a chemical and ultimately
assists EPA in making the most accurate risk
assessment and risk management decisions.
It is not always necessary, however,
for PMN submitters to provide EPA with
measured water solubility data. For
example, it is not necessary to measure the
aqueous solubility of substances that are
obviously very soluble, such as mineral salts
of amines, metal salts of sulfonic acids, and
quaternary ammonium compounds. For risk
assessment purposes, EPA is not concerned
with discerning the precise aqueous solubility
for substances that are considerably water
soluble. It is also, in general, not necessary
for PMN submitters to determine water
solubility for substances that are extremely
water insoluble. Chemicals that are
extremely hydrophobic (log Kow greater than
7) are so poorly soluble that for risk
assessment purposes, such substances are
regarded as essentially insoluble. Finally, it
is not necessary to measure water solubility
for polymeric materials that are dispersible.
To decide whether water solubility
should be measured, one should first
determine or estimate the log Kow of the
substance. It is best to measure water
solubility for substances whose log Kow
values are between -1 and 7. The generator
column method is preferred for measuring
water solubility for substances that have log
Kow values of 3 or greater. The shake-flask
method is acceptable for measuring water
solubility of substances having log Kow values
less than 3.
It is important that water solubility be
determined for the substance itself, not for
formulations of the substance. It is not
uncommon for EPA to receive PMN
submissions that include measured water
solubility data for formulations of the PMN
substance in co-solvents (e.g., alcohols,
dimethylformamide, or dimethylsulfoxide).
Such measured data are useless to EPA for
risk assessment purposes.
Terms such as "insoluble" or "not
very soluble" should not be used unless they
are accompanied by data from attempted
solubility measurements (such as "log Kow is
greater than 7"). A substance that is
regarded as "insoluble" by a chemist may be
sufficiently soluble to contribute to risk, as
determined by a toxicologist or
environmental fate specialist. Similarly,
terms such as "soluble" or "very soluble"
should not be used unless, again, they are
accompanied by data from attempted
solubility measurements (such as "water
solubility is greater than 100 g/L").
2.2.4 Soil/Sediment Adsorption
61
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Coefficient
to partition into water.
The soil/sediment adsorption
coefficient, Koc, is a measure of the tendency
of a chemical to be adsorbed onto soils or
sediments. Koc is defined as the ratio of the
amount of chemical adsorbed per unit weight
of organic carbon (oc) in soils or sediments
to the concentration of the chemical in
solution at equilibrium:
K
\ig adsorbed/g organic carbon
\ig/mL solution
Discussions on soil and sediment adsorption
are available (Karickhoff et al. 1979; Means
et al. 1982). Values of Koc can range from 1
to 1 x 107 (Lyman et al. 1982).
Koc is important in the assessment of
the fate and transport of chemicals in soils
and sediments. A chemical with a high Koc
value is likely to be adsorbed to soils and
sediments and thus, is likely to remain on the
soil surface. In contrast, a chemical with a
low Koc value is not likely to be adsorbed to
soils and sediments but is likely to leach
through these soils and sediments and, if not
degraded, may reach ground and surface
waters. Chemicals that adsorb tightly to
soils and sediments may accumulate in soils,
but will be less prone to environmental
transport in the gas phase or in solution.
Chiou and co-workers (1983) reported that
the extent of a chemical's insolubility in
water is the primary factor affecting its
adsorption to soils and determines its degree
of mobility in rivers, groundwater, and
runoff. Also, a substance that is tightly
adsorbed to soils is less likely to be subject
to other fate processes (such as
volatilization, photolysis, hydrolysis, and
biodegradation) than a substance that tends
EPA's Toxic Substances Control Act
Test Guidelines (USEPA 1985) describe an
experimental method for determining the
adsorption coefficient K, which can be used
to calculate Koc. The method involves
equilibrating various aqueous solutions
containing different concentrations of the
test chemical and a known quantity of
sediment or soil. After equilibrium is
reached, the distribution of the chemical
between the aqueous phase and the solid
phase is determined. The coefficient, K, is
determined from the following equation:
— KC'
m
where
x/m = (fig of chemical absorbed)/(g soil or sediment)
C = (fig ofchemical)/(mL of solution)
n = a parameter ranging from 0.7 to 1.1 (Lyman et al.
1982)
Koc is determined from K and the
percent of oc in the soil or sediment:
K
K
%oc
x 100
Several methods are available for the
estimation of Koc from empirical relationships
with other properties (Lyman et al. 1982).
Octanol/water partition coefficient (Kow) is
often used in regression equations for the
estimation of Koc. Other properties used to
estimate Koc include water solubility,
bioconcentration factor (BCF) for aquatic
life, and parachor. Swann et al. (1983)
found that the retention times of chemicals in
reversed-phase high performance liquid
chromatography (RP-HPLC) correlate well
62
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with measured Koc values. Bahnick and
Doucette (1988) and Sabljic (1984, 1987)
have reported the use of molecular
connectivity indices for estimation of Koc.
Meylan and co-workers (1992) have recently
reported a model for Koc estimations that
uses molecular connectivity indices and
fragment descriptors. This last method
appears to produce more accurate estimates
of Koc than other models, is easier to use
since measured or estimated Kow or water
solubility values are not needed, and is more
comprehensive in its applicability to a variety
of structurally diverse organic compounds.
Koc provides a measure of a
substance's distribution between soil and
water. For practical reasons, EPA does not
expect PMN submitters to measure Koc
values for substances submitted in PMNs. In
fact, EPA has, to date, never received a
PMN that included a Koc value; however,
EPA estimates Koc values for practically
every PMN substance submitted to the
Agency because of the importance of this
property in predicting environmental
partitioning and distribution. This
emphasizes the need for the inclusion of
certain physicochemical property data (such
as water solubility and Kow) in PMNs, which
EPA can then use in estimating Koc. Koc,
used with the Kow, BCF, and Henry's Law
constant, can predict the environmental
distribution of a chemical and, thus, is a
measure of environmental risk (McCall et al.
1983).
2.2.5 Henry's Law Constant
A substance that is introduced into
the environment by release to air, water, or
land tends to diffuse through all
environmental media in the direction of
establishing an equilibrium between these
media. Henry's Law describes the
distribution of a chemical between water and
air and states that when a substance is
dissolved in water, the substance will have a
tendency to volatilize from the water into the
air above until an equilibrium is reached.
Henry's Law constant (H) can be considered
an air-water partition coefficient and is
defined as the concentration of the chemical
substance in air relative to the concentration
of the chemical substance in water:
„ [chemical substance] in air
[chemical substance} in water
This equation is appropriate only for
equilibrium conditions of dilute solutions
(those typically observed in the
environment). Chemicals that have high H
values have a greater tendency to volatilize
from solution and partition towards air,
whereas relatively low H values indicate that
the substances will tend to partition into
water. Some groups of substances tend to
partition significantly toward air despite
possessing relatively low vapor pressures.
These high H values are primarily the result
of the poor solubility of these substances
(hydrocarbons, for example) in water.
Henry's Law constant can be
expressed as a ratio of the partial pressure of
a substance in the vapor above a solution to
the concentration of the substance in the
solution:
H
equilibrium vapor pressure
solubility
where vapor pressure is in atmospheres and
the solubility is in moles per cubic meter.
The vapor pressure of the pure
substance, typically in units of atmospheres-
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cubic meters per mole (atm-rrrVmol), is often
used as an approximation of the partial
pressure (Lyman et al. 1982). This
approximation is valid for substances with
low water solubilities. If the solubility of a
substance exceeds a few percent, then the
dissolved substance's vapor pressure will be
lower than that of the pure substance due to
its dilution by water (Mackay and Shiu
1981). The thermodynamic principles that
govern the relationships between vapor
pressure, water solubility, and H for solid
and liquid substances have been addressed in
detail by Mackay and Shiu (1981). Also
included in this discussion are experimental
techniques for obtaining these properties.
The inverse of the H value is also used by
some investigators (McCall et al. 1983);
therefore, the ratio H must be defined as
being either air/water or water/air. The
vapor pressure term can be expressed in
other units (e.g., Pascals, torr), and the
solubility term can be expressed in other
concentration units (e.g., grams per cubic
meter) or as a mole fraction.
The H value is often calculated from
data for vapor pressure and water solubility
that are measured independently (see the
sections on these two properties for
information on obtaining experimental
measurements). As mentioned, this method
may not be accurate for substances with
water solubilities exceeding a few percent,
but it is considered to be satisfactory for less
soluble substances (Mackay and Shiu 1981).
A second method for determining H involves
measuring the water solubility and vapor
pressure of a substance in a system that is at
equilibrium (Mackay and Shiu 1981). This
method is typically used for substances with
high water solubilities. A third method
described by Mackay and Shiu (1981) is
most appropriate for substances with very
low solubilities and vapor pressures. The
method involves measuring the relative
concentration changes in one phase during
an equilibrium air-water exchange process.
The H value is then determined from the
slope of a semilogarithmic plot of
concentration versus time.
EPA often estimates H using vapor
pressure and water solubility data. Several
methods are also available for estimating H
from molecular fragments (Bruggemann and
Munzer 1988; Hine and Mookerjee 1975)
and bond contribution values (Meylan and
Howard 1991).
Whereas the soil adsorption
coefficient (Koc) provides a measure of a
substance's distribution between soil and
water, H provides a measure of a substance's
distribution between water and air. As with
Koc, EPA does not expect PMN submitters
to measure H values for substances
submitted in PMNs. EPA, however, does
estimate H values for many PMN substances
submitted to the Agency to describe the
volatilization of a substance from water.
This further emphasizes the need for the
inclusion in PMNs of certain
physicochemical property data (such as
water solubility and vapor pressure, or at
least boiling point), which EPA can then use
for estimating H. The H value, water
solubility, Kow, Koc, and BCF are all
important properties used in determining the
environmental distribution pattern of a
substance and in assessing its environmental
risk.
2.2.6 Boiling Point
Boiling point is the temperature at
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which the vapor pressure of a substance in
the liquid state is equal to atmospheric
pressure. A substance boils when it has
absorbed enough thermal energy to
overcome the attractive forces between the
molecules of the substance. The heat
required to overcome these forces is the
latent heat of vaporization. Solid substances,
of course, must first liquify (melt) before
they can boil. Some solid chemicals sublime;
they pass directly from the solid to the
gaseous state without melting. Boiling
points and sublimation temperatures, like
melting points, are characteristic properties
of pure substances and may be used for the
purpose of identification. Boiling points can
also provide an indication of the purity of a
liquid. With the exception of azeotropes, a
liquid that is a mixture of several substances
will begin to boil at a temperature equal to
the boiling point of its most volatile
component. The temperature will then
gradually increase as the vapor phase
becomes more rich with the less volatile
component(s), until the temperature equals
the boiling point of the least volatile
component.
Boiling point is an indication of the
volatility of a substance. It is particularly
important in EPA's assessment of PMN
substances, because it can be used to
estimate vapor pressure, a vital property in
estimating exposure (see section on vapor
pressure). Boiling points are easily
measured; EPA's Toxic Substances Control
Act Test Guidelines (USEPA 1985) describe
five methods for measuring boiling points.
These methods include: (1) determination by
use of an ebulliometer, in which the
substance is heated under equilibrium
conditions at atmospheric pressure until it
boils; (2) the dynamic method, in which the
vapor recondensation temperature is
measured by means of a thermocouple; (3)
the distillation method, in which the liquid is
distilled and the vapor recondensation
temperature is measured; (4) the Siwolloboff
method, which involves heating the sample in
a heat bath and measuring the temperature at
which bubbles escape through a capillary
tube; and (5) the photocell method, in which
a photocell is used with the Siwolloboff
method to detect rising bubbles in the
capillary tube. Boiling point should always
be measured using a pure sample of the
substance and should never be measured
from a mixture or a solution containing the
substance.
The boiling points of members of a
homologous series of substances generally
increase in a uniform manner with increasing
molecular weight. Therefore, the boiling
point of a substance may be estimated using
its molecular weight, if boiling points for
homologous substances are available.
Boiling points measured or estimated at
reduced pressure can be used to estimate
boiling points at one atmosphere (760 mm
Hg).
Lyman et al. (1982) discuss seven
different methods for estimating boiling
point. At the time of this writing, no other
methods have been reported since. All of the
methods discussed by Lyman are capable of
estimating boiling point from structure alone.
Each method has its own advantages and
disadvantages with respect to applicability
and, therefore, is typically used only for a
particular class of substances. EPA chemists
often use these methods to estimate boiling
point when an experimental value is not
included in PMN submissions and is not
found in the literature. EPA chemists
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frequently have difficulty determining which
method is the most appropriate for a
chemical that has multiple functional groups
and falls into several different chemical
categories. In such cases, EPA usually
selects the estimation method that results in
the lowest boiling point, consequently
maximizing exposure to the PMN substance.
As with estimating water solubility, boiling
points of liquid substances are easier to
estimate than boiling points of solids, since
the latter include intermolecular,
intracrystalline forces (such as crystal
packing) that are very difficult to estimate
(see section on water solubility).
Experimental boiling points are
known for many chemicals and are easily
measured. PMN submitters, therefore,
should be able to provide boiling point data
for many new chemical submissions,
provided that the substance does not
decompose rather than melt or boil. It is not
necessary, however, for PMN submitters to
provide EPA with measured boiling point
data for every PMN substance. EPA is
concerned primarily with chemicals that melt
below 100 °C, since these substances are
most likely to volatilize readily. High
melting solids (> 150 °C) typically have very
high boiling points and, therefore, do not
volatilize significantly. Polymers and other
structurally large substances (solid or liquid)
usually have low volatilities because of their
high molecular weights, and often
decompose upon heating. Salts also have
low volatilities because of their strong ionic
forces and very high melting points.
Therefore, it is not necessary (or it may not
be possible) for a PMN submitter to provide
EPA with boiling point data for substances
that have high molecular weights or very
high melting points.
2.2.7 Vapor Pressure
Vapor pressure is the pressure at
which a liquid substance and its vapor are in
equilibrium at a given temperature. At this
equilibrium, the rate of condensation of the
vapor (conversion of gaseous substance to
liquid) equals the rate of vaporization of the
liquid (conversion of liquid substance to
vapor); the vapor phase in this equilibrium is
saturated with the substance of interest.
Vapor pressure is characteristic of a
substance at a given temperature, and is
usually expressed in units of millimeters of
mercury (mm Hg, or torr), atmospheres
(atm), or Pascals (Pa); EPA prefers mm Hg
or torr.
Because vapor pressure is an
indication of the volatility of a substance, it
can be used to estimate the rate of
evaporation of that substance and is very
important in the exposure assessment of
chemicals. EPA uses the vapor pressure and
molecular weight of PMN substances to
estimate their concentrations in air and assess
occupational exposure and potential
environmental releases. Vapor pressure is
also used in assessing potential exposure to
consumers from products that contain the
PMN substance. In the exposure evaluation
of PMN chemicals, EPA is particularly
concerned with substances that have vapor
pressures greater than 10"3 mm Hg.
Vapor pressure is also an important
property in the assessment of environmental
fate and transport of a chemical substance.
Volatilization is an important source of
material for airborne transport and may lead
to the distribution of a chemical over wide
areas and into bodies of water far from the
site of release (USEPA 1985). Chemicals
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with relatively low vapor pressure, high soil
adsorptivity, or high solubility in water are
less likely to vaporize and become airborne
than chemicals with high vapor pressure, low
water solubility, or low soil adsorptivity.
Chemicals that do become airborne are
unlikely: (1) to be transported in water; (2)
to persist in water and soil; or (3) to
biodegrade or hydrolyze. Such chemicals
may undergo atmospheric oxidation and
photolysis. Non-volatile chemicals,
however, are of greater concern for
accumulation in soil and water (USEPA
1985).
Several experimental procedures are
available for measuring vapor pressure; two
are described in EPA's Toxic Substances
Control Act Test Guidelines (USEPA 1985).
The first method, the isoteniscope technique,
is a standardized procedure applicable to
pure liquids with vapor pressures from
approximately 0.75 to 750 mm Hg. The
second method, the gas saturation
procedure, involves a current of inert gas
passed through or over the test material and
can be used for solids or liquids with vapor
pressures ranging from 7.5 x 10"8 to 7.5 mm
Hg (USEPA 1985).
Lyman et al. (1982) discuss several
methods for estimating vapor pressure. EPA
often uses these methods when vapor
pressure data for a substance are not
included in a PMN and are unavailable from
the literature. Theoretically derived
equations are used to estimate the vapor
pressures of solids, liquids, and gases from
measured or estimated normal (760 mm Hg)
boiling points or from boiling points obtained
at reduced pressure. Vapor pressure data,
either estimated or measured, are necessary
to estimate other properties such as Henry's
Law constant.
EPA encourages PMN submitters to
provide vapor pressure data in PMNs
whenever possible because of the importance
of vapor pressure in determining human
exposure and environmental fate. Vapor
pressure data should be obtained for the pure
PMN chemical and not for a formulation of
the substance. A frequent problem in PMNs
is that the vapor pressure data submitted
were measured for the PMN substance
dissolved in a solvent. In such cases, the
vapor pressure data represent the solvent,
not the PMN substance, and are, therefore,
useless to EPA. If measured vapor pressure
data are not supplied, then measured boiling
point data may be used to estimate vapor
pressure reliably. If measured boiling points
are not available, estimated boiling points
may also be used to estimate vapor pressure,
but estimated boiling points can decrease
accuracy and increase the possibility of
error. As with other physicochemical
properties, if EPA is uncertain about its
estimated vapor pressure, it will most likely
use a value that reflects a worst case
scenario, leading to greater exposure.
As with boiling point, PMN
submitters do not necessarily need to provide
EPA with measured vapor pressure data for
every PMN substance. EPA is concerned
primarily with chemicals that are liquids or
gases at room temperature or solids that melt
below 100 °C, since these substances are
most likely to volatilize readily, which can
result in significant exposure during
manufacture or use. High melting solids (>
150 °C) are expected to have very high
boiling points (and very low vapor pressures)
and, therefore, are not expected to volatilize
significantly. Polymers or other high
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molecular weight substances (solid or liquid)
typically have low volatility because of their
large size. PMN submitters do not need to
provide EPA with vapor pressure data for
such substances.
2.2.8 Reactivity
The reactivity of chemical substances
within biological and environmental systems
is crucial to EPA's risk assessment of PMN
substances. Toxicity is often the result of a
chemical's ability to interfere with normal
biochemical processes at the cellular level.
Many biochemical processes are enzyme-
mediated reactions involving various organic
molecules used to produce other organic
molecules for a specific function that is vital
to the organism. The mechanisms for these
enzyme-mediated reactions are
fundamentally identical to reaction
mechanisms of organic chemistry.
Biochemical reactions may involve, for
example, nucleophilic attack, electrophilic
substitution, loss of electrons (oxidation),
gain of electrons (reduction), or hydrolysis.
A knowledge of organic reaction
mechanisms is necessary in understanding
how a xenobiotic (a chemical that is not part
of a biological system or process) will
behave or react with molecules that are part
of a biochemical pathway. EPA chemists
and toxicologists examine every PMN
substance to ascertain how these substances
may react following absorption into the
human body. For example, PMN substances
that contain electrophilic substituents, such
as acid chlorides, isocyanates, anhydrides, or
a,P~unsaturated carbonyls (acrylates,
acrylamides, quinones), may undergo
nucleophilic attack by free amino (NH2)
groups present in proteins, thus perturbing
the biochemical pathway. In fact, substances
containing these functional groups are often
quite toxic because of their susceptibility to
nucleophilic attack by biological molecules
(Anders 1985; De Matteis and Lock 1987;
Gregus and Klaassen 1996). EPA does not
automatically assume, however, that a PMN
substance is toxic just because it contains a
reactive functional group. Physicochemical
properties must also be considered to assess
exposure and bioavailability. Poor water
solubility, for example, may mitigate EPA's
concerns for the toxicity of a PMN substance
containing a reactive functional group,
because substances with poor water
solubility are expected to be poorly
absorbed. This example further illustrates
the importance of physicochemical properties
in EPA's risk assessment of PMN substances.
EPA chemists and toxicologists
consider potential reactivity in predicting the
toxicity of PMN substances that contain
reactive functional groups and for which few
or no toxicological and physicochemical
property data are provided. However, it is
often difficult to predict the reactivity of a
functional group, especially if, for example,
the group is hindered or otherwise
chemically influenced by other substituents
contained within the molecule. In such
cases, EPA's policy is to assume reactivity,
which may lead EPA scientists to predict a
health concern. EPA chemists would prefer
to have more information from the PMN
submitter with respect to the relative
reactivity of any functional groups in a PMN
substance. EPA does not expect submitters
to conduct extensive laboratory experiments
investigating the reactivity of functional
groups. EPA believes, however, that the
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opinions of the submitter's in-house chemists,
with respect to chemical reactivity, would be
very helpful.
2.2.9 Hydrolysis
Substances may also react in the
environment to produce other substances
with properties different from those of their
precursors. A type of reaction of particular
interest is hydrolysis, which is the
decomposition of a substance upon reaction
with water. Hydrolysis is often described
using rate constants (the rate of
disappearance of the substance) and half-
lives (the time required for the concentration
of the substance undergoing hydrolysis to be
reduced to one-half its initial value). In
addition to hydrolysis, reactions with water
in the environment can include elimination of
a chemical group, isomerization, and acid-
base reactions. Hydrolysis is likely to be the
most important reaction of organic
substances in aqueous environments,
although elimination reactions can also be
significant (Lyman et al. 1982).
Chemicals released into the
environment are likely to come into contact
with water following direct release into
surface water, soil, or the atmosphere. It is
important to know whether a substance will
hydrolyze, at what rate, and under what
conditions. If a substance hydrolyzes
rapidly, then the hydrolysis products may be
more important than the original substance in
assessing environmental fate and effects.
For a substance that hydrolyzes slowly,
however, both the parent substance and the
hydrolysis products should be assessed.
Certain chemical groups (e.g.,
haloformates, acid halides, small
alkoxysilanes, epoxides) are very susceptible
to hydrolysis, while others hydrolyze more
slowly (e.g., alkyl halides, amides, esters).
Water solubility can be a limiting factor in
hydrolysis. Generally, the more soluble a
substance is, the faster it will hydrolyze.
Substances with very low water solubility
that contain hydrolyzable substituents may
hydrolyze very slowly, if at all. Half-lives
(the time required for the concentration of
the chemical to be reduced to half its initial
value) for the hydrolysis of even reasonably
similar chemicals can vary widely, from
seconds to years, depending primarily on
water solubility, but also on pH and
temperature.
EPA's Toxic Substances Control Act
Test Guidelines (USEPA 1985) describe a
procedure for determining hydrolysis rate
constants and half-lives at several pH levels.
The method involves preparing solutions of a
substance of known concentrations and then
determining the changes in concentrations of
these solutions at various time intervals.
This method is also applicable to elimination
reactions. The rate constants generated by
this method can be used to determine the
hydrolysis rates at any pH of environmental
concern.
In the absence of experimental data,
EPA makes qualitative and semi-quantitative
estimates of hydrolysis rates based upon
chemical structure, physicochemical
properties, and comparison to similar
substances with known rates of hydrolysis
(Mabey and Mill 1978; USEPA 1986, 1987,
1988a, 1988b). This estimation approach is
most reliable when measured
physicochemical properties (particularly
water solubility) for the substance of interest
are available, as well as measured hydrolysis
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rate constants for analogous substances.
Physicochemical properties for the substance
and rate constants for analogous substances,
however, are not always known. In such
cases, EPA bases hydrolysis estimates on
chemical structure and estimated
physicochemical properties. In the face of
uncertainty, EPA will rely on conservative
assumptions (e.g., EPA will assume a slower
hydrolysis if EPA has environmental
concerns for the intact chemical; if EPA has
concerns for the hydrolysis products, EPA
will assume a faster rate of hydrolysis). EPA
does not expect PMN submitters to provide
measured hydrolysis data routinely along
with their PMN submissions. However,
providing EPA with any qualitative or
quantitative information pertaining to
hydrolysis would be very helpful. This
information would make it possible for the
EPA to make more accurate risk assessments
and to avoid the use of credible worst case
assumptions.
2.2.10 Spectral Data
Many PMN submitters include
spectral data in their submissions, which
EPA finds helpful in verifying the identity of
PMN substances. Spectral data are also
helpful in identifying the presence of
unreacted functional groups (e.g.,
isocyanate) and unknown, possibly toxic
byproducts (e.g., dioxins, PCBs), especially
if EPA suspects that such chemical species
may be present. If EPA chemists suspect
that unreacted functional groups or toxic
byproducts may be present, given the
synthesis of a PMN chemical, but no spectral
data are provided, then their presence may
be assumed by EPA. In actuality, EPA
chemists often use spectral data provided by
PMN submitters to rule out (rather than
confirm) the presence of toxic byproducts or
unreacted functional groups.
The spectral data that EPA finds most
useful include mass spectra (MS), infrared
(IR), hydrogen (JH) and carbon (13C) nuclear
magnetic resonance (NMR), and ultraviolet
(UV). Each of these spectral techniques
provides unique information and collectively
this information is extremely useful for
structure elucidation (Pavia et al. 1979;
Silverstein et al. 1981).
Ideally, EPA would like to have
spectral data on a purified sample of the
PMN substance; however, spectral data on a
less pure commercial grade product are also
helpful. It is not necessary for PMN
submitters to provide spectral data for
polymers (other than the data obtained from
spectral techniques used to determine
molecular weight) that were synthesized
from monomer species with no reactive
functional groups other than those necessary
for the polymerization reaction.
2.2.11 Photolysis (Direct/Indirect)
Many chemicals released into the
atmosphere or surface water undergo
chemical transformation through absorption
of sunlight. Photolysis is the decomposition
of a substance as a result of absorbing one or
more quanta of sunlight radiation; it can take
place in water or in air. Rate constants
(measurement of the rate of disappearance of
the substance) and half-lives (the time
required for the concentration of the
substance undergoing photolysis to be
reduced to one-half its initial value) provide
information on photochemical transformation
in water and the atmosphere. In direct
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photolysis, a substance absorbs solar
radiation and undergoes a photochemical
reaction. In indirect photolysis, one
substance absorbs sunlight, then transfers the
energy to another substance, thus initiating a
chemical reaction. Absorption of light in
photochemical reactions (direct and indirect)
can result in intramolecular rearrangements,
isomerization, homolytic and heterolytic
cleavages, redox reactions, energy-transfer
reactions, and reactions with water.
Photochemical processes in the
atmosphere can produce reactive atoms and
free radicals such as the hydroxyl radical
(•OH). Chemicals that do not absorb
sunlight (i.e., do not undergo direct
photolysis) may undergo indirect photolysis
in the atmosphere by reacting with hydroxyl
radicals or with ozone (Finlayson-Pitts and
Pitts 1986). The oxygen present in water
may participate in direct or indirect
photochemical reactions as an acceptor of
energy or electrons. Decaying vegetation in
water may also absorb sunlight; energy is
then typically transferred to another
substance, thus initiating an indirect
photochemical reaction (Leifer 1988).
Photochemical reactions in the
atmosphere and water are important
examples of chemical transformations that
should be considered when assessing the
environmental fate of chemical substances.
The products of photochemical reactions and
their resulting effects on human health and
the environment are also important
considerations in chemical evaluations.
Like Koc, EPA has never received a
PMN submission that included photolysis
rate constants. EPA estimates photolysis
rate constants, however, for essentially every
PMN submitted. For practical reasons, the
Agency does not expect PMN submitters to
provide measured photolysis data in their
PMN submissions, although it would be
helpful to EPA if PMN submitters at least
provided UV absorption data. UV data can
be used by EPA to determine if a substance
will undergo direct photolysis and, if it does,
the data will then be used to estimate the
relative rates of the direct photolysis of the
substance (USEPA 1985).
EPA, in its Toxic Substances Control
Act Test Guidelines (USEPA 1985),
describes test methods for determining molar
absorptivity and reaction quantum yield (the
fraction of absorbed light that results in a
photoreaction at a fixed wavelength) for
direct photolysis of a substance in an
aqueous solution. The Guidelines also
discuss methods for determining the rate
constant and half-life of a substance in an
aqueous solution or in the atmosphere, as a
function of latitude and season of the year in
the United States.
Photolysis of chemicals in the
atmosphere and water can be estimated by
various methods. Computer programs are
available that calculate rate constants and
half-lives for reactions with hydroxyl radicals
and ozone in the atmosphere (e.g., the EPI
program described in Section 2.4.4 of this
chapter). Lyman et al. (1982) describe
several methods for estimating atmospheric
residence time, which is related to half-life.
Qualitative estimates of photolysis can be
made based on the types of compounds that
may be subjected to photolysis and the types
of reactions they may undergo. Certain
types of chemical groups are known to
absorb light and undergo photolysis;
therefore, the rate constant and half-life for a
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particular substance may be estimated
qualitatively by analogy to known data on
other compounds with similar structures.
2.2.12 Other Chemical Information
Use (Intended Use/Other
Uses/Potential Uses). Information on the
intended use(s) of a PMN substance and the
percent of total production estimated for
each use, both provided by the submitter, are
important to EPA's review of the substance.
EPA uses this information to trace a PMN
chemical's life cycle and to estimate health
and environmental exposures to the
chemical. Use and disposal information also
reveals which release scenarios are likely to
be the most significant with regard to
exposure to a substance, and could
determine which physicochemical properties
are most important during the review of the
substance. In addition to evaluating the
occupational exposure of workers to a
chemical during its manufacture, EPA
considers potential consumer exposure if the
chemical is to be used in a commercial
product. A substance with consumer use(s),
for example, will most likely lead to a
significantly greater number of exposures
than a chemical with only industrial uses.
In addition to the listing of intended
uses provided by the submitter, EPA
identifies and evaluates other possible or
potential uses of the chemical by searching
the literature and EPA's in-house database of
PMN submissions for structurally-analogous
substances, particularly those that pose a
potential risk to human health or the
environment. The identification of other
uses is important because anyone may
market or use a PMN substance for any
purpose once the substance is on the TSCA
Inventory (unless the substance is restricted
by a 5(e) consent order or a SNUR). If a
substance is used for an entirely different
purpose than originally stated in a PMN
submission, then production volume,
environmental releases, and human
exposures could be significantly different
than those estimated from the initial PMN.
A new use for a substance, therefore, could
pose a threat to human health and the
environment. The potential for other uses,
especially those involving high exposure or
release, leads EPA to restrict the future uses
of some PMN substances through SNURs.
The manufacturer of a chemical may not
always be aware of other potential uses for a
substance or may not be planning to pursue
other uses because of the substance's
marketability or the company's interests.
It would be helpful to EPA, however, if
submitters would provide known potential
uses of a substance even if they are not
planning to pursue them.
Synthesis. EPA requests information
on the synthesis of PMN substances,
including data on feedstocks, solvents,
catalysts, other reagents used in the synthetic
process, and byproducts (chemicals
produced in the synthetic process without a
separate commercial intent). This
information is supplemented by process and
operation descriptions and is utilized during
several stages of EPA's evaluation of PMN
substances.
Information on the synthesis of a
chemical is important in several ways.
Review of the synthetic process helps EPA
to verify the identity of the PMN substance.
From a review of reaction conditions, EPA
may also be able to predict the existence of
impurities and by-products, including toxic
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reaction products (e.g., PCBs, dioxins or
nitrosamines), that are unknown to the
submitter because, for example, such
substances may be present only in very small
concentrations.
EPA scientists also review the
synthetic processes for selected, potentially
higher-risk PMN substances with respect to
pollution prevention. EPA investigates
whether any modifications could feasibly be
implemented in this synthesis that would
limit or avert the use of hazardous
substances (including solvents and all
reactants) or that would reduce or prevent
the production, not just of hazardous waste,
but of all waste. In a few cases, EPA
scientists may also identify alternative
synthetic sequences that would at least
reduce the production of toxic byproducts or
the use of high-risk solvents and feedstocks.
Submitters may demonstrate to EPA
on the Optional Pollution Prevention page of
the PMN (page 11) any pollution prevention
strategies that they plan to implement. Some
companies provide detailed descriptions of
synthetic pathways that incorporate pollution
prevention (e.g., processes that give high
yields and use few or no organic solvents).
EPA would like to see more companies do
the same. For PMN submissions that do not
contain synthetic information (synthetic data
are not required for imported substances),
pollution prevention information voluntarily
supplied by submitters can assist EPA in its
review of the PMN substance. For example,
if a synthetic scheme is not given for a PMN
substance, EPA may be concerned about the
possible existence of toxic byproducts and
impurities, based on information known
about the synthetic scheme of similar
substances. If the submitter, however,
includes pollution prevention information
explaining how their synthesis has improved
upon known methods, then EPA would not
need to assume a worst case scenario.
Purity/Impurities. The purity of a
PMN substance, as well as the identities,
concentrations, and hazards of all impurities
are considered in the evaluation of every
PMN substance. During review, EPA
investigates whether any reported
physicochemical properties submitted for a
PMN substance (especially melting point and
boiling point) coincide with any data
previously recorded in the literature.
Discrepancies between literature values and
the data contained in the PMN submission
may be attributable to impurities. EPA will
contact the submitter if it is not clear in the
PMN what the identities of impurities are,
especially if impurities are predicted from
EPA's analysis of the synthetic process. The
presence of hazardous impurities (such as
dioxins, PCBs, or nitrosamines) is cause for
concern and, if present at significant levels,
such impurities would lead EPA to predict
potential risk to human health and the
environment, especially if the PMN
substance is intended for consumer use.
Molecular Weight. The molecular
weight of a substance is the sum of the
atomic weights of all the atoms in a
molecule. For a simple molecule, the
molecular weight is easily determined if the
structure is known. Polymers, however, are
typically comprised of a variable number and
sequence of monomer units that may
themselves also have varying chain length
and molecular weight. The molecular weight
of a polymer is frequently reported as a
number-average weight (the sum of the
molecular weights of the molecules divided
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by the number of molecules).
Very large molecules are unlikely to
be absorbed and, therefore, may be of little
concern to EPA unless, of course, they
contain reactive functional groups. EPA
consequently exempts under TSCA section
5(h)(4) certain polymers (those with number-
average molecular weights greater than
1,000 and certain polyesters, for example)
from some of the PMN requirements. EPA
does have concerns, however, for certain
polymers with average molecular weights of
10,000 daltons or greater. These concerns
are largely for lung toxicity (USEPA 1995).
2.3 Use of Chemical Information in
Assessment of PMN Chemicals
Each physicochemical property
discussed in this chapter is important in
EPA's evaluation of the potential risks posed
to human health or the environment by PMN
substances. Refer back to Figure 2-1, which
illustrates some of the physicochemical data
used, their interrelationships, and their
importance in risk assessment. Because of
the large volume of data that EPA uses in its
evaluation of PMN substances, Figure 2-1
does not attempt to include all of the types
of chemical information used or to describe
all of their functions in risk assessment.
2.4 How EPA Obtains Physicochemical
Information
2.4.1 General Approach
When physicochemical property data
required for chemical evaluation are not
reported in a PMN submission, EPA finds or
estimates values for the missing data. EPA's
general approach for obtaining
physicochemical property data is first to
search for data on the PMN substance by
following a sequence of literature and
database sources. If data on the PMN
substance cannot be found, EPA scientists
may identify close structural analogs and use
the same search strategies to find property
data for those analogs. EPA scientists then
use professional judgment to extrapolate
property values for the PMN substance from
the data available for the analogs. If the
required properties for structural analogs
cannot be found, EPA scientists estimate the
properties needed for the PMN substance
using the best estimation method available to
EPA (Lynch et al 1991). If properties for
structural analogs are found, EPA scientists
may still estimate the same properties for the
PMN substance. EPA scientists then analyze
and compare both sets of data to determine
which set is most reasonable. A flowchart
illustrating EPA's procedure for obtaining
physicochemical properties is presented in
Figures 2-3 and 2-4. The sources EPA uses
for searches and the
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Figure 2-3. Methods for Obtaining Measured Physicochemical Property Values on Exact Structures
(Continued)
Manual Search
Automated Search
Handbooks/Catalogs
Aldrich Catalog - data; Beilstein (Beil.) refs.; CAS RN
The Condensed Chemical Dictionary - some properties
CRC Handbook on Chem. and Phys. - data; Beil. refs.
CRC Handbook on Org. Comps.-(also as HODOC on-line database)
Dictionary of Organic Compounds-properties; spectra refs.
Fairfield Research Chemicals Catalog - some properties
Farm Chemicals Handbook '87 - pesticides
Fluka Catalog-some physical properties
Handbook of Environmental Data on Organic Chemicals
Hills Silicon Compounds Register and Review
Kirk-Othmer's Encycl. of Chemical Tech. - industrial uses
Lancaster Synthesis Catalog - some properties
Lange's Handbook - data; refs.
Merck Index - data; some solvent solubilities
P/C Handbooks and Printed sources - index, matrix
Pesticide Index - CAS RN, properties
The Pesticide Manual - pesticides
The Sigma Aldrich Handbook of Stains, Dyes, and Indicators -
water solubility for many compounds
Sphere Data - by CAS RN, water solubility, vapor pressure,...
Ullmann's Encyclopedia of Industrial Chemistry
Water Solubility Database
Search for exact molecule
I
PMN Confidential Database
(1979-Present)
1) Search by skeletal structure, CAS RN,
name, or PMN ID #
2) Search for exact molecules
Confidential Business Information Center
Check Original PMN for additional information
or if any values are in question
Company Literature
1) ICB files
2) RIB files
3) MSDS
I
Patents
1) CAS on-line
2) IFIPAT on-line
3) Patent Office
Journal References
Experimental section
PC NOMO
If have a boiling point, but not at 760 mm
and/or a boiling point, but no vapor pressure:
1) Reduced boiling point reduction to 760 mm
2) Boiling point (at 760) conversion to vapor pressure
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Figure 2-3. Methods for Obtaining Measured Physicochemical Property Values on Exact Structures
Chemical
1) Use CAS Registry Number (CAS RN), structure, or name
a) Determine molecular formula
b) Determine molecular weight
I
CAS On-Line
1) Search by CAS RN (or name or molecular formula) in file registry: verify structure and name
2) Search file CA for journals, patents, and/or abstracts; search for the synthesis using preparation suffix
3) Check for other on-line locations (e.g., Beilstein, Index Medicus)
I
National Library of Medicine On-Line
Search by CAS RN or by chemical name
I
CHEMLINE
- Chemical identity
HSDB
(Hazardous Substances
Data Bank)
- Chemical identity
- Manufacture
- Physical/chemical properties
- Toxicity information
- Environmental fate
- Environmental exposure
I
RTECS
(Registry of Toxic Effects
Chemical Substances)
- Chemical identity
- Toxicity
- Mutagenicity
"SANDRA" Computer Search
1) Draw chemical skeleton of structure
2) Search for Beilstein location (provides system no. range)
I
Beilstein
1) Locate exact molecule
a) via on-line
b) via Handbook
• Continued
76
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Figure 2-4. Methods for Identifying Analogs of PMN Substances and Their Physicochemical Properties
PMN Confidential Database
1) Search substructure
2) Select minimum substituents
3) Narrow hits to structurally similar
substances
I
Water Solubility Database
Search substructure
I
Design Appropriate Analogs
Determine molecular formula
I
CAS On-Line Search
1) Search by molecular formula
2) Expand
3) Search "expand" results
4) Search results with name segments
to narrow the field
5) Retrieve CAS RN
I
Beilstein On-Line Search
1) Search by CAS RN
2) Search "ide" and "phy" only
I
"SANDRA" Computer Search
1) Draw substructure
2) Search for Beilstein locations (range)
Beilstein Handbook
Browse through selected range
for structural analogs
Merck Index
Browse using designated analogs
Handbooks/Catalogs
Aldrich Catalog - data; Beilstein (Beil.) refs.; CAS RN
The Condensed Chemical Dictionary - some properties
CRC Handbook on Chem. and Phys. - data; Beil. refs.
CRC Handbook on Org. Comps.-(as HODOC on-line database)
Dictionary of Organic Compounds - properties; spectra refs.
Fairfield Research Chemicals Catalog - some properties
Farm Chemicals Handbook '87 - pesticides
Fluka Catalog - some physical properties
Handbook of Environmental Data on Organic Chemicals
Hills Silicon Compounds Register and Review
Kirk-Othmer's Encycl. of Chemical Tech. - industrial uses
Lancaster Synthesis Catalog - some properties
Lange's Handbook - data; refs.
Merck Index - data; some solvent solubilities.
Pesticide Index - CAS RN, properties
The Pesticide Manual - pesticides
The Sigma Aldrich Handbook of Stains, Dyes, and Indicators -
water solubility for many compounds
Ullmann's Encyclopedia of Industrial Chemistry
I
PC GEMS or EPI
Determine:
1) Log Kow
2) Other physicochemical properties
3) Compare measured values of analogs to those
estimated by GEMS
4) Use only in conjunction with other analog data
Note: Once an analog has been found, further data can be searched using Figure 2-3.
77
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programs used for estimating property values
are discussed below. Additional information
on the on-line databases, reference books
(e.g., Verscheuren 1983), and computer
programs EPA uses to obtain property data
is provided below.
2.4.2 Methods of Searching for Measured
Physicochemical Properties
CAS On-line Search. The American
Chemical Society's Chemical Abstracts
Service (CAS) On-Line Database includes
several files that can be searched for
chemical information. EPA first conducts a
CAS On-Line search on the Registry File by
CAS Registry Number (CAS RN), chemical
name, or molecular formula. The easiest
search to perform uses the CAS RN, if it is
available. If EPA does not have a CAS RN
for the PMN substance, then an accurate
chemical name or molecular formula is used
for searching.
Linking a molecular formula in a
search with a chemical name or name
fragments can also be useful for finding the
exact substance or a closely related analog.
The CAS Registry File provides, among
other information, the most recent CAS
Registry chemical name, molecular formula,
the chemical structure, other on-line sources
where the substance may be found (e.g.,
Beilstein On-Line, discussed below), and
abstracts of the literature references to that
substance. This information can be used to
verify any name and structural information
already provided.
Information on the synthesis of a
substance can be obtained by searching the
Chemical Abstracts file using the CAS RN.
This file provides references (usually
scientific journal citations or patents) and
may contain physicochemical property data
(in the experimental sections of scientific
papers) or potential uses.
GMELIN On-Line Database For
information on organometallic or inorganic
compounds, EPA searches the Gmelin on-
line database which contains the critically
reviewed and evaluated data from the
Gmelin Handbook of Inorganic and
Organometallic Chemistry. Useful
information includes structural data,
structural images, chemical and physical
properties, and bibliographic data.
National Library of Medicine (NLM) On-
Line Databases. This inexpensive on-line
system contains individual databases that
include information on chemical
identification, physicochemical properties,
manufacturing processes, and uses. These
databases are, therefore, useful for obtaining
a variety of information on many chemicals
or on analogous substances. NLM databases
include the Hazardous Substance Data Bank
(HSDB), the Registry of Toxic Effects of
Chemical Substances (RTECS), and
Chemline.
HSDB entries contain information
and data on chemical identity (name,
CAS RN, synonyms, molecular formula),
methods of manufacture (including
impurities and formulations), manufacturers,
major uses, and chemical and physical
properties (such as color, physical state,
odor, boiling point, melting point, molecular
weight, density, dissociation constant, heat
of combustion, heat of vaporization,
octanol/water partition coefficient, pH,
solubility, spectral properties, surface
tension, vapor density, and vapor pressure).
78
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Toxicity, environmental fate, and exposure
data may also be provided.
RTECS is primarily a database of
toxicological data and references, including
information on acute and chronic toxicity,
mutagenesis, and skin and eye irritation. The
database also includes chemical identity
information such as chemical name, CAS
RN, synonyms, molecular formula, and
molecular weight.
Chemline is an interactive chemical
dictionary file containing approximately one
million chemical substance records. The data
elements consist of CAS RN, molecular
formula, synonyms, ring information, and a
locator to other on-line databases that might
contain further information on a compound.
Beilstein On-Line Database. The
Beilstein On-Line Database is an on-line
version of the Beilstein Handbook of
Organic Chemistry (see below), an extensive
compilation of information on organic
compounds comprised of a multi-volume
Home Register and five supplements.
Information includes synthetic methods,
measured physicochemical properties, and
references. If the CAS On-Line search
(described above) identifies a compound as
listed in Beilstein, then a Beilstein On-Line
search can be performed to provide physical
data quickly, particularly if a CAS RN is
known. Specific data can be selected for
retrieval. References for the data are
provided, but Beilstein Handbook citations
are not included.
SANDRA Computer Search
SANDRA is a computer program that
provides information on the general location
of where a substance might be found in the
Beilstein Handbook, and therefore, enables
rapid searching of the handbook. If a CAS
On-Line search of a substance does not list
the chemical as being available from Beilstein
On-Line, one can use SANDRA to draw the
structure of the substance, of an analog, or
of a fragment of either, and then one can
search to locate the range of the structure
(system number, home register page(s), and
supplement volumes) within the Beilstein
Handbook.
Beilstein Handbook. The Beilstein
Handbook (see the discussion of Beilstein
On-Line and SANDRA, above) can be
searched manually using the molecular
formula indexes. EPA typically uses
SANDRA, as described above, to expedite
the search. Physicochemical properties most
commonly found in Beilstein are melting
point, boiling point, density, and refractive
index. Other data such as vapor pressure or
water solubility are less commonly reported.
Other Handbooks/Catalogs EPA
also may search various handbooks and
commercial chemical catalogs for data on
PMN chemicals, although these sources are
most useful if the substance in question is
relatively simple or if a close structural
analog is commercially marketed.
Handbooks and catalogs EPA uses include
the Aldrich Chemical Company Catalog
Handbook of Fine Chemicals, the Merck
Index, Hiils Silicon Compounds Register and
Review, and the Farm Chemicals Handbook
(includes data on pesticide intermediates).
Confidential PMN Database EPA
has an in-house confidential PMN database
that contains chemical structures and data
from chemistry reports from over 8,000
PMNs submitted since January 1993. Most
79
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entries provide physicochemical properties
that were either measured by the submitter
or estimated by EPA chemists. All
information in this database is regarded and
treated as confidential business information
(CBI), and only EPA personnel with TSCA
CBI clearance have access to it.
Water Solubility Database EPA
has developed a water solubility database file
that can be searched by structure. At
present, this database contains over 6,000
substances with measured water solubility
values (expressed as grams per liter at
measured temperatures) and contains other
measured physical properties for some of
these substances as well. It currently
contains data from the Arizona database
(also known as the AQUASOL
DATABASE, see Yalkowsky and Banerjee
1992), the PHYSPROP® database (available
from Syracuse Research Corporation,
Syracuse, NY), the Merck Index, Beilstein,
and other pertinent literature and journal
articles. All information is referenced within
this database.
Patents. EPA periodically searches
for patents that may have useful
physicochemical property data,
manufacturing information, and use
information. The IFIPAT (IFI Patent
Database) file in the STN computer network
system contains records for granted U.S.
chemical and chemically-related patents from
1950 to the present. Patents on some other
subjects are also included. Hard copies of
U.S. patents can be obtained from the Public
Search Room at the U.S. Patent Office in
Arlington, Virginia. The location of a patent
within the Public Search Room can be found
from the classification number (determined
from the U.S. Patent number, which can be
obtained from a CAS On-Line search).
Scientific Literature. EPA often
uses articles published in scientific journals
to obtain information on synthetic methods
as well as physicochemical and spectral
properties.
2.4.3 Methods For Estimating
Physicochemical Properties From
Structural Analogs
When measured physicochemical
property data are unavailable for a specific
PMN chemical, EPA attempts to obtain the
needed data by extrapolating from measured
data available for close structural analogs.
EPA searches the same information sources
for analogs as for specific chemicals, but the
search strategy differs in that compounds
that are structurally and functionally similar
to the substance under consideration must
either be "designed" or found using
handbooks and databases.
Confidential PMN Database
EPA's confidential PMN database is searched
using a skeletal drawing of the PMN
substance, if the structure is not too novel or
complex. More often, a fragment that
contains the important structural features of
the PMN substance is used in the search.
The PMN database has evolved to contain
numerous classes of chemicals that are
structurally very similar, and all entries found
that possess the same basic structural and
functional features as the PMN substance
can be identified and reviewed for useful
information.
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Designing Structural Analogs. One
effective method that EPA uses for searching
the enormous expanse of chemicals in the
literature is to design appropriate structural
analogs that may have been previously
reported. By changing functional groups,
alkyl chain lengths, ring sizes, or other
features in a step-wise fashion, close
structural analogs can be created and
prioritized for searching. The molecular
formula, as well as a chemical name are then
determined for each analog. EPA searches
CAS On-Line for these analogs, as described
below, to determine whether they actually
exist and, if they do, whether
physicochemical property data are available.
CAS On-Line Search. Searching
CAS On-Line for an analog designed for a
PMN substance can be accomplished most
readily by simply entering the analog's
molecular formula. If a relatively small
number of entries are obtained from the
search, then all are retrieved and reviewed.
If a large number of entries are obtained,
then the search can be narrowed by using
selected name segments. From this
narrowed search, any entries that are suitable
analogs are retrieved to obtain CAS RNs and
to determine if Beilstein data are available.
EPA has found that expanding on the
molecular formula of pre-designed analogs is
successful for finding very close structural
analogs.
The Merck Index. EPA periodically
uses this comprehensive, interdisciplinary
encyclopedia of organic chemicals,
Pharmaceuticals, and biological substances to
scan for new analogs or to search for
designed analogs. The Merck Index is an
excellent source for obtaining measured
physicochemical properties for over 50,000
chemical substances.
2.4.4 Methods For Estimating
Physicochemical Properties Using
Computer Estimation Programs
If measured property values are
unavailable or cannot be found for the PMN
substance or for compounds that are
structurally analogous to the PMN
substance, then EPA tries to estimate the
properties using appropriate estimation
methods. EPA uses several computerized
chemical property estimation programs,
including PC-NOMOGRAPH,
PC-Graphical Exposure Modeling System
(PC-GEMS), Oligo 56, and Estimation
Programs Interface (EPI). Values obtained
from these estimation programs are
scrutinized at CRSS meetings (see chapter 1)
by EPA chemists, who exercise professional
judgment to determine whether the values
are reasonable. Some of the computer
estimation programs used by EPA are
discussed briefly below.
PC-NOMOGRAPH This computer
program calculates a normal boiling point
(boiling point at one atmosphere pressure,
760 torr) from either a measured or
estimated boiling point obtained at reduced
pressure. The vapor pressure at 25 °C also
can be calculated from a normal or reduced
boiling point. Actual boiling point-pressure
nomographs (pressure-temperature
alignment charts) can also be used in boiling
point estimations by helping to verify the
computer calculations. These charts allow
the conversion of a reduced pressure boiling
point to a boiling point at one atmosphere.
Separate vapor pressure nomographs are
available for low-boiling and high-boiling
compounds.
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PC-GEMS. The estimation routines
in PC-GEMS represent a computerized
version of well-known methods from the
Handbook of Chemical Property Estimation
Methods (Lyman et al. 1982). Estimation
routines are available for the octanol/water
partition coefficient, water solubility, soil
adsorption coefficient, boiling point, vapor
pressure, melting point, and Henry's Law
constant.
EPI. EPI, developed by Syracuse
Research Corporation, Syracuse, New York,
integrates several computer programs.
Programs are included for estimating:
octanol-water partition coefficient; Henry's
Law constant; soil adsorption coefficient;
rate of hydrolysis (for substances with a
hydrolyzable group); atmospheric oxidation
(including half-lives for reaction with
hydroxyl radicals and ozone); probability of
biodegradation (based on several different
models); and, removal during wastewater
treatment.
OLIGO 56. Oligo 56, developed by
the Mitre Corporation, McLean, Virginia, is
used to estimate molecular weight and
functional group equivalent weight of
polymers.
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(ASTM) STP 707.
Klopman G, Wang S, Balthasar DM. 1992. Estimation of aqueous solubility of organic molecules
by the group contribution approach. Application to the study of biodegradation. J Chem Inf
Comput Sci 32: 474-482.
Leifer A. 1988. The Kinetics of Environmental Aquatic Photochemistry. Washington, DC:
American Chemical Society.
Leo AJ. 1990. Methods of calculating partition coefficients. In: Comprehensive Medicinal
Chemistry: the rationale design, mechanistic study & therapeutic application of chemical
compounds, volume four, chapter 18.7 pages 295-319 (Ramsden CA, ed.). New York: Pergamon
Press.
Leo AJ. 1993. Calculating log P from structures. Chem Rev 93:1289-1306.
Lins CLK, Block JH, Doerge RF, Barnes GJ. 1982. Determination of octanol-water equivalent
partition coefficients of indolizine and substituted 2-phenylindolizines by reversed-phase high
pressure liquid chromatography and fragmentation values. J Pharm Sci 71: 614-617.
Lu PY, Metcalf RL. 1975. Environmental fate and biodegradability of benzene derivatives as
studied in a model aquatic ecosystem. Environ Health Perspect 10: 269-284.
Lyman WJ, Reehl WF, Rosenblatt DH. 1982. Handbook of Chemical Property Estimation
Methods. New York: McGraw-Hill.
Lynch DG, Tirado NF, Boethling RS, Huse GR, Thorn GC. 1991. Performance of on-line
chemical property estimation methods with TSCA premanufacture notice chemicals. Sci Total
Environ 109/110: 643-648.
Mackay D, Shiu WY. 1981. A critical review of Henry's law constants for chemicals of
environmental interest. J Phys Chem Ref Data 10: 1175-1199.
Mabey W, Mill T. 1978. Critical review of hydrolysis of organic compounds in water under
environmental conditions. J Phys Chem Ref Data 7: 383-415.
Martin YC. 1978. Quantitative Drug Design. New York: Marcel Dekker.
McCall PJ, Laskowski DA, Swann RL, Dishburger HJ. 1983. Estimation of environmental
partitioning of organic chemicals in model ecosystems. Residue Rev 85: 231-243.
86
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Means JC, Wood SG, Hassett JJ, Banwart WL. 1982. Sorption of amino- and carboxy-substituted
polynuclear aromatic hydrocarbons by sediments and soils. Environ Sci Technol 16: 93-98.
Meylan WM, Howard PH. 1991. Bond contribution method for estimating Henry's law constants.
Environ Toxicol Chem 10: 1283-1293.
Meylan WM, Howard PH. 1995. Atom/fragment contribution method for estimating octanol-
water partition coefficient. J Pharm Sci 84:83-92.
Meylan W, Howard PH, Boethling RS. 1992. Molecular topology/fragment contribution method
for predicting soil sorption coefficients. Environ Sci Technol 26: 1560-1567.
Moriguchi I, Hirono S, Liu Q, Nakagome I, Matsushita Y. 1992. Simple method of calculating
octanol/water partition coefficient. Chem Pharm Bull 40: 127-130.
Minick DJ, Frenz JH, Patrick MA, Brent DA. 1988. A comprehensive method for determining
hydrophobicity constants by reversed-phase high performance liquid chromatography. J Med
Chem 31: 1923-1933.
Noegrohati S, Hammers WE. 1992. Regression models for octanol-water partition coefficients,
and for bioconcentration in fish. Toxicol Environ Chem 34: 155-173.
Pavia DL, Lampman GM, Kriz GS Jr. 1979. Introduction to Spectroscopy: a Guide for
Students of Organic Chemistry. Philadelphia: Saunders College.
Sabljic A. 1984. Predictions of the nature and strength of soil sorption of organic pollutants by
molecular topology. J Agric Food Chem 32: 243-246.
Sabljic A. 1987. On the prediction of soil sorption coefficients of organic pollutants from
molecular structure: application of molecular topology model. Environ Sci Technol 21: 358-366.
Sasaki Y, Kubodera H, Matuszaki T, Umeyama H. 1991. Prediction of octanol/water partition
coefficients using parameters derived from molecular structures. J Pharmacobio-Dyn 14:
207-214.
Shah PV. 1990. Environmental Exposure to Chemicals Through Dermal Contact. In: Saxena J
(ed) Hazard Assessment of Chemicals, Volume 7. New York: Hemisphere Publishing Corp., pp.
111-156.
Shiu WY, Doucette W, Gobas FAPC, Andren A, Mackay D. 1988. Physical-chemical properties
of chlorinated dibenzo-p-dioxins. Environ Sci Technol 22: 651-658.
87
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Shriner RL, Fuson RC, Curtin DY, Morrill TC. 1980. The Systematic Identification of Organic
Compounds. New York: John Wiley and Sons., pp. 13, 37-45.
Silverstein RM, Bassler GC, Morrill TC. 1981. Spectrometric Identification of Organic
Compounds, 4th ed. New York: John Wiley & Sons.
Swann RL, Laskowski DA, McCall PJ, Vander Kuy K, and Dishburger HJ. 1983. A rapid
method for the estimation of the environmental parameters octanol/water partition coefficient, soil
sorption constant, water to air ratio, and water solubility. Residue Rev 85: 18-28.
USEPA. 1979. U.S. Environmental Protection Agency. Office of Toxic Substances. Toxic
Substances Control Act Premanufacture Testing of New Chemical Substances. (44 FR 16240).
USEPA. 1985. U.S. Environmental Protection Agency. Office of Toxic Substances. Toxic
Substances Control Act Test Guidelines. (50 FR 39252).
USEPA. 1986. U.S. Environmental Protection Agency. Measurement of Hydrolysis Rate
Constants for Evaluation of Hazardous Waste and Land Disposal: Volume I. Washington, DC:
U.S. Environmental Protection Agency. EPA/600/3-86/043.
USEPA. 1987. U.S. Environmental Protection Agency. Measurement of Hydrolysis Rate
Constants for Evaluation of Hazardous Waste and Land Disposal: Volume II. Washington, DC:
U.S. Environmental Protection Agency. EPA/600/3-87/019.
USEPA. 1988a. U.S. Environmental Protection Agency. Measurement of Hydrolysis Rate
Constants for Evaluation of Hazardous Waste and Land Disposal: Volume III. Washington, DC:
U.S. Environmental Protection Agency. EPA/600/3-88/028.
USEPA. 1988b. U.S. Environmental Protection Agency. Interim Protocol for Measuring
Hydrolysis Rate Constants in Aqueous Solutions. Washington, DC: U.S. Environmental
Protection Agency. EPA/600/3-88/014.
USEPA. 1992. U.S. Environmental Protection Agency. Office of Research and Development.
Dermal Exposure Assessment: Principles and Applications. Interim Report. Washington, DC:
U.S. Environmental Protection Agency. EPA/600/8-91/01 IB.
USEPA. 1995. U.S. Environmental Protection Agency. Office of Pollution Prevention and
Toxics. Premanufacture Notification; Revisions of Premanufacture Notification Regulations; Final
Rule. (60 FR 16298-16352).
USEPA. 1996 (August 28). U.S. Environmental Protection Agency. Office of Pesticides and
Toxic Substances. Test guidelines; Notice of Availably. (61 FR 44308-44311).
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van de Waterbeemd H, Mannhold R. 1996. In: Lipophilicity in Drug Action and Toxicology.
Pliska V, Testa B, van de Waterbeemd H, eds. New York: VCH Publishers, Inc. pp. 401-415.
Verscheuren K. 1983. Handbook of environmental data on organic chemicals, 2nd ed. New
York: Van No strand Reinhold.
Wakita K, Yoshimoto M, Miyamoto S, and Watanabe H. 1986. A method for calculation of the
aqueous solubility of organic compounds by using new fragment solubility constants. Chem
PharmBull 11:4663-4681.
Waller CL. 1994. A three-dimensional technique for the calculation of octanol-water partition
coefficient. Quant Struct.-Act. Relat. 13:172-176.
Yalkowsky SH. 1988. Estimation of the aqueous solubility of organic compounds. In: Jochum
C, Hicks MG, Sunkel J (eds.). Physical Property Prediction in Organic Chemistry, Proceedings of
the Beilstein Workshop. Schloss Korb, Italy, May 16-20, 1988. Sponsor: BMFT.
Yalkowsky SH, Banerjee S. 1992. Aqueous Solubility. Methods of Estimation for Organic
Compounds. New York: Marcel Dekker.
Yalkowsky SH, Valvani SC. 1976. JMed Chem 19:727-728.
Yalkowsky SH, Valvani SC. 1979. Solubility and partitioning 2. Relationships between aqueous
solubilities, partition coefficients, and molecular surface areas of rigid aromatic hydrocarbons. J
Chem Eng Data 24: 127-129.
Yalkowsky SH, Valvani SC. 1980. Solubility and partitioning I: solubility of nonelectrolytes in
water. J Pharm Sci 69: 912-922.
Yalkowsky SH, Orr RJ, Valvani SC. 1979. Solubility and partitioning 3. The solubility of
halobenzenes in water. Ind Eng Chem Fundam 18: 351-353.
Yalkowsky SH, Sinkula AA, Valvani SC, eds. 1980. Physical Chemical Properties of Drugs.
New York: Marcel Dekker.
Yamagami C, Ogura T, Takao N. 1990. Hydrophobicity parameters determined by reversed-
phase liquid chromatography. I. Relationship between capacity factors and octanol-water partition
coefficients for mono substituted pyrazines and the related pyridines. J Chromatog 514: 123-136.
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List of Selected Readings for Chapter 2
Use of physicochemical properties in risk assessment: estimating biological (toxicological)
activity
Albert A. 1987. Xenobiosis. Food, Drugs and Poisons in the Human Body. New York: Chapman
and Hall.
Albert A. 1985. Selective Toxicity, The Physico-Chemical Basis of Therapy. Seventh Edition.
New York: Chapman and Hall.
Amdur MO, Doull J, Klaassen CD, eds. 1991. Casarett andDoull's Toxicology, The Basic
Science of Poisons. Fourth Edition. New York: Pergamon Press.
Bradbury SJ, Lipnick RL, eds. 1990. Structural Properties for Determining Mechanisms of Toxic
Action (papers from an EPA Workshop, October 18-20, 1988, Duluth, MN). Environ Health
Perpect87: 180-271.
Gerrity TR, Henry CJ, eds. 1990. Principles of Route-to-Route Extrapolation for Risk
Assessment. New York: Elsevier.
Hermens JLM, Opperhuizen A, eds. 1991. QSAR in Environmental Toxicology-IV. New York:
Elsevier.
Hansch C, Clayton JM. 1973. Lipophilic character and biological activity of drugs II: the
parabolic case. J Pharm Sci 62: 1-20.
Hansch C, Dunn WJ III. 1972. Linear relationships between lipophilic character and biological
activity of drugs. J Pharm Sci 61: 1-19.
Hansch C, Leo A. 1979. Substituent Constants for Correlation Analysis in Chemistry and
Biology. New York: John Wiley and Sons.
Karcher W, Devillers J, eds. 1990. Practical Applications of Quantitative Structure-Activity
Relationships (QSAR) in Environmental Chemistry and Toxicology. Dordrecht, The Netherlands:
Kluwer Academic Publishers.
Kubinyi H. 1979. Lipophilicity and drug activity. Prog Drug Res 23: 97-198.
Lu PY, Metcalf RL. 1975. Environmental fate and biodegradability of benzene derivatives as
studied in a model aquatic ecosystem. Environ Health Perspect 10: 269-284.
90
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Lyman WJ, Reehl WF, Rosenblatt DH, eds. 1991. Handbook of Property Estimation Methods.
Washington, DC: American Chemical Society.
Martin YC. 1978. Quantitative Drug Design. New York: Marcel Dekker.
National Academy of Sciences. 1983. Risk Assessment in the Federal Government, Managing the
Process. Washington, DC: National Academy Press.
Ramsden CA, ed. 1989. Quantitative Drug Design. Comprehensive Medicinal Chemistry: the
rationale design, mechanistic study & therapeutic application of chemical compounds (volume
four). New York: Pergamon Press.
USEPA. 1992. U.S. Environmental Protection Agency. Office of Research and Development.
Dermal Exposure Assessment: Principles and Applications. Interim Report. Washington, DC:
U.S. Environmental Protection Agency. EPA/600/8-91/01 IB.
Yalkowsky SH, Sinkula AA, Valvani SC, eds. 1980. Physical Chemical Properties of Drugs.
New York: Marcel Dekker.
Witschi FTP, ed. 1980. The Scientific Basis of Toxicity Assessment. New York: Elsevier.
Octanol-Water Partition Coefficient (log K^}: estimation and measurement of
Bowman BT, Sans WW. 1983. Determination of octanol-water partitioning coefficients (K^ of
61 organophosphorus and carbamate insecticides and their relationship to respective water
solubility (S) values. J Environ Sci Health B18: 667-683.
Brent DA, Sabatka JJ, Minick DJ, Henry DW. 1983. A simplified high-pressure liquid
chromatography method for determining lipophilicity for structure-activity relationships. J Med
Chem26: 1014-1020.
Da YZ, Ito K, Fujiwara H. 1992. Energy aspects of oil/water partition leading to the novel
hydrophobic parameters for the analysis of quantitative structure-activity relationships. J Med
Chem35: 3382-3387.
Danielsson L-G, Zhang Y-H. 1996. Methods for determining n-octanol-water partition constants.
Trends Anal Chem 15: 188-196.
de Bruijn J, Busser F, Seinen W, Hermens J. 1989. Determination of octanol/water partition
coefficients for hydrophobic organic chemicals with the "slow-stirring" method. Environ Toxicol
Chem 8: 499-512.
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de Bruijn J, Hermens J. 1990. Relationships between octanol/water partition coefficients and total
molecular surface area and total molecular volume of hydrophobic organic chemicals. Quant
Struct-Act Relat 9: 11-21.
Doucette WJ, Andren AW. 1988. Estimation of octanol/water partition coefficients: evaluation of
six methods for highly hydrophobic aromatic hydrocarbons. Chemosphere 17: 345-359.
Doucette WJ, Andren AW. 1987. Correlation of octanol/water partition coefficients and total
molecular surface area for highly hydrophobic aromatic compounds. Environ Sci Technol 21:
821-824.
Dunn WJ, Block JH, Pearlman RS, eds. 1986. Partition Coefficient, Determination and
Estimation. New York: Pergamon Press.
Dunn WJ, Nagy PI. 1992. Relative log P and solution structure for small organic solutes in the
chloroform/water system using monte carlo methods. J Computat Chem 13: 468-477.
Dunn WJ, Nagy PI, Collantes ER. 1991. A computer-assisted method for estimation of the
partition coefficient. Monte carlo simulations of the chloroform/water \ogP for methylamine,
methanol, and acetonitrile. J Am Chem Soc 113: 7898-7902.
Dunn WJ, Nagy PI, Collantes ER, Glen WG, Alagona G, Ghio C. 1991. Log P and solute
structure. Pharmacochem Libr 16: 59-65.
Garst JE. 1984. Accurate, wide-range, automated, high performance liquid chromatographic
method for the estimation of octanol/water partition coefficients II: equilibrium in partition
coefficient measurements, additivity of substituent constants, and correlation of biological data. J
PharmSci73: 1623-1629.
Garst JE, Wilson WC. 1984. Accurate, wide-range, automated, high-performance liquid
chromatographic method for the estimation of octanol/water partition coefficients I: effect of
chromatographic conditions and procedure variable on accuracy and reproducibility of the
method. JPharm Sci 73: 1616-1622.
Guesten H, Horvatic D, Sabljic A. 1991. Modeling n-octanol/water partition coefficients by
molecular topology: polycyclic aromatic hydrocarbons and their alkyl derivatives. Chemosphere
23: 199-213.
Hansch C, Leo A. 1979. Substituent Constants for Correlation Analysis in Chemistry and
Biology. New York: John Wiley and Sons.
Kamlet MJ, Doherty RM, Carr PW, Mackay D, Abraham MH, Taft RW. 1988. Linear solvation
energy relationships. 44. Parameter estimation rules that allow accurate prediction of
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octanol/water partition coefficients and other solubility and toxicity properties of polychlorinated
biphenyls and polycyclic aromatic hydrocarbons. Environ Sci Technol 22: 503-509.
Kishi H, Hashimoto Y. 1989. Evaluation of the procedures for the measurement of water
solubility and n-octanol/water partition coefficient of chemicals. Results of a ring test in Japan.
Chemosphere 18: 1749-1759.
Leo AJ. 1990. Methods of calculating partition coefficients. In: Comprehensive Medicinal
Chemistry: the rationale design, mechanistic study & therapeutic application of chemical
compounds, volume four, chapter 18.7 pages 295-319 (Ramsden CA, ed.). New York: Pergamon
Press.
Lins CLK, Block JH, Doerge RF, Barnes GJ. 1982. Determination of octanol-water equivalent
partition coefficients of indolizine and substituted 2-phenylindolizines by reversed-phase high
pressure liquid chromatography and fragmentation values. J Pharm Sci 71: 614-617.
Minick DJ, Frenz JH, Patrick MA, Brent DA. 1988. A comprehensive method for determining
hydrophobicity constants by reversed-phase high performance liquid chromatography. J Med
Chem 31: 1923-1933.
Moriguchi I, Hirono S, Liu Q, Nakagome I, Matsushita Y. 1992. Simple method of calculating
octanol/water partition coefficient. Chem Pharm Bull 40: 127-130.
Niemi GJ, Basak SC, Veith GD, Grunwald G. 1992. Prediction of octanol/water partition
coefficient (K^ with algorithmically derived variables. Environ Toxicol Chem 11: 893-900.
Noegrohati S, Hammers WE. 1992. Regression models for octanol-water partition coefficients,
and for bioconcentration in fish. Toxicol Environ Chem 34: 155-173.
Rekker RF. 1977. The Hydrophobic Fragment Constant. Amsterdam: Elsevier.
Rekker RF, Mannhold R. 1992. Calculation of Drug Lipophilicity. Weinheim, Germany: VCH
Publishers, Inc.
Sasaki Y, Kubodera H, Matuszaki T, Umeyama H. 1991. Prediction of octanol/water partition
coefficients using parameters derived from molecular structures. J Pharmacobio-Dyn 14: 207-214.
Shiu WY, Mackay D. 1986. A critical review of aqueous solubilities, vapor pressures, Henry's law
constants, and octanol-water partition coefficients of the polychlorinated biphenys. J Phys Chem
Ref Data 15: 911-929.
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Shiu WY, Doucette W, Gobas F, Andren A, Mackay D. 1988. Physical-chemical properties of
chlorinated dibenzo-p-dioxins. Environ Sci Technol 22: 651-658.
Yalkowsky SH, Valvani SC. 1976. Partition coefficients and surface areas of some alkylbenzenes.
JMedCheml9: 727-728.
Yamagami C, Ogura T, Takao N. 1990. Hydrophobicity parameters determined by reversed-
phase liquid chromatography. I. Relationship between capacity factors and octanol-water partition
coefficients for mono substituted pyrazines and the related pyridines. J Chromatog 514: 123-
136.
Yamagami C, Takao N, Fujita T. 1991. Hydrophobicity parameter of diazines. II. Analysis and
prediction of partition coefficients of disubstituted pyrazines. J Pharm Sci 80: Ill-Ill'.
Yamagami C, Takao N, Fujita T. 1990. Hydrophobicity parameter of diazines (1). Analysis and
prediction of partition coefficients of mono substituted diazines. Quant Struct-Act Relat
9: 313-320.
Information on Ecological Risk Assessment
Zeeman M, Gilford J. 1993. Ecological Hazard Evaluation and Risk Assessment Under EPA's
Toxic Substances Control Act (TSCA): An Introduction. In: Environmental Toxicology and Risk
Assessment, Volume 1. Landis W, Hughes J, Lewis M, eds. ASTM STP 1179. Philadelphia, PA:
American Society for Testing & Materials, pp. 7-21.
Zeeman M. 1995. EPA's Framework for Ecological Effects Assessment. In: Screening and
Testing Chemicals in Commerce. U.S. Congress, Office of Technology Assessment. OTA-BP-
ENV-166. Washington, DC: Office of Technology Assessment, pp. 69-78.
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Chapter 3
POLLUTION PREVENTION AND PREMANUFACTURE NOTIFICATIONS
3.1 Introduction: Pollution Prevention
The preceding chapters describe the
evolution of EPA's PMN Program and the
approaches that EPA uses to characterize
and understand the risks new chemical
substances may pose to human health and
the environment. Characterized risks are
then balanced against the expected economic
and societal benefits of a new chemical.
TSCA empowers EPA to regulate risks
associated with the manufacture, use, and
disposal of a new chemical substance.
Traditionally, however, the focus of the
PMN Program has been on the toxicity of a
new chemical substance itself and the risks
associated with its use and disposal, with
less emphasis on the risks from the pollution
created as a result of the manufacture or use
of the new substance.
Although TSCA and the other
environmental statutes have had a positive
impact in protecting human health and the
environment, the United States still produces
millions of tons of pollution annually and
spends tens of billions of dollars per year
controlling this pollution. EPA realizes that
there may still be significant opportunities
for industry to reduce or prevent pollution at
the source through cost-effective changes in
production, operation, use of raw materials,
or chemical design. Such changes have the
potential to offer industry substantial savings
in reduced costs for raw material, pollution
control, and liability as well as to help
protect the environment and reduce risks to
the environment and human health. In
addition, EPA realizes that the costs of
complying with regulations imposed under
existing statutes are becoming prohibitive
for the chemical industry and the consuming
public. A more preventative way of solving
the problem of pollution is needed.
In 1990, the EPA embarked on a new
approach, termed "pollution prevention," to
reduce the releases of toxic wastes into the
environment through eliminating or
minimizing creation of such wastes. At
approximately the same time, the Pollution
Prevention Act (PPA) was passed by
Congress (PPA 1990). This act articulates
the interest of Congress to have both the
EPA and industry apply pollution prevention
principles to their efforts to reduce toxic
waste generation and subsequent discharge.
The underlying philosophy of pollution
prevention is fundamentally simple: the
creation of pollution must be avoided
whenever and wherever possible. The
pollution prevention paradigm is very much
like the preventative medicine paradigm.
The goal of preventative medicine is to
prevent illnesses from occurring rather than
to find cures or treatments after illnesses
have occurred, whereas the goal of pollution
prevention is to prevent the creation of
pollution, so as not to have to deal with the
health and ecological damage it causes. The
basic pollution prevention strategy,
therefore, is to avoid generating waste in the
first place.
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Any practice that reduces the amount
of any hazardous substance entering any
waste stream or otherwise released into the
environment (including fugitive emissions)
prior to recycling (except in-process
recycling), treatment or disposal is
considered pollution prevention.
The PPA identifies several general
approaches to preventing pollution and
establishes a pollution prevention hierarchy
as a national policy. The approaches,
starting with the most important, are:
• pollution should be prevented at
the source wherever feasible;
• pollution that cannot be prevented
at the source should be reduced at the
source wherever feasible;
• pollution that cannot be prevented
or reduced at the source should be recycled
in an environmentally safe manner
wherever feasible;
• pollution that cannot be recycled
should be treated in an environmentally
safe manner whenever feasible;
• disposal or other release into the
environment should be employed only as a
last resort and should be conducted in an
environmentally safe manner.
Pollution prevention has become the
preferred method in the hierarchy of
environmental practices and the foremost
priority of the EPA (Browner 1993).
Although recycling, treatment, and disposal
are clearly important components of
pollution control, they are not included in
the definition of pollution prevention
because they do not represent preventative
approaches to controlling pollution.
The PPA also provides the
framework for creative thought and
collaborations on the part of the chemical
industry and the EPA to reduce pollution
and exposure to toxic substances. Newer
EPA programs (e.g., OPPT's Design for the
Environment Program, Green Chemistry
Program, and Pollution Prevention Division)
devoted to pollution prevention have
evolved in recent years, and many of EPA's
existing programs, including the PMN
Program (see below), have been or are being
analyzed to determine how pollution
prevention can be incorporated. In addition,
many collaborations and initiatives between
EPA, the chemical industry, and academia
are identifying and implementing new ways
of preventing pollution.
EPA's Design for the Environment
(DfE) Program, for example, is a voluntary
initiative that forges partnerships with
stakeholder groups in an effort to
incorporate environmental considerations
into the decision-making of the chemical
industry and to build incentives for
continuous environmental improvement.
EPA's 33/50 Program is another voluntary
program under which EPA and the chemical
industry collaborate to reduce the
environmental releases of certain substances
on the Toxics Release Inventory.19
19. The Toxics Release (TRI) Inventory is a publicly-available compilation of chemical releases
updated annually under the authority of Section 313 of the Emergency Planning and Community
Right to Know Act (EPCRA 1986). More information on TRI is available from TRI User
Support (phone: 202-260-1531).
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These and other EPA initiatives aimed at
pollution prevention have been very
successful in pollution prevention and in
establishing collaborations between the
chemical industry, EPA, other federal
agencies, and academic institutions.
A very recent EPA initiative is Green
Chemistry. Green Chemistry strives to
encourage the development of safer
commercial substances and non-polluting
commercial syntheses. Traditionally, during
the commercial development of chemical
substances, chemists concentrate on those
chemicals that can be synthesized in the
highest yield at the lowest direct cost to
satisfy particular intended uses. Generally,
chemists give little or no consideration to
the inherent toxicity or hazardous nature of a
desired chemical substance, or to alternative
syntheses that neither use toxic reagents or
solvents, nor produce toxic byproducts.
This traditional approach to chemical design
creates pollution and is clearly incompatible
with achieving the pollution prevention
needs of society and the goals of the
Pollution Prevention Act.
EPA's Green Chemistry initiative
represents a more rational approach to the
design of chemicals and syntheses. Green
Chemistry is based on the premise that the
most desirable and efficient way of
preventing pollution is to: 1) intentionally
design chemicals such that they will have
minimal or no toxicity, while maintaining
their commercial efficacy with respect to
intended use; and, 2) intentionally design
synthetic pathways such that they neither
utilize toxic reagents or solvents, nor
produce toxic byproducts. Through the
Green Chemistry initiative, the federal
government, universities, and the chemical
industry are forming collegial relationships
(Anastas and Farris 1994; Anastas and
Williamson 1996; DeVito and Garrett 1996),
and the Agency hopes that these
relationships will lead to the design and
commercialization of less toxic chemical
substances and less polluting syntheses. In
fact, President Clinton has made Green
Chemistry one of the highest priorities of the
EPA (Clinton 1995).
3.2 Pollution Prevention Initiatives within
EPA's PMN Program
Because the PMN Program
characterizes the risks new chemical
substances may pose to human health and
the environment before they enter commerce
and takes necessary action to prevent or
control such risks, the PMN Program may be
considered a pollution prevention program.
In addition to traditional PMN review,
however, the PMN Program offers other
approaches to preventing pollution. These
are not regulatory, but rather voluntary or
collaborative on the part of EPA and the
chemical industry. This section discusses
two relatively recent pollution prevention
initiatives that have been incorporated into
the review of PMNs.
3.2.1 Optional Pollution Prevention
Information (page 11 of the PMN form)
In 1991 the PMN form was modified
to include a section containing "optional
pollution prevention information" (page 11
of the PMN form). This was the first direct
indication that pollution prevention had
become an important component of PMN
review. On this page, the submitter may
provide information regarding its efforts to
reduce or minimize pollution associated
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with activities surrounding manufacturing,
processing, use, and disposal of the PMN
substance. PMN submitters should describe
net benefits such as: 1) the extent to which
the new chemical substance may be a
substitute for an existing substance that
poses a greater overall risk to human health
or the environment; 2) a reduction in the
volume of the new substance manufactured
compared to a competitive existing
substance, if the new and existing substances
are equally toxic but more of the existing
substance is required for commercial use;
3) elimination or reduction in the amount of
waste materials through source prevention,
source reduction, recycling, or other means;
4) low toxicity of the PMN substance; and
5) a reduction in human exposure to the
PMN substance and/or a reduction in
environmental release.
It is up to the discretion of the
submitter to provide EPA with this
information. All pollution prevention
information provided in this section of the
PMN is considered by EPA during PMN
review, and EPA strongly encourages PMN
submitters to incorporate such information
in their PMNs as it helps the Agency to
balance the benefits of a PMN substance
against any risks it poses. This information
is, of course, considered confidential by
EPA if so indicated by the submitter.
Most current PMN submissions
contain some optional pollution prevention
information. However, most of the
information currently provided by submitters
deals with the benefits of the PMN
substance with respect to its intended use,
and little information is provided with
respect to pollution prevention in the
manufacture of the substance, even when
such benefits exist. PMN submitters
probably know (or should at least be able to
discern) whether the manufacturing process
for their PMN substance offers pollution
prevention advantages over an alternative
process used for a similar substance.
Although ICB chemists are sometimes able
to identify the advantages of such syntheses
during routine PMN review, PMN
submitters should compare their
manufacturing processes to known
alternative processes for making the same
substance (or similar substances) and
indicate on page 11 of the PMN form any
advantages that their processes may have.
3.2.2 Synthetic Method Assessment for
Reduction Techniques (SMART) Review
Simultaneous with the traditional
chemistry review of PMN substances
(discussed in Chapter 1), ICB chemists now
perform a pollution prevention review
known as the Synthetic Method Assessment
for Reduction Techniques (SMART)
Review for PMN substances (Farris et al.
1994). The SMART review is a non-
regulatory review designed to identify PMN
substances (or related substances) for which
individual companies may be able to prevent
pollution in an economically feasible
manner. In this review ICB chemists
attempt to identify potential pollution
prevention opportunities based on
information in the PMN and reference
sources. Pollution prevention opportunities
may include: using an alternative reaction
pathway that is less polluting; switching to a
less toxic solvent; recycling of solvents or
unreacted starting reagents; or, recovery of
toxic byproducts, unreacted starting
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reagents, or PMN substance lost to waste
streams.
The SMART review process is
described briefly here; a detailed description
is also available (Farris et al. 1994). The
SMART review is performed as follows.
During the regular chemistry review of a
PMN, the chemist will also screen the PMN
to determine if the submission meets the
criteria for a SMART review. These
criteria include: the notice must be a non-
exempt Premanufacture Notice; the PMN
substance must be a Class 1 substance (see
Appendix, section A.3.3); the third year
production volume must be greater than
10,000 kg/year; and manufacture of the
PMN substance must take place within the
United States. These criteria are merely
guidelines; a PMN submission that does not
meet these criteria may still undergo a
SMART review. For example, PMN
submissions for which pollution prevention
opportunities are readily apparent will most
likely undergo a SMART review in any
case.
Each PMN submission selected for
SMART review is first subjected to a
preliminary assessment. The objective of
the preliminary assessment is to determine
the source, identity, and quantity of each
waste component associated with the
manufacture of the PMN substance.
Sufficient information needs to be provided
in PMN submissions in order for a
preliminary review to be completed (much
of this information is required). General
information that is necessary for preliminary
reviews includes: chemical name; chemical
structure; process description; identity of
impurities; and production volume.
Chemists also assess the types of
wastes (i.e., extremely toxic, hazardous,
potentially hazardous, or innocuous)
produced by (or during) the manufacture or
processing of the PMN substance, as well as
the sources and quantities of such wastes
(Farris etal. 1994). The classification of
waste in terms of relative toxicity is based
upon several Agency lists. ICB chemists
estimate the percentages of waste substances
relative to the production volume of the
PMN substance. These percentages are
compared to trigger levels (the quantity of a
given type of waste relative to the quantity
of the PMN substance produced) established
by ICB chemists, to ascertain whether a
particular waste component from a given
manufacturing process is present in an
excessive quantity. Different sets of trigger
levels are used for hazardous wastes and for
potentially hazardous wastes.
The outcome of the preliminary
SMART assessment determines whether a
detailed assessment is warranted. If the
quantities of the hazardous wastes produced
from the manufacture of a PMN substance
do not exceed their trigger levels, ICB
chemists do no further assessment. In cases
where the hazardous wastes exceed their
trigger levels, ICB chemists perform a more
detailed assessment. The main purpose of
the detailed assessment is to determine the
fate of hazardous wastes. In cases where
hazardous wastes are treated or will enter the
environment from waste streams, stack
emissions, or other sources, ICB chemists
try to identify opportunities for preventing or
reducing these wastes. These opportunities
may include: (1) using a less toxic solvent
(if the hazardous waste is a solvent used in
the manufacture of a PMN substance); (2)
using an alternative synthesis that utilizes
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fewer or no toxic reagents or solvents, or
does not generate toxic byproducts or
wastes; and, (3) in cases where these two
opportunities are not feasible, recycling of
the waste materials. If as a result of the
detailed assessment ICB chemists identify
possible pollution prevention opportunities,
the ICB chemist performing the assessment
will inform the PMN submitter of the
findings (either orally or in writing).
The purpose of such communication
is to solicit the submitter's voluntary
consideration to study and perhaps
incorporate the pollution prevention
opportunities identified by ICB. To date,
several PMN submitters have responded that
they will attempt to incorporate Agency
suggestions into their manufacturing
processes, and will inform the Agency of
their success or failure. In some instances,
PMN submitters have replied that the
pollution prevention opportunities identified
by ICB chemists may not be feasible for
reasons that are apparent only to the
submitter. For example, an alternative
synthesis identified by an ICB chemist may
already have been studied by the submitter
prior to PMN submission and found to be
unsuccessful for commercial synthesis of the
PMN substance.
Feedback from PMN submitters is
very important to ICB chemists, because
PMN submitters are generally in a better
position to evaluate the practicality of
incorporating changes into their
manufacturing processes than are ICB
chemists. The Agency appreciates the
additional insight from such feedback that
may not be available from PMNs or other
sources. Such non-regulatory
communication stimulates creative
collaboration between PMN submitters and
the Agency in identifying feasible
opportunities for preventing pollution.
3.3 Considerations in Implementing
Pollution Prevention Practices Prior to
Submission of PMN Substances
Pollution prevention is an
overarching goal of the Agency, particularly
OPPT. This chapter has briefly described
two EPA pollution prevention initiatives
(the Optional Pollution Prevention section of
the PMN form, and the SMART review) that
were designed specifically for incorporating
pollution prevention into PMN review. EPA
is currently pursuing additional initiatives
such as: funding universities to develop
new, environmentally-benign synthetic
strategies for the manufacture of commercial
substances; funding universities to develop
synthesis software that can assist in the
identification of environmentally-benign
syntheses; and the Green Chemistry
Challenge, which encourages, identifies, and
awards innovative chemistry achievements
in preventing pollution. Although these
additional initiatives are not formally part of
PMN review, the Agency expects they will
eventually influence PMN submissions.
Information on these broader pollution
prevention projects may be obtained from
the TSCA Assistance Information Service
and the Pollution Prevention Information
Clearinghouse. (See Table A-l for
addresses and phone numbers.)
The EPA realizes that PMN
submitters are faced with many challenges in
developing substances that must not only
satisfy customer needs and remain
competitive with other products, but must
also comply with existing regulations.
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Some PMN submitters may view EPA's
recent emphasis on pollution prevention as
an additional burden to product
development. It is not the intent of EPA to
stifle or impede the creativity of chemical
producers in the development of chemical
products by encouraging pollution
prevention practices. In fact, the pollution
prevention initiatives described in the
preceding paragraphs are intended to help
PMN submitters design products that are
useful and safe for human health and the
environment, and are manufactured safely.
As safer substances and environmentally
friendly syntheses replace existing toxic
chemical substances and polluting syntheses,
respectively, fewer regulations will be
needed.
In recent years the EPA has noticed
that PMN submitters are beginning to
incorporate pollution prevention practices
into the design and synthesis of new
chemical substances. Specific examples
cannot be provided here due to the
confidentially of the submissions.
Generally, some PMN submitters are using
available toxicity data on related existing
chemicals as a basis for designing new
chemicals that are less toxic but equally
efficacious for commercial use. In such
instances PMN submitters often obtain data
on the structure-activity (toxicity)
relationships and biochemical (mechanistic)
bases of toxicity of existing related
substances, and from these data infer
structural modifications that reduce toxicity
without affecting use efficacy (see Chapter 2
in DeVito and Garrett 1996). In addition,
some PMN submitters are beginning to
develop and use syntheses that require fewer
toxic reagents or solvents, or do not produce
toxic byproducts. More detailed discussions
of approaches that can be used for the design
of safer chemicals and the design of
environmentally friendly syntheses are
available (Devito and Garrett 1996; Anastas
and Farris 1994; Anastas and Williamson
1996).
PMN submitters may find the
following considerations helpful in
implementing pollution practices prior to
submission of PMN substances to EPA.
• Consider any toxicity or
environmental hazard potential of
the chemical product. Decide if the
chemical product must be made, or if
an analogous substance (or use
substitute) that is known or likely to
have less hazard potential can be
used instead. Gather any available
toxicity data on related substances
and, if possible, use the data to
design a new substance that is less
toxic.
• Consider potential savings by
thinking of environmentally safer
products or reaction pathways
during product development. Keep
in mind that regulations generally
have become stricter over time and
may become even more strict in the
future. For example, certain methods
of disposal and treatment of
hazardous wastes may one day be
outlawed or become prohibitively
costly. On-site disposal or treatment
may not be practical or economically
feasible. It is best to consider the
long-term cost of making a PMN
substance.
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Rethink your approach to organic
chemistry and the synthetic
reactions traditionally used to
construct chemical substances. Do
not consider reaction yield only; put
more emphasis on alternative,
environmentally-friendly reaction
pathways. When selecting a
reaction, consider the following:
- what reactions can be used to make
the PMN substance ?
- why has a particular reaction been
selected ?
- is it environmentally friendly ?
- is the reaction cost-effective in the
long run ?
- how feasible is commercial scale-
up of the reaction ?
- what will disposal of the PMN
substance and associated substances
cost?
- what are the liability costs of waste
treatment on-site ?
- what are the liability costs from
potential release of the PMN
substance and associated substances
and ultimately prevent many of the
environmental and human health problems
that have occurred in the past as a result of
the manufacture and use of chemicals.
- what are the costs of storing
hazardous wastes on site ?
These considerations help to establish a
framework that can be used to incorporate
pollution prevention strategies in the design
and synthesis of new chemical substances,
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References for Chapter 3
Anastas PT, Farris CA. 1994. Benign by Design. Alternative Synthetic Design for Pollution
Prevention. ACS Symposium Series 577, American Chemical Society, Washington, DC, 1994.
Anastas PT, Williamson TC. 1996. Green Chemistry: Designing Chemical Syntheses for the
Environment. ACS Symposium Series 626, American Chemical Society, Washington, DC, 1996.
Browner CM. 1993. Pollution Prevention Takes Center Stage. EPA Journal, 19, pp 6-8.
Clinton W. 1995. Inside E.P.A. Weekly Report. (Special Report) March 16, 1995, p S-9.
Devito SC, GarrettRL. 1996. Designing Safer Chemicals: Green Chemistry for Pollution
Prevention. ACS Symposium Series 640, American Chemical Society, Washington, DC, 1996.
EPCRA. 1986. The Emergency Planning and Community Right to Know Act. 42 U.S.C. §11023.
Farris CA, Podall HE, Anastas PT. 1994. Alternative Syntheses and Other Source Reduction
Opportunities for Premanufacture Notification Substances at the U.S. Environmental Protection
Agency. In: Benign by Design, Alternative Synthetic Design for Pollution Prevention. Anastas
PT, Farris CA, eds. ACS Symposium Series 577, American Chemical Society, Washington, DC,
1994, pp 156-165.
PPA. 1990. The Pollution Prevention Act, 42 U.S.C. §§ 13101-13109 (1990).
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List of Selected Readings for Chapter 3
For Additional Information on Pollution Prevention and EPA Pollution Prevention Initiatives
see:
Chemical and Engineering News, September 5, 1994 issue.
Breen JJ, DellarcoM. 1992. Pollution Prevention: The New Environmental Ethic. In: Pollution
Prevention in Industrial Processes; the Role of Process Analytic Chemistry. Breen JJ, Dellarco
MJ, eds. ACS Symposium Series 508, American Chemical Society, Washington, DC, 1992, pp
2-12.
Ford AM, Kimerle RA, Werner AF, Beaver ER, Keffer CW. 1992. Industrial Approaches to
Pollution Prevention. In: Pollution Prevention in Industrial Processes; the Role of Process
Analytic Chemistry. Breen JJ, Dellarco MJ, eds. ACS Symposium Series 508, American
Chemical Society, Washington, DC, 1992, pp 13-20.
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Appendix
THE TOXIC SUBSTANCES CONTROL ACT: HISTORY AND IMPLEMENTATION
A.I Introduction
The Toxic Substances Control Act (TSCA
1976) was the result of six years of
negotiating and compromising among the
House and Senate, the President's Council
on Environmental Quality (CEQ), the
Environmental Protection Agency (EPA),
the chemical industry, the Commerce
Department, and other interested parties.
TSCA expanded existing federal authority to
regulate the chemical industry by giving
EPA the authority to require testing, as well
as to regulate the production, use, and
disposal of new and existing chemicals.
Because it was one of the most important
pieces of legislation ever passed to regulate
the chemical industry, its provisions were
hotly debated by all parties. The following
is a brief history of the events that led to the
enactment of TSCA.
The CEQ was established by the 1969
National Environmental Policy Act as an
agency within the Executive Office of the
President. This occurred shortly before the
establishment of the EPA in December,
1970. Soon after its inception, CEQ began a
study of the potential for metals and
synthetic organic chemicals to endanger
human health and the environment. At that
time, the government had no power to
require that chemicals, with the exception of
those used as pesticides, drugs, and food
additives, be tested before they were put into
commerce.
By late 1970, the CEQ had produced a draft
report of its study. The publication of this
report was delayed until April, 1971,
however, so that the CEQ staff could draft
the Toxic Substances Control Act of 1971,
the first version of the present TSCA. The
CEQ report reached the following major
conclusions:
1. Toxic Substances are Entering the
Environment
"U.S. consumption of metals with
known toxic effects has increased
greatly in the last 20 years. ...
Similarly, use of synthetic organic
chemicals is growing rapidly. ...
Although many of these substances
are not toxic, the sheer number of
them, their increasing diversity and
use, and the environmental problems
already encountered from some
indicate the existence of a problem."
(CEQ 1971)
2. These Substances can have Severe
Effects
"The environmental effects of most
of the substances discussed in this
report are not well understood.
Testing has largely been confined to
their acute effects, and knowledge of
the chronic, long-term effects, such
as genetic mutation, is inadequate.
Although far from complete,
available data indicate the potential
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or actual danger of a number of
these substances." (CEQ 1971)
3. Existing Legal Authorities are
Inadequate
"Government controls over the
introduction of toxic substances into
the environment are of two types.
The first is control over the initial
production of a substance and its
distribution. ... Although this control
technique can be very effective,
current authorities cover only a
small portion of the total number of
potentially toxic substances and do
not deal with all uses of a substance
which may produce toxic effects."
(CEQ 1971)
"The second type of control is media
oriented and thus is directed at air
and water pollution from various
sources. ... Most toxic substances
are not exclusively air or water
pollutants but can be found in
varying quantities in air, water, soil,
food, and industrial and consumer
products. The multiplicity of ways
by which man can be exposed to
these substances makes it difficult
for the media-oriented authorities to
consider the total exposure of an
individual to a given substance, a
consideration necessary for the
establishment of adequate
environmental standards. Also, in
the past no agency has considered
itself completely responsible for all
such substances in all media." (CEQ
1971)
4. New Legal Authority is Required
"The Council's study indicates the
high-priority need for a program of
testing and control of toxic
substances. ... We should no longer
be limited to repairing damage after
it has been done; nor should we
continue to allow the entire
population or the entire environment
to be used as a laboratory." (CEQ
1971)
The CEQ report concluded that there
were essentially no laws regulating the
manufacture, importation, or use of toxic
chemical substances in the United States
and, therefore, that regulation was critical.
Hence, the findings in this report became the
basis for TSCA. By early December of
1970, the CEQ was ready to circulate a draft
bill to other government agencies for
comment. Among its provisions, this bill
required manufacturers to notify the EPA at
least 90 days before manufacture and
distribution of a new chemical substance,
gave EPA authority to require testing of the
new chemical before manufacture could
begin, and gave EPA the power to ban or
restrict chemicals that posed substantial
risks to human health or the environment.
The issues of premanufacture
notification and testing were of concern to
the Department of Commerce and the Office
of Management and Budget, and were raised
to President Nixon for a decision in early
February, 1971. The President decided that
the premanufacture testing provision should
be removed from the bill. Finally, the bill
was sent to Congress on February 11, 1971,
by EPA Administrator William
Ruckelshaus.
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The U.S. House of Representatives
and Senate passed separate versions of the
bill during 1972. Among other differences,
the Senate version had considerably more
stringent premanufacture controls over
chemical substances than the House version,
requiring EPA to expressly approve new
chemicals. The chemical industry generally
supported the much weaker House version.
Early versions of the bill died in the
Senate-House Conference Committee during
the 92nd and 93rd Congresses. During this
time, President Ford's administration first
supported and later opposed the premarket
provisions of TSCA. In the end, it was the
Congressional and chemical companies'
Washington staffs who hammered out the
compromise bill that was finally passed.
In 1976, Congress was still
agonizing over the bill. As fate would have
it, Kepone, an insecticide for home use that
was manufactured in a dusty refurbished gas
station in Hopewell, Virginia, caused an
outbreak of severe neurological disorders in
dozens of workers. Virginia's Governor
closed the nearby James River to
commercial and sport fishing. CBS's "60
Minutes" segment on Kepone gave the
chemical national media exposure and
increased public pressure for the passage of
TSCA. There was also considerable public
pressure over the risks from polychlorinated
biphenyls (PCBs), fluorocarbons, and vinyl
chloride.
Finally, the Senate-House
Conference Committee reached agreement
on the provisions of TSCA in the fall of
1976, just before the Presidential election.
The lobbying efforts on all sides had been
intense. Chemical industry representatives
expressed afterwards that they had agreed to
premanufacture notification (which
remained in the final bill) in exchange for
reduced reporting provisions.
During September, 1976, both the
Senate and the House of Representatives
finally approved the bill, and sent it to
President Ford for his signature. The
President's support for the bill was in doubt,
because Ford had stated his opposition to
major new federal spending programs,
especially those that would impose new
regulations on industry. The wide-ranging
support for the bill, however, effectively
precluded his veto. President Ford signed
TSCA into law just hours before the bill
would have died from a pocket veto. The
next day, the President released a statement
in support of the bill.
TSCA, as finally passed, covers all
organic and inorganic chemical substances
and mixtures, both synthetic and naturally-
occurring, with the exception of food, food
additives, drugs, cosmetics, nuclear
materials, tobacco, and pesticides, which are
all covered by other legislation. TSCA
provides the Agency with authority to:
• require that manufacturers and
importers submit information on all
new chemical substances prior to
manufacture for commercial
purposes;
• require that manufacturers and
processors collect, maintain, and
possibly submit information on
chemical substances; and
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• regulate chemical substances (both
new and existing) that are expected
to present or are presenting
unreasonable risks to health and the
environment.
The provisions for premanufacture
review of new chemical substances20 are
contained in section 5 of TSCA. Congress
intended section 5 "to provide the
administrator with an opportunity to review
and evaluate information with respect to the
substance to determine if manufacture,
processing, distribution in commerce, use or
disposal should be limited, delayed or
prohibited because data is [sic] insufficient
to evaluate the health and environmental
effects or because the substance or the new
use presents or will present an unreasonable
risk of injury to health or the environment."
Congress also realized that "the most
desirable time to determine the health and
environmental effects of the substance, and
to take action to protect against any potential
adverse effects, occurs before commercial
production begins. Not only is human and
environmental harm avoided or alleviated,
but the cost of any regulatory action in terms
of loss of jobs and capital investment is
minimized." (U.S. Congress 1976)
Congress charged EPA with the
responsibility of preventing chemicals from
presenting unreasonable risks to health and
the environment: the Act specifies that the
risks of using a substance must be compared
with the benefits derived from its use.
Further, the Agency was directed to
implement TSCA in such a manner as not to
"unduly impede technological innovation."
The objective of creating a balance between
preventing unreasonable risk and not
hampering innovation has been at the heart
of the Agency's premanufacture review
program since its beginning.
A.2 The Premanufacture Provisions of
TSCA
The Toxic Substances Control Act
provides EPA with the authority to identify
and control the use of new and existing
chemical substances in order to protect
human health and the environment. Under
section 5 of TSCA, titled Manufacturing and
Processing Notices, the EPA is given the
authority to regulate new chemical
substances prior to their manufacture or
import21 for commercial purposes. The text
below discusses the provisions of TSCA that
are relevant to the premanufacture authority.
First, the terms "chemical substance" and
"new" are defined, then section 5 is
summarized. Finally, other sections of
TSCA that are tangentially relevant to
premanufacture review are briefly
mentioned.
To date, Congress has not modified
the basic provisions of TSCA as presented
20. The term "new chemical substance" is defined in section 3 of TSCA as any chemical
substance not included in the Chemical Substance Inventory that is compiled and published
under section 8(b).
21. TSCA applies both to substances that are manufactured within the U.S. and to substances
imported into the U.S. In the following discussion, the words manufacture or manufacturer are
meant to include import or importer.
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below. The Agency, in its implementation
of TSCA, has promulgated a variety of
regulations. Summaries of EPA's
regulations are found in Section 1.5, below.
A.2.1 Definition of "Chemical
Substance" Under TSCA
The term "chemical substance" is
defined in section 3 of TSCA as:
"any organic or inorganic
substance of a particular
molecular identity, including
(/') any combination of such
substances occurring in
whole or in part as a result of
a chemical reaction or
occurring in nature, and (/'/')
any element or uncombined
radical."
This definition does not include:
"(/') any mixture, (/'/') any
pesticide (as defined by the
Federal Insecticide,
Fungicide, and Rodenticide
Act) when manufactured,
processed, or distributed in
commerce for use as a
pesticide, (Hi) tobacco or any
tobacco product, (/v) any
source material, special
nuclear material, or
byproduct material
(as...defined in the Atomic
Energy Act...), (v) any
article22..., and (v/) any food,
food additive, drug, cosmetic,
or device (as...defined in
section 201 of the Federal
Food, Drug, and Cosmetic
Act) when manufactured,
processed, or distributed in
commerce for use as a food,
food additive, drug, cosmetic,
or device."
A.2.2 Definition of "New" Chemical
Substance
Section 8(b) of TSCA requires the
EPA to identify, compile, keep current, and
publish the TSCA Inventory, a list of
chemical substances manufactured,
imported, or processed for commercial
purposes in the United States. The
Inventory defines what chemical substances
are "existing" in U.S. commerce for TSCA
purposes. The Inventory includes not only
chemical substances that have been
manufactured or imported since
January 1, 1975 for "distribution in
commerce" but also substances
manufactured as intermediates for use by the
manufacturer. Substances that are subject to
TSCA but are not on the Inventory are
considered "new" and are subject to
premanufacture notification under section 5
of TSCA. Further discussion of the
Inventory and EPA's Inventory reporting
regulations is found in the final section of
this chapter (A.3.9).
A.2.3 Section 5: Manufacturing and
Processing Notices
One of the primary provisions of
TSCA is the requirement in section 5 that
22. The Agency has clarified its interpretation of "article" in USEPA 1977c.
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manufacturers or importers of new
chemicals notify the Agency 90 days before
manufacturing a new chemical substance.
EPA uses this time to determine if an
unreasonable risk may or will be presented
by any aspect of the new chemical's
lifecycle: its manufacture, processing,
distribution in commerce, use, or disposal.
If the chemical may or will present an
unreasonable risk, EPA has the authority to
limit or ban it, thereby reducing the potential
for adverse effects to human health and the
environment.
Unlike the Federal Food, Drug and
Cosmetic Act (FFDCA 1982) administered
by the Food and Drug Administration
(FDA), which requires drug manufacturers
to submit a plethora of test data for a new
substance, section 5 of TSCA does not
require PMN submitters to test their
chemical substances before PMN
submission. In short, the FFDCA is a
registration statute, whereas TSCA is a
weaker notification statute. Frequently, little
or no data on health or environmental effects
are available for PMN substances, yet EPA
must decide within 90 days if such chemical
substances are likely to present hazards to
human health or the environment. Because
EPA is usually operating in the absence of
data, section 5(e) of TSCA gives EPA the
authority to regulate a new chemical
substance if EPA concludes that a chemical
substance may present an unreasonable risk.
If there is sufficient information to make the
determination that the substance will present
an unreasonable risk, EPA has the authority
to regulate a new chemical substance under
section 5(f).
The nine subsections of section 5 are
as follows:
Subsection 5(a). In general.
Manufacturers must submit a PMN to the
Agency at least 90 days before
manufacturing a chemical substance that is
not either listed on the TSCA Chemical
Substance Inventory or being used for a
significant new use. This section also gives
EPA authority to promulgate rules
establishing significant new uses for certain
chemicals if the new uses would increase
exposure.
Subsection 5(b). Submission of Test Data
This section relates the section 4
requirements for test data to the
requirements for PMN notices and
Significant New Use Notices (SNUNs).
Any test data required by a section 4 rule
must be submitted along with a PMN or
SNUN. If a section 4(c) exemption has been
granted pending submission of test data, the
submitter of a PMN or SNUN substance
may not commence manufacture until at
least 90 days following submission of the
section 4 test data to EPA. In section
5(b)(4), the EPA is given authority to
promulgate rules listing chemicals and their
respective uses (or other activities) that
present or may present an unreasonable risk.
If a PMN or SNUN is required for a
chemical on this 5(b)(4) list, the PMN or
SNUN must contain data to show that the
proposed uses will not present an
unreasonable risk to health or the
environment. Data submitted to EPA under
section 5(b) must be made available to the
public, subject to the limitations of section
14 (Disclosure of Data, under which EPA
must protect certain confidential business
information).
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Subsection 5(c). Extension of Notice
Period. The Administrator may extend the
review period for a PMN, a SNUN, or test
data by up to 90 additional days if the
Administrator has good cause to do so. The
extension and the reasoning behind it must
be published in the Federal Register (subject
to section 14 constraints).
Subsection 5(d). Content of Notice;
Publications in the Federal Register. This
subsection lists the information to be
included in a PMN: (1) information listed in
TSCA section 8(a)(2)23 that is known to or
reasonably ascertainable by the submitter;
(2) any test data in the possession or control
of the submitter that are related to effects on
health or the environment; and (3) a
description of any other reasonably
ascertainable data concerning health or
environmental effects. Under section
5(d)(2), EPA is required to publish periodic
notices in the Federal Register (FR) subject
to the limitations of section 14. Within five
working days following receipt of a new
PMN, SNUN, or test data, EPA must
publish the following information: chemical
identity (or generic name), use, and a
description of test data received. Monthly,
EPA must publish in the FR a list of
chemical notices received since the last FR
notice, and a list of notices for which the
review period has expired since the last
notice.
Subsection 5(e). Regulation Pending
Development of Information. Under
section 5(e), if the Agency determines
(1) that the information submitted for a
chemical substance is insufficient for
assessment of health or environmental
effects and that the chemical substance may
present an unreasonable risk or (2) that the
chemical substance may result in substantial
human or environmental exposure, it may
issue an order that limits or bans
manufacture, processing, distribution in
commerce, use, or disposal of the substance.
The order cannot take effect if the Agency
does not provide affected parties with 45
days notice prior to the PMN or SNUN
expiration date, or if the affected parties
object to the order. If objections are filed
and the Agency has made the required
determination, the Agency is required to file
for an injunction in the U.S. District Court.
The injunction is given if the court
determines that the information provided
with the notice is insufficient and that
continuing to allow the manufacture or
processing of the chemical would present
unreasonable risks to human health and the
environment. The court has the right to
extend the notification period if it will
expire before the injunction proceedings are
23. The items required by TSCA are: the common or trade name, chemical identity, and
molecular structure of each chemical substance; the categories or proposed categories of use for
such substance; estimates of the total amount of the substance that is manufactured and used, and
estimates of the amount that will be manufactured and used, broken out by category of use; a
description of the byproducts associated with the substance; the number of individuals exposed,
the number that is estimated to be exposed, and the exposure duration; and the manner by which
the substance will be disposed. Note that subparagraph 8(a)(2)(e) requires health and safety data,
but these data are not under the "reasonably ascertainable" standard.
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concluded. The injunction is dissolved once
the needed data have been submitted to and
evaluated by the Agency.
Subsection 5(f). Protection Against
Unreasonable Risks. Section 5(f) gives
EPA the authority to limit or ban a PMN or
SNUN chemical substance if the use of the
substance will present an unreasonable risk
before the time that the Agency could
promulgate a standard rule under section 6
to protect against such risk. The Agency
may issue a proposed rule under
section 6(a) that is effective immediately
upon its publication in the Federal Register
to limit manufacture or use. Alternatively,
the Agency may issue a proposed section
5(f) order to prohibit manufacture or use, or
may seek a court injunction to prohibit
manufacture or use.
Subsection 5(g). Statement of Reasons for
Not Taking Action. If EPA does not take
regulatory action under sections 5, 6, or 7
against a chemical for which SNUN or
section 4 test data are submitted, it then
must publish in the Federal Register the
reasons explaining why it did not do so.
Subsection 5(h). Exemptions. The Agency
may grant exemptions from some or all of
the requirements for PMN, SNUN, and test
data submissions. Exemptions may be
granted from: (1) a PMN or SNUN for a
chemical used only for test marketing
purposes if there will be no unreasonable
risk; (2) test data requirements for a
substance that is identical to the one on
which data have been submitted under
section 5(b)(2); (3) all or part of section 5
requirements for a substance that will not
present an unreasonable risk to human
health or the environment; and (4) PMN,
SNUN, or test data requirements for a
substance that is produced temporarily as the
result of a chemical reaction used to produce
another chemical and to which there will be
no human or environmental exposure.
Further, a substance used for
scientific experimentation, research, and
analysis is exempt from PMN, SNUN, and
test data requirements, provided that all
parties involved are informed of the risks
associated with the particular chemical.
Subsection 5(i). Definition. The terms
"manufacturing" and "processing" are
defined as manufacturing and processing for
commercial purposes.
A.2.4 Other Sections of TSCA Related to
Section 5
A.2.4.1 Section 4. Testing of Chemical
Substances and Mixtures. The EPA, under
TSCA section 4, has the authority to
promulgate rules to require manufacturers
and processors to test certain new or existing
substances for their effects on human health
and the environment. This section also
establishes the Interagency Testing
Committee to assist EPA in prioritizing the
chemicals to be tested.
A.2.4.2 Section 6. Regulation of
Hazardous Chemical Substances and
Mixtures. The EPA has the authority under
TSCA section 6, to promulgate rules that
regulate the manufacture, processing,
distribution, use, or disposal of an existing
chemical substance, if it determines that
these activities pose an unreasonable risk to
human health or the environment. Section
6(e) requires that PCBs be regulated
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immediately, and that their manufacture and
use be phased out over time.
A.2.4.3 Section 7. Imminent Hazards.
EPA may commence a civil action in a U.S.
District Court to seize an imminently
hazardous chemical substance or mixture, or
for relief against its manufacturer or user.
An imminently hazardous chemical
substance or mixture is one that will present
an unreasonable risk of serious or
widespread injury to health and the
environment before a final section 6 rule
could protect against the risk.
A.2.4.4 Section 8. Reporting and
Retention of Information. Section 8(a)
gives EPA the authority to promulgate rules
to require manufacturers and processors to
collect, maintain, and submit data about the
manufacture and processing of chemical
substances in response to Agency requests.
These rules do not apply to small
manufacturers or processors, or to
substances produced only in small quantities
for research and development purposes.
Under section 8(b), EPA is required
to compile, keep current and publish the
Chemical Substance Inventory. Either
individual chemical substances or categories
of chemical substances may be listed on the
Inventory. New substances are added to the
Inventory following PMN review and actual
manufacture for commercial purposes.
Section 8(c) requires manufacturers,
processors, and distributors to maintain
records of significant adverse reactions to
health or the environment alleged to have
been caused by chemical substances.
Section 8(d) allows EPA to
promulgate rules under which
manufacturers, processors, and distributors
are required to submit health and safety data
known to or reasonably ascertainable by
them.
Under section 8(e), manufacturers,
processors, or distributors must immediately
submit to EPA any information supporting
the conclusion that a chemical substance
presents a substantial risk of injury to health
and the environment.
A.2.4.5 Section 12. Exports In general,
chemical substances manufactured or
processed solely for export are exempt from
regulation under TSCA. However, if a
substance produced for export presents an
unreasonable risk to health or the
environment of the United States, EPA may
regulate the substance. The Agency may
also require section 4 testing of an exported
substance to determine whether the
substance presents such a risk. A person
who intends to export a substance for which
information is required under sections 4 or
5(b), or that is subject to a regulatory order
or action under Section 5, 6, or 7, must
notify EPA, which will, in turn, notify the
government of the recipient country.
A.2.4.6 Section 13. Entry into Customs
Territory of the United States No
chemical substance, mixture, or article
containing a chemical substance or mixture
will be allowed into the customs territory of
the United States if it fails to comply with
any rule or is otherwise in violation of the
Act.
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A.2.4.7 Section 14. Disclosure of Data.
EPA is required to protect confidential
business information submitted to the
Agency under TSCA from disclosure to the
public. Such confidential business
information may be disclosed if EPA
determines that disclosure is necessary to
protect against an unreasonable risk; thus, all
data from health and safety studies
submitted under TSCA are subject to
disclosure.
A.3 Implementation of TSCA
Since TSCA was signed into law in
1976, the EPA has promulgated rules, issued
orders, and developed interpretations to
implement the provisions of TSCA. This
section highlights those rules, orders, and
policies that are the most relevant to
premanufacture review.
A.3.1 The TSCA Inventory
The TSCA Chemical Substance
Inventory, compiled under section 8(b) of
TSCA, defines which chemical substances
are "existing" in U.S. commerce for
purposes of implementing TSCA. The
Inventory is not a list of toxic chemicals;
toxicity was not a criterion used in
determining the eligibility of chemical
substances for inclusion on the Inventory.
In 1977, EPA issued its Inventory
Reporting Regulations (USEPA 1977a).
These regulations and their associated
instruction manual (USEPA 1977b)
provided guidance for manufacturers to
report their existing substances for the
Inventory, and, more importantly,
established the rules under which all
reported substances would be listed on the
Inventory. During 1977 and 1978 (USEPA
1979a), manufacturers reported their
substances for the Inventory, which was first
published in 1979 (USEPA 1979b). Shortly
thereafter, there was a reporting period
during which processors reported substances
they processed that were not already listed
on the Inventory (USEPA 1979c). Since
that time, new substances have been added
following premanufacture review24 and
through corrections of initial Inventory
reports and PMNs, incorrectly-reported
substances have been removed (for example,
see USEPA 1985a). Currently, the
Inventory lists over 70,000 chemical
substances whose manufacture or processing
for commercial purposes in the U.S. has
taken place since January 1, 1975. Section
710.4 of the Inventory Reporting
Regulations contains the detailed rules for
determining which chemical substances
were subject to initial Inventory reporting
and describes the circumstances under which
the manufacture of a substance would be
excluded from reporting. These rule
provisions were largely carried over into
24. Following PMN review, if EPA has not banned a PMN substance under section 5(f) of
TSCA, the manufacturer is free to begin production within any restrictions the Agency may have
placed on the substance. The manufacturer must submit a Notice of Commencement (NOC) to
the Agency within 30 days following the start of manufacture. Submitters must use EPA Form
7710-56 (USEPA 1995a) for NOCs. Upon receipt of the NOC form, EPA places the PMN
substance on the TSCA Inventory. For more information, see 40 CFR Part 720. Premanufacture
Notification. Subpart F. Commencement of Manufacture or Import.
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section 720.30 of the PMN rule, and are
used to determine which substances are
subject to PMN notification requirements;
because they are so central to the PMN
program, they are included in section A.3.9
at the end of this chapter. In addition, the
Agency has published two clarifications of
the definition of articles, which are excluded
from TSCA reporting (USEPA 1985c).
Manufacturers are responsible for
determining whether a substance is a new
chemical substance under TSCA. The
TSCA Chemical Substance Inventory: 1985
Edition (USEPA 1986a) and the 1990
Supplement to the 1985 Edition of the
TSCA Inventory (USEPA 1990a) are the
most recent hard-copy publications of the
non-confidential chemical substance
identities. They are available at some public
libraries and all federal depository libraries,
or may be purchased from the Government
Printing Office and National Technical
Information Service (NTIS). The NTIS also
has computer tape, diskette, and CD-ROM
versions of the Inventory that are updated
twice a year. In addition, several
commercial or government databases
including CAS On-line and Dialog
Information Services contain up-to-date
versions of the non-confidential Inventory.
Table A-l (located at the end of this chapter)
lists some of the sources for inventory and
other OPPT information.
No publicly available printed or
electronic version of the Inventory can be
completely up-to-date, because the Inventory
is continually changing. Furthermore,
detailed information regarding chemical
identities claimed as confidential is not
included in the published version of the
Inventory. The Agency, however,
maintains and continually updates a Master
Inventory File, which includes all eligible
substances that have been reported.
The Agency provides a service to
assist those who wish to query the Inventory.
A person who intends to manufacture a
chemical substance that does not appear on
the published Inventory may ask EPA to
determine whether the substance in question
is included in the Master Inventory File.
The Agency will provide an answer only if
the person who submits the inquiry is able to
demonstrate a "bona fide intent" to
manufacture the substance for a commercial
purpose.
To demonstrate this intent, in a
notice of bona fide intent to manufacture, a
manufacturer must submit certain
information to EPA. This information
includes: the specific chemical identity of
the substance (using the currently correct
Chemical Abstracts Service name); a signed
statement of intent to manufacture for a
commercial purpose; a description of the
research and development activities
conducted to date and the year they were
started or, for importers unable to provide
this information, substitute information
concerning foreign use of the substance; a
description of the major intended application
or use; an infrared (IR) spectrum or other
spectrum if an IR spectrum is not suitable;
the estimated date of PMN submission (if
the substance is not found on the Inventory);
the address of the facility for that is most
likely to be used for manufacture or
processing; and a description of the most
probable manufacturing process. The exact
procedures for establishing and submitting a
notice of bona fide intent are discussed in
detail in the Agency's recent Revision of
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Premanufacture Notification Regulations
(USEPA 1995a; this supersedes the
Agency's former guidance, found in USEPA
1983a). When a bona fide intent has been
established with a formal submission, the
Agency will perform a comprehensive
search of the Master Inventory File to
determine conclusively whether the
substance in question is already included.
The Agency has made a commitment to
respond to a bona fide inquiry within 30
days.
A.3.2 Inventory Update Rule
In 1986, the EPA promulgated a rule
that requires manufacturers to submit data
on production volumes and manufacturing
sites for certain chemicals every four years
(USEPA 1986b). This rule does not affect
the status of any chemicals as being on or
not on the TSCA Inventory.
A.3.3 Premanufacture Notification Rule
and Form
Any person who plans to
manufacture a new chemical substance must
submit a PMN, SNUN, or an exemption
application25 to EPA at least 90 days prior to
the intended date of the activity. The EPA
promulgated regulations governing the PMN
process and established the mandatory PMN
form in 1983 (USEPA 1983b, USEPA
1983c); the rule and form were revised in
1986 (USEPA 1986c). The form was
revised in 1991 (USEPA 199la), and again
in May 1995 (USEPA 1995e). The rule was
revised again in 1995 (USEPA 1995a; see
also USEPA 1993a). Copies of the current
rule, form, and the Instructions Manual for
Premanufacture Notification26 (USEPA
1991b) for PMN submissions are available
from the TSCA Assistance Information
Service at (202) 554-1404.
As part of the New Chemical
Program, the Office of Pollution Prevention
and Toxics (OPPT) reviews PMN
submissions and determines whether the
proposed activities will or may present
unreasonable risks. In recent years, an
average of nearly 2,300 new chemical
substances have been reviewed annually
within the New Chemical Program.
The PMN form, as revised in 1995,
is used for routine PMNs as well as PMN
exemptions and SNUNs; it includes three
main sections with additional pages for
optional pollution prevention information
and a physicochemical properties worksheet.
Part I, general information, includes
submitter and chemical identity as well as
production, import, and use information.
Part II contains human exposure and
environmental release information for
industrial sites controlled by the submitter
and for sites controlled by others. Part in is
a list of attachments for information
requested in Parts I and n and for test data or
other information related to the chemical.
The submitter is required to provide all
information requested in the form to the
25. Certain classes of chemicals are eligible for exemptions under rules promulgated under
section 5(h)(4) of TSCA. An exemption application may replace a PMN in these cases, and may
allow manufacture sooner than 90 days.
26. A new instructions manual is under development.
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extent that it is known or reasonably
ascertainable. If a requested item is not
applicable or truly unavailable, the submitter
should explain that on the form. Any item
that is left blank may cause EPA to declare
the PMN incomplete. The 90-day review
period for the PMN (or less for exemptions)
cannot begin until the submitter provides the
missing information.
In 1988, the EPA promulgated a rule
requiring PMN submitters to pay user fees
(USEPA 1988a). Submitters must remit a
user fee of $2,500. This fee is reduced
under the certain circumstances: if the
submitter is a small business, the user fee is
$100; if a PMN for an intermediate
substance is submitted simultaneously with a
final product PMN, the fee for the
intermediate product is $1,000; and if a
PMN is filed (with prior Agency consent)
for multiple chemicals that are related, the
total fee is $2,500.
A.3.4 Biotechnology
TSCA applies to all chemical
applications not specifically exempted in the
Act. Microorganisms intended for general
commercial and environmental applications
(e.g., metal leaching, pollutant degradation,
enhanced nitrogen fixation) are subject to
TSCA. In 1986, the federal agencies
involved with the review of biotechnology
products announced a policy requiring,
among other things, PMN reporting for
commercial uses of certain genetically
modified microorganisms (OSTP 1986).
The notice also requested voluntary
reporting for research and development
(R&D) uses of these microorganisms
involving introductions into the
environment. EPA has published a
proposed rule under TSCA section 5 that
would deal specifically with microorganisms
(USEPA 1994). Until this rule is
promulgated, submitters should use EPA's
Points to Consider (USEPA 1990b) as
guidance in the preparation of PMNs for
microorganisms. Submitters are also
strongly encouraged to have a prenotice
consultation with EPA before submitting a
PMN for a microorganism. Submitters
interested in determining whether a
microorganism is already on the TSCA
Inventory may submit bona fide inquiries
following the Agency's guidance, given in
USEPA 1990b.
A.3.5 Exemptions
A.3.5.1 Test Market Exemptions
TSCA section 5(h)(l) authorizes an
exemption from PMN requirements for new
chemical substances manufactured for test
marketing purposes, as long as this activity
does not present an unreasonable risk to
human health or the environment. These
exemptions are granted or denied by EPA
following review of a test market exemption
application (TMEA). The Agency's
regulations for TMEAs are found in the
PMN rule and instruction manual,
referenced above, and are also addressed in a
New Chemical Information Bulletin
(USEPA 1986d). The exemption permits a
company to assess the commercial viability
of a new chemical and to receive customer
feedback on product performance before
proceeding with a PMN. TMEAs also are
advantageous to submitters because the
Agency must grant or deny them within 45
days and they require no user fee. EPA
reviews a TMEA in essentially the same
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manner as a PMN27 and thus needs similar
information from submitters.
A.3.5.2 5(h)(3) Exemption for Research
and Development
Section 5(h)(3) of TSCA exempts
chemical substances from PMN provisions
if they are manufactured only in small
quantities solely for purposes of scientific
experimentation, analysis, or research and
development. The Agency's interpretation
of this exemption is given in two Federal
Register notices (USEPA 1984b; USEPA
1986c) and a New Chemical Information
Bulletin (USEPA 1986d).
A.3.5.3 5(h)(4) Exemptions
To date, EPA has promulgated three
5(h)(4) exemption rules to limit reporting
requirements for new chemical substances
(see USEPA 1991c and other references
given with the specific exemptions):
• substances used in or for
instant or "peel-apart" film
articles;
• substances manufactured or imported
in small quantities and substances
with low release and exposure; and,
• polymers that meet certain specified
criteria.
More detail about these exemptions
is provided below.
A.3.5.4 Instant Film Exemption
Under the terms of this rarely-used
exemption, manufacturers may commence
manufacture of new chemical substances for
incorporation into instant photographic
articles immediately after submitting an
exemption notice to EPA. The manufacturer
must file a PMN and wait until the review
period has expired, however, before
distributing the new chemical in commerce.
Special procedures to contain exposure must
also be used until PMN review is completed
(USEPA 1982).
A.3.5.5 Low Volume Exemption
In 1985, EPA published a TSCA
section 5(h)(4) rule granting a partial
exemption from TSCA section 5 reporting
requirements for persons who manufacture
chemical substances produced in quantities
less than 1,000 kilograms per 12 month
period (USEPA 1985b). This rule was
developed in response to petitions by the
Chemical Manufacturers Association
(CMA) and other industry groups28. The
Agency published proposed revisions to this
27. Because the review period for TMEAs is only 45 days, the Agency uses its usual PMN
review process only until the Focus Meeting. During this meeting, Agency staff decide whether
to grant or deny any TMEA still in the review process at this point. Refer to Chapter 1 for a
discussion of the PMN review process.
28. Section 21 of TSCA allows citizens to petition the Agency for changes in the Agency's
implementation of TSCA.
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rule in 1993 (USEPA 1993d) and a final
revised rule in 1995 (USEPA 1995c).
Under the revised rule, chemical
substances may qualify for exemption if
their annual production volume is less than
10,000 kg. Manufacturers must submit
exemption notices 30 days prior to
commencement of manufacture.
Exemptions granted previously under the
superseded rule will remain effective (and
binding).
A.3.5.6 Low Release and Exposure
Exemption
Along with the revised low volume
exemption, the Agency proposed (USEPA
1993d) and later made final a new
exemption, the low release and exposure
exemption (LoREX; USEPA 1995c).
Substances may qualify for the LoREX
exemption, regardless of their production
volume, if they meet the release and
exposure criteria stated in the rule. To apply
for an exemption, manufacturers must
submit an exemption notification at least 30
days before beginning production. The
Agency is preparing an instruction manual
for this new rule; a draft manual is available
for comment through the TSCA Assistance
Information Service (USEPA 1995f).
A.3.5.7 Polymer Exemption
In 1984, EPA published a TSCA
section 5(h)(4) rule granting an exemption
for persons who manufacture or import
certain polymers (USEPA 1984a). This rule
was developed in response to petitions by
industry groups. In February 1993, the
Agency proposed revisions to this
exemption rule (USEPA 1993b) and in
March 1995, the Agency published the final
rule (USEPA 1995b). A technical guidance
manual to assist submitters in complying
with the revised exemption is in preparation;
a draft manual is available through the
TSCA Assistance Information Service
(USEPA 1995g).
In general, to be manufactured under
this exemption a polymer must meet the
polymer definition given in the rule and one
or more of three criteria:
• polymers with number-average
molecular weight (MW) greater than
or equal to 1,000 and less than 10,000
daltons (and oligomer content less
than 10 percent below MW 500 and
less than 25 percent below MW
1,000);
• polymers with number-average MW
greater than or equal to 10,000
daltons (and oligomer content less
than 2 percent below MW 500 and
less than 5 percent below MW
1,000); and
• polyester polymers manufactured
solely from one or more reactants
listed in the exemption rule.
In addition, certain classes of
polymers cannot be manufactured under this
exemption. These polymers include:
• certain cationic polymers;
• polymers that do not meet certain
elemental limitations;
• polymers that degrade, decompose, or
depolymerize;
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• polymers manufactured or imported
from monomers and reactants not on
the TSCA Chemical Substance
Inventory; and
• water-absorbing polymers with
number-average MW 10,000 and
greater.
Submitters using this exemption are
required to keep certain records to verify
their eligibility for and compliance with the
exemption. They are not required to submit
an exemption notification or a Notice of
Commencement, but are to report annually
the number of polymers being manufactured
for the first time during the preceding
calendar year under the exemption. In part
because submitters do not report the
chemical identities of their polymers to
EPA, the Agency does not list these
polymers on the Inventory.
Manufacturers who submitted
polymers to EPA under the previous
polymer exemption rule (prior to the
effective date of the new rule, May 30,
1995) may either continue to comply with
the requirements of the previous exemption
rule (USEPA 1984a) or may follow all of the
requirements of the new, revised exemption
rule (USEPA 1995b).
A.3.6 TSCA Section 5(e) Consent Orders
and Significant New Use Rules
Under certain circumstances, EPA
uses a section 5(e) order to place restrictions
on the manufacture of a new chemical
pending development of test data. The order
allows manufacture of the new chemical to
commence subject to restrictions on
processing methods, production volume,
and/or use that reduce or limit risks to
human health or the environment. Under
TSCA, EPA has authority to impose a
section 5(e) order by unilateral action, but in
practice, EPA usually negotiates section 5(e)
consent orders with the affected PMN
submitter.
An order restricts the PMN submitter
to the aforementioned conditions, but it is
not binding on other companies wishing to
produce or use the same chemical once the
chemical is listed on the TSCA Inventory.
Hence, the Agency often promulgates a
Significant New Use Rule (SNUR) to
restrict the exposure and use of the
substance to those identified as acceptable
under the section 5(e) order. SNURs apply
to all manufacturers. Anyone who desires to
use a substance that is subject to a SNUR for
a use defined as a significant new use in the
SNUR must submit a SNUN at least 90 days
before starting to manufacture the substance
for the new use. The Agency uses the
standard PMN review process to review
SNUNs and make an appropriate regulatory
determination.
The SNUR procedures (USEPA
1988b; USEPA 1993c; USEPA 1995d) and
subsequent SNUN submissions allow EPA
to control exposures (and thus, risks)
associated with new uses of PMN (or
existing) chemicals, changes in processing,
and increased production volumes before
they become potential problems.
Designation of PMN substances for a TSCA
section 5(e) order, and subsequently for a
SNUR, is based on information received
during the initial PMN review. Often, the
Agency is forced to base its review of the
risks posed by new chemicals on inadequate
information received from submitters. In
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these instances, the Agency may need to
make worst-case (i.e., highest exposure and
risk) estimates regarding certain use or
exposure factors because submitter data
have not been provided. This may lead to
more stringent control than necessary.
Therefore, if submitters provide
comprehensive information, the Agency will
be able to make more realistic
determinations of the potential for
unreasonable risk, such that restrictions may
not be necessary.
A.3.7 Polymers: The Two Percent Rule
Originally, identification of new
polymers for TSCA Inventory and PMN
purposes was based on the amounts of
monomers and other reactants used in the
reaction, "as charged" to the reaction vessel,
and on the dry weight of the polymer
(USEPA 1977a). This approach was
adopted because it was believed that it
would be difficult to identify the exact
amounts of monomers or other reactants
incorporated in the final polymers. More
recently, the Agency revised its two percent
rule (USEPA 1995a) so that the two percent
could either be interpreted as "as charged" or
"as incorporated." For a discussion of the
practical application of the revised two
percent rule, refer to the Agency's polymer
technical guidance manual.
All constituents of a polymer must be
listed in a PMN, but a submitter may choose
which constituents present at two percent or
less will be used in the Inventory description
of the polymer. Since July 28, 1989
(USEPA 1989), free radical initiators
charged to the reaction vessel at over two
percent have also been required to be part of
the chemical identity29. At present, if free
radical initiators are incorporated at less than
or equal to two percent, they do not have to
be part of the chemical name (USEPA
1995a).
Any constituent listed in the
Inventory description must always be
present in the PMN substance. The use of
additional monomers or reactants will not
result in a "new" chemical substance if each
of the additional monomers or reactants, as
charged or incorporated, amounts to two
percent or less of the weight of the polymer.
A.3.8 Importing Chemical Substances
The U.S. Department of the Treasury
has amended its customs regulations to fully
support the implementation of TSCA
(TREAS 1983a; TREAS 1983b; TREAS
1983c). The EPA published companion
requirements at about the same time
(USEPA 1983d). Importers are required to
certify that their shipments are on the TSCA
Inventory and are not in violation of TSCA.
The EPA has published a two-volume Guide
for Chemical Importers/Exporters (USEPA
199Id) that is available from the TSCA
Assistance Information Service. Also
available are copies of the Agency's
database, Chemicals on Reporting Rules
Database (CORR) (USEPA 1991e).
A.3.9 Addendum to Appendix: Inventory
Reporting Regulations
The following text is copied from the
29. Initiators used at > 2% have only had to be included in the chemical identity of polymers
added to the Inventory since July 28, 1989, the effective date of the Agency's clarification in the
Federal Register (USEPA 1989).
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Agency's Inventory Reporting Regulations,
40 CFR 710.4. Its purpose here is to clarify
the definition of chemical substances for
TSCA purposes.
Section 710.4 Scope of the Inventory
(a) Chemical substances subject to
these regulations. Only chemical substances
which are manufactured, imported, or
processed "for a commercial purpose," as
defined in section 710.2, are subject to these
regulations.
(b) Naturally occurring chemical
substances automatically included. Any
chemical substance which is naturally
occurring and
(1) which is (I) unprocessed or (ii)
processed only by manual, mechanical, or
gravitational means; by dissolution in water;
by flotation; or by heating solely to remove
water; or
(2) which is extracted from air by any
means, shall automatically be included in the
inventory under the category "Naturally
Occurring Chemical Substances." Examples
of such substances are: raw agricultural
commodities; water, air, natural gas, and
crude oil; and rocks, ores, and minerals.
(c) Substances excluded by definition
or section 8(b) of TSCA. The following
substances are excluded from the Inventory:
(1) Any substance which is not
considered a "chemical substance" as
provided in subsection 3(2)(B) of the Act
and in the definition of "chemical substance"
in section 710.2(h);
(2) Any mixture as defined in section
710.2(q);
NOTE. — A chemical substance that
is manufactured as part of a mixture is
subject to these reporting regulations. This
exclusion applies only to the mixture and
not to the chemical substances of which the
mixture is comprised. The term "mixture"
includes alloys, inorganic glasses, ceramics,
frits, and cements, including Portland
cement.
(3) Any chemical substance which is
manufactured, imported, or processed solely
in small quantities for research and
development, as defined in section 710.2(y);
and
(4) Any chemical substance not
manufactured, processed or imported for a
commercial purpose since January 1, 1975.
(d) Chemical substances excluded
from the inventory. The following chemical
substances are excluded from the inventory.
Although they are considered to be
manufactured or processed for a commercial
purpose for the purpose of section 8 of the
Act, they are not manufactured or processed
for distribution in commerce as chemical
substances per se and have no commercial
purpose separate from the substance,
mixture, or article of which they may be a
part. NOTE: In addition, chemical
substances excluded here will not be subject
to premanufacture notification under section
5 of the Act.
(1) Any impurity.
(2) Any byproduct which has no
commercial purpose.
NOTE: A byproduct which has
commercial value only to municipal or
private organizations who (I) burn it as a
fuel, (ii) dispose of it as a waste, including in
a landfill or for enriching soil, or (iii) extract
component chemical substances which have
122
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commercial value, may be reported for the
inventory, but will not be subject to
premanufacturing notification under section
5 of the Act if not included.
(3) Any chemical substance which
results from a chemical reaction that occurs
incidental to exposure of another chemical
substance, mixture, or article to
environmental factors such as air, moisture,
microbial organisms, or sunlight.
(4) Any chemical substance which
results from a chemical reaction that occurs
incidental to storage of another chemical
substance, mixture or article.
(5) Any chemical substance which
results from a chemical reaction that occurs
upon end use of other chemical substances,
mixtures, or articles such as adhesives,
paints, miscellaneous cleansers or other
household products, fuels and fuel additives,
water softening and treatment agents,
photographic, (sic) films, batteries, matches,
and safety flares, and which is not itself
manufactured for distribution in commerce
or for use as an intermediate.
(6) Any chemical substance which
results from a chemical reaction that occurs
upon use of curable plastic or rubber
molding compounds, inks, drying oils, metal
finishing compounds adhesives, or paints; or
other chemical substances formed during
manufacture of an article destined for the
marketplace without further chemical
change of the chemical substance except for
those chemical changes that may occur as
described elsewhere in this section 710.4(d).
(7) Any chemical substance which
results from a chemical reaction that occurs
when (I) a stabilizer, colorant, odorant,
antioxidant, filler, solvent, carrier,
surfactant, plasticizer, corrosion inhibitor,
antifoamer or de-foamer, dispersant,
precipitation inhibitor, binder, emulsifier,
de-emulsifier, dewatering agent, or quality
control reagent functions as intended or (ii) a
chemical substance, solely intended to
impart a specific physicochemical
characteristic, functions as intended.
(8) Chemical substances which are
not intentionally removed from the
equipment in which they were
manufactured.
NOTE. — See note to definition of
"intermediate" at section 710.2(n) for
explanation of "equipment in which it was
manufactured."
123
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References for Appendix
CEQ. 1971 (Apr.). Council on Environmental Quality, Toxic Substances, reprinted in Staff
House Committee on Interstate and Foreign Commerce, 94th Congress, 2nd Session, Legislative
History of the Toxic Substances Control Act (TSCA Legislative History) at 760 (Comm. Print
1976), pp. 759-760.
FFDCA. 1982. The Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 301-392.
OSTP. 1986 (June 26). Office of Science and Technology Policy. Coordinated Framework for
Regulation of Biotechnology; Announcement of Policy and Notice for Public Comment. (51 FR
23313-23336).
TREAS. 1983a (August 1). Department of the Treasury. Customs Service. Customs Regulations
Amendments Relating to Special Classes of Merchandise. 19 CFR Parts 12 and 127.
(48 FR 34734).
TREAS. 1983b (September 19). Department of the Treasury. U.S. Customs Service. Customs
Information Service. Other Agency Compliance Circular 111. CIEN-122/83.
TREAS. 1983c (December 23). Department of the Treasury. U.S. Customs Service. Customs
Information Exchange. Other Agency Compliance Circular No. Ill, Supplement No. 1.
CIEN-122/83, Supplement#1.
TSCA. 1976. The Toxic Substances Control Act, 15 U.S.C. §§2601-2629 (1982 & Supp. IE
1985).
U.S. Congress. 1976 (December). Staff House Committee on Interstate and Foreign Commerce.
94th Congress, 2nd Session, Legislative History of the Toxic Substances Control Act (TSCA
Legislative History) at 760 (Comm. Print 1976). New York: U.S. Government Printing Office.
pp. 757-788.
USEPA. 1977a (December 23). U.S. Environmental Protection Agency. Toxic Substances
Control Act. Inventory Reporting Requirements. (42 FR 64572). Also in 40 CFR 710.
USEPA. 1977b (December). U.S. Environmental Protection Agency. Office of Toxic Substances.
The Toxic Substances Control Act. Public Law 94-469. Reporting for the Chemical Substance
Inventory. Instructions for Reporting for the Initial Inventory. Washington, DC: U.S.
Environmental Protection Agency.
USEPA. 1977c. U.S. Environmental Protection Agency. FR notice about articles. 42 FR 64583.
124
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USEPA. 1979a (May 15). U.S. Environmental Protection Agency. Toxic Substances Control:
Initial and Revised Inventories; Premanufacturing Notification Requirements and Review
Procedures. (44 FR 28558).
USEPA. 1979b (May). U.S. Environmental Protection Agency. Office of Toxic Substances.
Toxic Substances Control Act Chemical Substance Inventory. Initial Inventory. Washington, DC:
U.S. Environmental Protection Agency.
USEPA. 1979c (June). U.S. Environmental Protection Agency. Office of Toxic Substances.
The Toxic Substances Control Act. Public Law 94-469. Reporting for the Chemical Substance
Inventory. Instructions for Reporting for the Revised Inventory. Washington, DC: U.S.
Environmental Protection Agency. Office of Toxic Substances.
USEPA. 1982 (June 4). U.S. Environmental Protection Agency. Premanufacture Notification;
Exemption for Chemicals Used in or for the Manufacture or Processing of Instant Photographic
and Peel-Apart Film Articles. (47 FR 24308). Also in 40 CFR723.175.
USEPA. 1983a. U.S. Environmental Protection Agency. § 720.25. Determining whether a
chemical substance is on the Inventory. In: Premanufacture Notification. 40 CFR 720. (48 FR
21722)
USEPA. 1983b (May 13). U.S. Environmental Protection Agency. Premanufacture Notification;
Premanufacture Notice Requirements and Review Procedures; Final Rule and Notice Form. (48
FR21742).
USEPA. 1983c (September 13). U.S. Environmental Protection Agency. Premanufacture
Notification; Revision of Regulation and Partial Stay of Effective Date. (48 FR 41132).
USEPA. 1983d (December 13). U.S. Environmental Protection Agency. Chemical Imports and
Exports; General Import Requirements and Restrictions Policy for Import of Chemical
Substances. (48 FR 55462).
USEPA. 1984a (November 21). U.S. Environmental Protection Agency. Premanufacture
Notification Exemptions; Exemptions for Polymers; Final Rule. (49 FR 46066). Also, 40 CFR
723.
USEPA. 1984b (December 27). U.S. Environmental Protection Agency. Premanufacture
Notification; Proposed Revisions of Regulation. (49 FR 50202).
USEPA. 1985a (October 11). U.S. Environmental Protection Agency. TSCA Chemical
Substance Inventory; Removal of 104 Incorrectly Reported Chemical Substances from the TSCA
Inventory. (50 FR 41585).
125
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USEPA. 1985b (April 26). U.S. Environmental Protection Agency. 40 CFRPart 723.
Premanufacture Notification Exemption; Exemption for Chemical Substances Manufactured in
Quantities of 1,000 Kg or Less Per Year. (50 FR 16477).
USEPA. 1985c (October 1). U.S. Environmental Protection Agency. Clarification of the
Interpretation of "Article" Under TSCA. A 1-page statement, available from the TSCA
Assistance Information Service.
USEPA. 1986a. U.S. Environmental Protection Agency. Toxic Substances Control Act Chemical
Substance Inventory. TSCA Inventory: 1985 Edition. Washington, DC: USEPA, Office of
Toxic Substances. EPA-560/7-85-002a.
USEPA. 1986b (June 12). U.S. Environmental Protection Agency. 40 CFRPart 710. Partial
Updating of TSCA Inventory Data Base; Production and Site Reports; Final Rule.
(51 FR 21438).
USEPA. 1986c (April 22). U.S. Environmental Protection Agency. 40 CFRPart 720. Toxic
Substances; Revisions of Premanufacture Notification Regulations; Final Rule. (51 FR 15096).
USEPA. 1986d (November). U.S. Environmental Protection Agency. New Chemical Information
Bulletin. Exemptions for Research and Development and Test Marketing. Washington, DC:
USEPA.
USEPA. 1988a (August 17). U.S. Environmental Protection Agency. 40 CFR Part 700. Fees for
Processing Premanufacture Notices, Exemption Applications and Notices, and Significant New
Use Notices; Final Rule. (53 FR 31248-54).
USEPA. 1988b (July 27). U.S. Environmental Protection Agency. 40 CFRPart 721. Significant
New Use Rules; Amendments to General Provisions; Final Rule (53 FR 28354-62).
USEPA. 1989 (June 28). U.S. Environmental Protection Agency. Polymers Manufactured Using
Free-Radical Initiators; Clarification of Reporting Requirements. (54 FR 27174).
USEPA. 1990a. U.S. Environmental Protection Agency. Toxic Substances Control Act Chemical
Substance Inventory. 1990 Supplement to the 1985 Edition of the TSCA Inventory. Washington,
DC: USEPA, Office of Toxic Substances. EPA-560/7-90-003.
USEPA. 1990b (July 23). U.S. Environmental Protection Agency. Points to Consider in the
Preparation and Submission of TSCA Premanufacture Notices (PMNs) for Microorganisms.
Available from the TSCA Assistance Information Service.
USEPA. 199la. U.S. Environmental Protection Agency. Premanufacture Notice for New
Chemical Substances. EPA Form 7710-25.
126
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USEPA. 1991b. U.S. Environmental Protection Agency. Instructions Manual for Premanufacture
Notification of New Chemical Substances. Washington, DC: Office of Toxic Substances. EPA-
7710-25(1).
USEPA. 1991c (November). U.S. Environmental Protection Agency. New Chemicals Program.
Washington, DC: U.S. Environmental Protection Agency. Office of Toxic Substances.
EPA 560/1-91-0.
USEPA. 1991d (April). U.S. Environmental Protection Agency. Toxic Substances Control Act.
A Guide for Chemical Importers/Exporters. Volume 1: Overview and Volume 2: List of
Import/Export Chemicals.
USEPA. 1991e (October 31). U.S. Environmental Protection Agency. Chemicals on Reporting
Rules Database. (In hard copy form.) Washington, DC: U.S. Environmental Protection Agency.
Office of Pesticides and Toxic Substances. Office of Toxic Substances.
USEPA. 1993a (February 8). U.S. Environmental Protection Agency. 40 CFRPart 720.
Premanufacture Notification; Revisions of Notification Regulations; Proposed Rule. (58 FR
7661-7676).
USEPA. 1993b (February 8). U.S. Environmental Protection Agency. 40 CFRPart 723.
Premanufacture Notification; Exemptions for Polymers; Proposed Rule. (58 FR 7679-7701).
USEPA. 1993c (February 8). U.S. Environmental Protection Agency. 40 CFRPart 721. Toxic
Substances; Significant New Use Rules; Proposed Amendment to Expedited Process for Issuing
Significant New Use Rules; Proposed Rule. (58 FR 7676-7679).
USEPA. 1993d (February 8). U.S. Environmental Protection Agency. 40 CFRParts 700 and 723.
Premanufacture Notification Exemption; Revision of Exemption for Chemical Substances
Manufactured in Quantities of 1,000 Kg or Less Per Year; Proposed Rule. (58 FR 7646-7661).
USEPA. 1994 (September 1). U.S. Environmental Protection Agency. 40 CFRPart 700, et al.
Microbial Products of Biotechnology; Proposed Regulation Under the Toxic Substances Control
Act; Proposed Rule. (59 FR 45526-45585).
USEPA. 1995a (March 29). U.S. Environmental Protection Agency. 40 CFR Parts 704, 720 and
721. Premanufacture Notification; Revisions of Premanufacture Notification Regulations; Final
Rule. (60 FR 16298-16311).
USEPA. 1995b (March 29). U.S. Environmental Protection Agency. 40 CFR Part 723.
Premanufacture Notification Exemptions; Revisions of Exemptions for Polymers; Final Rule. (60
FR 16316-16336).
127
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USEPA. 1995c (March 29). U.S. Environmental Protection Agency. 40 CFRPart 723.
Premanufacture Notification Exemption; Revision of Exemption for Chemical Substances
Manufactured in Small Quantities; Low Release and Exposure Exemption; Final Rule. (60 FR
16336-16351).
USEPA. 1995d (March 29). U.S. Environmental Protection Agency. 40 CFR Part 721.
Amendment for Expedited Process to Issue Significant New Use Rules for Selected New
Chemical Substances; Final Rule. (60 FR 16311-16316).
USEPA. 1995e. U.S. Environmental Protection Agency. Premanufacture Notice for New
Chemical Substances. EPA From 7710-25 (rev, 5-95).
USEPA. 1995f (March 28). U.S. Environmental Protection Agency. DRAFT Guidance for
Reporting Human Exposure and Environmental Release Information under Premanufacture
Notice Exemption at 40 CFR §723.50 for Chemical Substances Manufactured with Low
Environmental Releases and Low Human Exposures (LoREX).
USEPA. 1995g (March 29). U.S. Environmental Protection Agency. Draft Polymer Exemption
Guidance Manual.
128
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List of Selected Readings for Appendix
Historical Perspective on TSCA
Ackerly and O'Connor. May 1977. Toxic Substances Control Act: Its Background and Purpose.
Chemical Times and Trends.
CEQ. 1971 (Apr.). Council on Environmental Quality. Toxic Substances. Reprinted In: Staff
House Committee on Interstate and Foreign Commerce, 94th Congress, 2nd Session, Legislative
History of the Toxic Substances Control Act (TSCA Legislative History). New York: U.S.
Government Printing Office. December 1976. pp. 757-788.
DeKany J, Malkenson S. 1979. Meeting the Challenge of the Toxic Substances Control Act with
Technological Innovation. American Chemical Society Symposium Series (Fed. Regul. Chem.
Innovation), pp. 167-72.
Portney PR, ed. 1990. Public Policies for Environmental Protection. Washington, DC:
Resources for the Future, pp. 195-241.
Randall WS, Solomon SD. 1975. Chapter Eleven: Two Seasons of Cherry Blossoms, pp. 211-
231 and Chapter Twelve: More Cherry Blossoms, pp. 232-259. In: Building 6: The Tragedy of
Bridesburg. Boston, MA: Little, Brown and Company.
ReVelle C, ReVelle P. 1984. The Environment: Issues and Choices for Society. Boston, MA:
PWS Publishers, pp. 614-625.
Ritch JB Jr. Oct. 1977. The Toxic Substances Control Act: Impact on Industry. Chem Times
Trends. 1(1): 12-16.
Schwartz I, Marion L. April 27, 1977. How They Shaped the Toxic Substances Law. Chem
Week pp. 52-59.
Slesin L, Sandier R. 1978. Categorization of Chemicals Under the Toxic Substances Control Act.
Ecol Law Qrtly. 7: 359-396.
Textile Chemist and Colorist (TCAC). 1978. The Toxic Substances Control Act: How Will It
Affect the Textile Industry? 10(1): 6-16.
The Toxic Substances Control Act, 15 U.S.C. §§2601-2629 (1982 & Supp. HI 1985).
129
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What TSCA Says
Congressional Research Service, The Library of Congress. 1989. Summaries of Environmental
Laws Administered by the Environmental Protection Agency (Congressional Research Service
Report for Congress by the Environmental Protection Section of the Environment and Natural
Resources Policy Division). ENR report no. 89/217/ENR.
Connor JD, Jr., Ebner LS, Landfair SW, et al. 1989. The TSCA Handbook, 2nd ed. Rockville,
MD: Government Institutes, Inc. 505 pp.
Elkins CL. 1987 (February 9). Office of Toxic Substances, U.S. Environmental Protection
Agency, 401 M St., SW, Washington, DC 20460. Letter to [addressee deleted]. In Connor JD,
Jr., Ebner LS, Landfair SW, et al. 1989. The TSCA Handbook, 2nd ed. Rockville, MD:
Government Institutes, Inc. pp. 103-105.
Novick SM, ed. 1987. Law of Environmental Protection. Vol. U. New York: Clark Boardman
Co., Ltd. pp. 15-42.
O'Connor CA. Apr. 1979. Premanufacture Notification: TSCA is Coming of Age. Chem Times
Trends, pp. 61-63.
USEPA. 1987. The Layman's Guide to the Toxic Substances Control Act (Office of Toxic
Substances). Washington, DC: U.S. Environmental Protection Agency. EPA report no.
EPA/560/1-87/011.
Implementation of TSCA
USEPA. Various dates. U.S. Environmental Protection Agency. Chemicals in Progress Bulletin.
Washington, DC: U.S. Environmental Protection Agency. Office of Pollution Prevention and
Toxics. Published periodically.
USEPA. Various dates. U.S. Environmental Protection Agency. Annual Report to Congress.
Washington, DC: U.S. Environmental Protection Agency. Office of Toxic Substances. Published
periodically.
USEPA. 1986 (November). U.S. Environmental Protection Agency. New Chemical Information
Bulletin. Exemptions for Research and Development and Test Marketing.
USEPA. 1991 (November). U.S. Environmental Protection Agency. New Chemicals Program.
Washington, DC: U.S. Environmental Protection Agency. Office of Toxic Substances.
EPA 560/1-91-005.
130
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Table A-l. Sources of Office of Pollution Prevention and Toxics Information
Government Printing Office
c/o Superintendent of Documents
Washington, D.C. 20402
(202) 783-3238
National Library of Medicine
TRI Representative
Specialized Information Services
8600 Rockville Pike
Bethesda, MD 20894
(301)496-6531
National Technical Information Service
5285 Port Royal Road
Springfield, VA 22161
(703) 487-4650
OPPT Document Control Office
U.S. EPA
401 M Street, S.W. (TS-790)
Washington, DC 20460
(202) 260-1532
OPPT Public Docket Office
U.S. EPA
401 M Street, S.W. (TS-793)
Room G-004, Northeast Mall
Washington, DC 20460
(202) 260-7099
Toxic Release Inventory User Support (TRI/US)
U.S. EPA
401 M Street, S.W. (TS-793)
Room B-0011, Northeast Mall
Washington, DC 20460
(202)260-1531
TSCA Assistance Information Service
(TSCA hotline)
U.S. EPA
401 M Street, S.W. (TS-799)
Washington, DC 20460
(202) 554-1404
Fax: (202)554-5603
TDD: (202)554-0551
OPPT Chemical Library
U.S. EPA
401 M Street, S.W. (TS-793)
Room B-002, Northeast Mall
Washington, DC 20460
(202) 260-3944
CAS Inventory Expert Service
2540 Olentangy River Road
P.O. Box 3012
Columbus OH 43210-0012
(800) 848-6538, ext. 2308
or (614) 447-3600
Fax: (614) 447-3747
Dialog Information Services
TSCA Inventory search requests:
(800) ALERT91 (253-7891)
Online access to inventory:
(800) 334-2564
Chemical Information Systems, Inc.
7215 York Road
Baltimore, MD 21212
(301) 321-8440
(800) CIS-USER (247-8737)
Biotechnology Program Information
David Giamporcaro, Chief
Section II
(202) 260-6362
Pollution Prevention Information Clearinghouse
(PPIC)
(202) 260-1023 (24-hour answering machine)
131
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Index
Absorption 11, 27, 29-32, 48, 49, 53, 68, 70, 71
Acute toxicity 28, 29, 79
Adsorb 31,32, 50, 62
Adsorption 31, 49, 50, 59, 60, 62, 64, 82
Air-water partition coefficient 63
BCF; see Bioconcentration factor
Beilstein On-Line 79
Bioaccumulation 49, 50, 59
Bioconcentration factor (BCF) 62-64
Biodegradation 31, 32, 34, 62, 67, 82
Biotechnology 117
Biotechnology products 117
Biotransformation 29
Boiling point 23, 45, 64-67, 73, 78, 79, 81, 82
estimation 65, 66
importance 65
measurement methods 65
relationship to melting point 66
Bona fide inquiries 117
Bona fide intent 115, 116
Byproduct 25, 109, 122
CAS On-Line 78, 79, 81, 115
Case number 12, 24, 25
Categories of Concern 36
CBI; see Confidential business information
CBIC; see Confidential business information center
Chemical Name 7, 11, 13, 15, 17,24,25,44,78,79, 81,99, 121
Chemical Review and Search Strategy (CRSS) 13, 15, 24-27, 32, 35, 36, 81
Chemical structure 70
Chemical substance 1, 5, 6, 15, 25-27, 31, 35, 36, 40, 48-50, 59, 63, 67, 79, 95, 97, 98, 106,
108-116, 120-126
naturally occurring 122
Chemical substance Inventory 113-115, 120
Chemistry report 13, 15, 16, 24, 25, 27, 31
Chemistry review 6, 11-15, 22-24, 27, 32, 33, 98, 99
Chemline 78, 79
Class 1 substance 16, 22, 53
Class 2 substance 16, 22, 53
Commercial use 22, 107-109, 112-115, 117, 122
Confidential Business Information (CBI) 11, 12, 16, 25, 27, 80, 114
Confidential Business Information Center (CBIC) 11, 12, 27
Consent orders 120
Consumer exposure 34, 36, 38, 66, 72
-------
Consumer use 72, 74
Cosmetic 109
CRSS; see Chemical Review and Search Strategy
Delayed submission 24
Dermal exposure 33, 49
Developmental toxicity 28
Device 109
Disposal 36, 37, 72, 88, 95, 96, 98, 101, 102, 105, 108, 110-112
Dissociation constants 29
Distillation method 65
Distribution in commerce 109-111, 122, 123
Division director 39
DrugS, 109, 110
Ebulliometer 65
Ecological effects 27, 32-35, 38
Environmental effect 33, 110, 111
Environmental exposure 31, 33-36, 38, 111, 112
Environmental fate 10, 27, 31-33, 35, 38, 42, 44, 45, 50, 55, 59, 61, 67, 69, 71, 79, 86, 90
Environmental lifetime 31, 36
Environmental release 36, 63, 66, 69, 70, 72, 96, 98, 116
Estimation method 23, 31, 55, 58, 59, 66, 74
Estimation Programs 44, 81
Excluded from reporting 16
Excluded substance 122
Excretion 29
Exemptions 13, 15, 24, 26, 36, 41, 112, 116-119, 125-127, 130
exemption application 116, 117
exemption for research and development 118
exemption notice 13, 24, 118, 119
Instant film exemption 118
LoREX exemption 15, 119
low release and exposure exemption 119
low volume exemption 118
Polymer exemption 119
Existing substance 109, 114
Exports 113
Exposure 1, 6-8, 11, 22, 23, 26, 30, 31, 33-38, 41, 44, 45, 48-50, 59, 65-68, 72, 79, 81, 87,
91, 96, 98, 106, 107, 110-112, 116, 118-121, 123, 128
Exposure evaluation 6, 33, 35, 66
Exposure review 33
Federal Food, Drug and Cosmetic Act (FFDCA) 5, 40, 110, 124
Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) 5
FFDCA; see Federal Food, Drug and Cosmetic Act
FIFRA; see Federal Insecticide, Fungicide and Rodenticide Act
Focus meeting 33, 35, 36, 38
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Food 109
Fungicide 5, 109
Gas saturation procedure 67
Generator column method 53, 59-61
GMELIN On-Line 78
Green chemistry 96, 97, 100, 103
H value 64
Hazard assessment 27
Hazard evaluation 27, 32, 94
Hazard identification 27, 29, 31-34, 42
Hazardous Substance Data Bank (HSDB) 78
Health effect 33, 35, 110, 111
Henry's Law 31, 63, 67, 82, 86, 87, 93
use of vapor pressure in calculating 67
vapor pressure 63, 64
water solubility 64
Henry's Law Constant (H) 63, 64
HSDB; see Hazardous Substance Data Bank
Human exposure 31,33, 48, 67, 72, 98, 111, 112, 116
Human toxicity 27, 29
Hydrolysis 31, 32, 59, 62, 68-70, 82
calculation of rate 69
determining rate 69
estimation 70
estimation of rate 70
Imminent hazards 113
Import 20, 116, 119, 125, 127
Impurities 19, 22, 27, 47, 73, 78, 99
Impurity 122
Incomplete submission 24
Infrared (IR) spectrum/spectra 70, 115
Inhalation exposure 33, 34, 49
Insecticide 5, 109
Intended use 22, 23, 32, 35, 72, 74, 115, 117, 123
Interagency Testing Committee 112
Intermediates 79, 109
Invalid submission 24
Inventory reporting regulations 114
Inventory review 13, 15, 27
Inventory Update Rule 116
Isoteniscope technique 67
Koc 50, 62-64, 71, 83; see also soil adsorption coefficient
Kow 3, 4, 47, 49-64, 91, 93; see also octanol/water partition coefficient
estimation of 53, 55, 58
importance of 59
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measurement methods 52, 53
use in water solubility estimation 50
use of 50
Lifecycle 110
Log P; see octanol/water partition coefficient
LoRex?, 15,36, 119, 128
Mass spectra (MS) 70
Melting point 23, 29, 45, 47, 48, 50, 60, 73, 78, 79, 82-84
estimation 48
importance of 47
indicator of water solubility 47
Melting point range 47
Metabolite 29, 32
Microorganisms 117
Mixture 17, 26, 52, 65, 109, 113, 122, 123
Molecular formula 78, 79, 81
Molecular weight 14, 17, 18, 22-24, 33, 45, 55, 65, 66, 68, 70, 74, 78, 79, 82, 119
Mutagenicity 28
Neurotoxicity 28
New Chemical Substance 1, 5, 15, 25-27, 31, 95, 98, 106, 110, 115, 116
Not valid submission 16
Notice of Commencement 120
Nuclear magnetic resonance (NMR) spectra 70
Nuclear material 109
Number-average molecular weight 14, 24, 74, 119
Occupational exposure 33-36, 38, 66, 72
Octanol/water partition coefficient 3, 23, 29-31, 45, 47, 49, 50, 52-54, 56, 58, 62, 78, 82, 87, 88,
93
Office of Pollution Prevention and Toxics (OPPT) 6, 8, 12, 16, 24, 27-29, 31-33, 39, 100, 115,
116, 131
Oncogenicity 28
OPPT; see Office of Pollution Prevention and Toxics
Organ toxicity 28
Oxidation 68
PCBs; see Poly chlorinated biphenyls
Pesticides, 15,79, 109
Pharmacokinetics 27, 29, 32
Photocell method 65
Photolysis 31, 32, 34, 59, 62, 67, 70-72
direct 71
estimation 71
indirect 71
rate constants 71
Physicochemical properties 1, 4, 11, 16, 20-23, 25, 27, 29, 31-34, 44-47, 49, 67, 68, 70, 72-74,
78-81,90, 116
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Physicochemical property data 1, 23, 31, 33, 34, 45, 63, 64, 68, 74, 78, 80, 81
Physicochemical property estimation 31
PMN database 79
PMNform 116
Pollution prevention 1, 3, 4, 6, 8, 14, 20, 25, 40, 41, 73, 88, 95-104, 116, 130, 131
Pollution Prevention Act (PPA) 95
Polychlorinated biphenyls (PCBs) 47, 58, 70, 73, 107, 112
Polymer exemption 7, 13, 14, 41, 119, 120, 128
Polymers 7, 10, 13, 14, 18, 20, 24, 41, 53, 66, 68, 70, 74, 82, 118-121, 125-127
two percent rule 121
POTW31,34
Pre-CRSS drop 13, 24, 27
Premanufacture notification regulations 116
Production volume 11, 13, 19, 24, 35, 36, 72, 99, 119, 120
Publicaly owned treatment works (POTWS) 31
Purity 44, 47, 48, 60, 65, 73
QSARs; see Quantitative structure-activity relationships
Quantitative structure-activity relationships (QSARs) 11, 29, 31
Reactive functional groups 14, 68, 70, 74
Reactivity 68
importance 68
relationship to water solubility 68
Redistribution 29
Reduction 68
Registry of Toxic Effects of Chemical Substances (RTECS) 78, 79
Reproductive toxicity 28
Reversed-phase high performance liquid chromatography (HPLC) 53, 55, 57, 58, 63
Reversed-phase HPLC; see Reversed-phase high performance liquid chromatography
Risk assessment 1, 4-6, 8, 11, 14, 16, 23, 27, 30, 33, 35, 36, 38, 39, 41, 42, 44-46, 48, 49, 51, 53,
59, 61, 68, 74, 90, 91, 94
Risk characterization 35, 38, 39
Risk management 1, 5, 6, 32, 35, 36, 39, 44, 61
Rodenticide 5, 109
RTECS; see Registry of Toxic Effects of Chemical Substances
SARs; see Structure-activity relationships
SAT; see Structure-activity team
Shake-flask method 52, 53, 55, 58-61
Significant New Use Notices (SNUN) 24, 37, 110-112, 116, 120
Significant New Use Rule (SNUR) 37, 72, 120
Significant new uses 110
Siwolloboff method 65
Slow-stir method 52, 53
SMART; see Synthetic Method Assessment for Reduction Techniques
SNUN; see Significant New Use Notices
SNUR; see Significant New Use Rule
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Soil adsorption coefficient 31, 62, 64, 82
estimation 62
importance of 62
Spectral data 70
use of 70
Standard Review 38, 39
Structure-activity relationships (SARs) 11, 27-29
Structure-activity team (SAT) 27, 32-35
Synthesis 22, 25, 32, 44, 45, 70, 72, 73, 78, 99-102
Synthetic Method Assessment for Reduction Techniques (SMART) 14, 25, 98, 99
Test data 3, 6, 10, 11,21,27,37, 110-112, 116, 120
Test Market Exemptions 117
Tobacco 109
Toxicity 5, 6, 10, 22, 23, 26-32, 35, 36, 38, 42, 44, 45, 49, 50, 59, 68, 74, 79, 83-85, 90, 91, 93,
95,97-99, 101, 114
Toxic Substances Control Act (TSCA) 1, 5-8, 11, 12, 15, 19, 20, 22, 24-28, 32, 40-42, 72, 74,
80, 86, 88, 94, 95, 100, 105-122, 124-126, 129-131
enactment 105
implementation 114
premanufacture provisions 108
section 12 113
section 13 113
section 14 110, 114
section 3 109
section 4 110, 112
section4(c) 110
section 5 5, 108, 109
section 5(a) 110
section5(b) 110
section 5(c) 111
section 5(d) 111
section 5(e) 36, 72, 110, 111, 120
section 5(f) 110, 112
section 5(g) 112
section 5(h) 112, 117-119
section 5(i) 112
section 6 112
section 6(e) 112
section 7 113
section 8 113
section 8(a) 111, 113
section 8(b) 109, 113, 114, 122
section 8(c) 113
sectionS(d) 113
section 8(e) 28, 113
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TSCA; see Toxic Substances Control Act
TSCA Inventory 12, 15, 22, 25, 26, 40, 72, 109, 114-117, 120, 121, 125, 126, 131
Ultraviolet (UV) spectrum/spectra 70, 71
Unreasonable risk 1, 5, 13, 35, 37, 108, 110-114, 117, 121
User fee 117
UV spectra/spectrum; see Ultraviolet (UV) spectrum/spectra
Vapor Pressure 21, 23, 31, 33, 34, 45, 64-68, 78, 79, 81, 82
estimation 67
importance 66
measurement methods 67
relationship to water solubility 67
Volatilization 34, 59, 62, 64, 67
Volatilize 31,32, 63, 66, 68
Wastewater treatment plant 31,32
Water solubility 21, 23, 29-31, 34, 45, 47-50, 52, 59-64, 66-70, 79, 80, 82, 83, 86, 88, 91, 93
estimation 60, 61
measurement methods 59
risk assessment 59
Water solubility database 80
Withdrawn submission 24
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