[Federal Register Volume 63, Number 154 (Tuesday, August 11, 1998)]
[Notices]
[Pages 42852-42855]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-21522]


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ENVIRONMENTAL PROTECTION AGENCY

[OPPTS-42206; FRL-6021-3]


Endocrine Disruptor Screening Program

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: As mandated by the Federal Food, Drug, and Cosmetic Act, as 
amended by the Food Quality Protection Act of 1996, EPA is setting 
forth its screening program for determining which pesticide chemicals 
and other substances may have an effect in humans that is similar to an 
effect produced by a naturally occurring estrogen or other endocrine 
effects. In developing the screening program, EPA considered 
recommendations of the Endocrine Disruptor Screening and Testing 
Advisory Committee, a panel chartered pursuant to the Federal Advisory 
Committee Act. EPA refers to this program as the ``Endocrine Disruptor 
Screening Program'' or the ``Screening Program.'' This document 
describes the major elements of EPA's Endocrine Disruptor Screening 
Program. EPA will provide operational details regarding the Screening 
Program, its regulatory implementation, and provide an opportunity for 
public comment in a later Federal Register document. After public 
comment and before implementation, EPA will submit the Screening 
Program for review to a joint panel of the Federal Insecticide, 
Fungicide, and Rodenticide Act Scientific Advisory Panel and the EPA 
Science Advisory Board.

ADDRESSES: The official record for this document, including a public 
version, has been established for this document under docket control 
number OPPTS-42206. The public version of this record is available for 
inspection from noon to 4 p.m., Monday through Friday, excluding legal 
holidays. The public record is located at the TSCA Nonconfidential 
Information Center, Rm. NE-B607, 401 M St., SW., Washington, DC 20460.

FOR FURTHER INFORMATION CONTACT: For general information or copies of 
the EDSTAC report: Environmental Assistance Division (7408), Office of 
Pollution Prevention and Toxics, Environmental Protection Agency, 401 M 
St. SW., Washington DC, 20460; telephone 202-554-1404; TDD 202-554-
0551; e-mail: TSCA-H[email protected].
    For technical information: Anthony Maciorowski, Ph.D., Senior 
Technical Advisor, Office of Prevention, Pesticides and Toxic 
Substances; telephone: 202-260-3048; e-mail: 
[email protected] or Gary Timm, Senior Technical Advisor, 
Chemical Control Division, Office of Pollution Prevention and Toxics; 
telephone: 202-260-1859; e-mail: [email protected]).
SUPPLEMENTARY INFORMATION:

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I. General Information

A. Does this document apply to me?

    This document describes the major elements of EPA's Endocrine 
Disruptor Screening Program, and does not require any action by any 
potentially affected entity. EPA will provide operational details 
regarding the Endocrine Disruptor Screening Program and its regulatory 
implementation in a later Federal Register document. EPA will provide 
an opportunity for public comment on the Screening Program in this 
later document. You may be interested in the program set forth in this 
document if you produce, manufacture or import pesticide chemicals, 
substances that may have an effect cumulative to an effect of a 
pesticide, or substances found in sources of drinking water. To 
determine whether you or your business may have an interest in this 
document you should carefully examine section 408(p) of the Federal 
Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality 
Protection Act (FQPA) of 1996 (Pub. L. 104-170), 21 U.S.C. 346a(p) and 
amendments to the Safe Drinking Water Act (Pub. L. 104-182), 42 U.S.C. 
300j-17. If you have any questions regarding the applicability of this 
action to a particular entity, consult the technical person listed in 
the ``FOR FURTHER INFORMATION CONTACT'' section at the beginning of 
this document.

B. How can I get additional information or copies of this document.

    1. Electronically. You may obtain electronic copies of this 
document from the EPA internet Home Page at http://www.epa.gov/. On the 
Home Page select ``Laws and Regulations'' and then look up the entry 
for this document under the ``Federal Register - Environmental 
Documents.'' You can also go directly to the ``Federal Register'' 
listings at http://www.epa.gov/homepage/fedrgstr/.
    2. In person or by phone. If you have any questions or need 
additional information about this action, contact the technical person 
identified in the ``FOR FURTHER INFORMATION CONTACT'' section at the 
beginning of this document. A public version of this record, including 
printed, paper versions which does not include any information claimed 
as CBI, is available for inspection at the address in the ``ADDRESSES'' 
section at the beginning of this document. The Document Control Office 
telephone number is 202-260-7093.

II. Background

    Section 408(p) of the Federal Food, Drug, and Cosmetic Act, as 
amended by the Food Quality Protection Act of 1996 (Pub. L. 104-170), 
21 U.S.C. 46a(p), requires EPA, not later than August 3, 1998, to:

    * * *develop a screening program using, appropriate validated 
test systems and other scientifically relevant information, to 
determine whether certain substances may have an effect in humans 
that is similar to an effect produced by a naturally occurring 
estrogen, or such other endocrine effect as the Administrator may 
designate.

    When carrying out the Screening Program, EPA ``shall provide for 
the testing of all pesticide chemicals'' and ``may provide for the 
testing of any other substance that may have an effect that is 
cumulative to an effect of a pesticide chemical if the Administrator 
determines that a substantial population may be exposed to such a 
substance.'' 21 U.S.C. 346a(p)(3).
    In addition, Congress amended the Safe Drinking Water Act and gave 
EPA authority to provide for the testing, under the FQPA Screening 
Program, ``of any other substance that may be found in sources of 
drinking water if the Administrator determines that a substantial 
population may be exposed to such substance.'' 42 U.S.C. 300j-17.
    This document sets forth the Screening Program that EPA has 
developed to comply with requirements of section 408(p) of the FFDCA as 
amended by FQPA. In a later Federal Register document, EPA will provide 
additional information about the Screening Program and its 
implementation and an opportunity for the public to comment on it. 
After public comment and before implementation, EPA will submit the 
Screening Program to a joint panel of the Federal Insecticide, 
Fungicide, and Rodenticide Act Scientific Advisory Panel and the EPA 
Science Advisory Board for review.

III. Endocrine Disruptor Screening Program

    EPA has considered recommendations of the Endocrine Disruptor 
Screening and Testing Advisory Committee (EDSTAC) in developing its 
Screening Program. The full text of the EDSTAC Draft Final Report is 
available on EPA's worldwide web site at: www.epa.gov/opptintr/
opptendo. Paper copies can be obtained upon request from the TSCA 
Hotline at the address listed in ``FOR FURTHER INFORMATION CONTACT'' at 
the beginning of this document.
    Initially, the Endocrine Disruptor Screening Program will focus on 
estrogenic, androgenic, and thyroid hormone effects. These three 
hormone systems are presently the most studied of the approximately 50 
known vertebrate hormones. In vitro and in vivo test systems to examine 
estrogen, androgen, and thyroid effects exist, and are currently the 
most amenable for regulatory use. Further, inclusion of estrogen, 
androgen, and thyroid effects will cover aspects of reproduction, 
development, and growth.
    EPA recognizes that there is a great deal of ongoing research 
related to other hormones and test systems. As more scientific 
information becomes available, EPA will consider expanding the scope of 
the Endocrine Disruptor Screening Program to other hormones. For now, 
however, the estrogen, androgen, and thyroid hormone effects and test 
systems represent a scientifically reasonable focus for the Agency's 
Endocrine Disruptor Screening Program.
    EPA's Endocrine Disruptor Screening Program uses a tiered approach 
for determining whether a substance may have an effect in humans that 
is similar to an effect produced by naturally occurring estrogen, 
androgen, or thyroid hormones. The core elements of the tiered approach 
include initial sorting, priority setting, Tier 1 analysis, and Tier 2 
analysis.

A. Initial Sorting

     Chemicals under consideration for estrogen, androgen, and thyroid 
screening will undergo initial sorting based on existing, 
scientifically relevant information. EPA will use the existing 
information to place a chemical into one of the following four 
categories.
    1. Category 1--Hold. Chemicals with sufficient, scientifically 
relevant information to determine that they are not likely to interact 
with the estrogen, androgen, and thyroid hormone systems. If EPA is 
able to determine, based on scientifically relevant information, that a 
specific chemical is not likely to interact with the estrogen, 
androgen, or thyroid hormone systems, it will place that chemical in a 
hold category. Chemicals in this hold category will have the lowest 
priority for further analysis and may not undergo further analysis 
unless new and compelling information suggests that the chemical may 
interact with the endocrine system. Although EPA will place chemicals 
in the hold category during the initial sorting phase of the Screening 
Program, it may add chemicals to this category if, during a later phase 
of the Screening Program (priority setting, Tier 1 analysis, or Tier 2 
analysis), the Agency determines that a particular chemical is not 
likely to interact with the endocrine system.
    2. Category 2--Priority Setting/Tier 1 Analysis. Chemicals for 
which there is

[[Page 42854]]

insufficient, scientifically relevant information to determine whether 
or not they are likely to interact with the estrogen, androgen, and 
thyroid systems. If EPA is not able to determine, based on 
scientifically relevant information, whether or not a chemical is 
likely to interact with the estrogen, androgen, and thyroid hormone 
systems, it will place that chemical into a ``priority setting'' 
category. Category 2 chemicals are those for which there is 
insufficient scientifically relevant information to be placed on hold 
(Category 1), or assigned to Tier 2 analysis (Category 3) or hazard 
assessment (Category 4). EPA anticipates that it will likely place the 
majority of chemicals into this category. Category 2 chemicals will be 
subjected to formal priority setting, Tier 1 analysis, and as 
appropriate, Tier 2 analysis.
    3. Category 3--Tier 2 Analysis. Chemicals with sufficient, 
scientifically relevant information comparable to that provided by the 
Tier 1 analysis. Recognizing the need for flexibility, EPA has included 
Tier 1 analysis bypass possibilities. For example, if sufficient, 
scientifically relevant information exists regarding a specific 
chemical, EPA may move that chemical directly into Tier 2 analysis. In 
addition, EPA may allow a chemical to bypass Tier 1 analysis if the 
chemical's producer or registrant chooses to conduct Tier analysis 
without performing Tier 1.
    4. Category 4--Hazard Assessment. Chemicals with sufficient, 
scientifically relevant information to bypass Tier 1 and Tier 2 
analysis. For certain chemicals, there already may be sufficient, 
scientifically relevant information regarding their interaction with 
the estrogen, androgen, thyroid hormone systems--information comparable 
to that derived from Tier 1 and Tier 2 analysis--to move them directly 
into hazard assessment for endocrine disruption. These chemicals, thus, 
will bypass Tier 1 and Tier 2 analysis. It is anticipated that this 
will be a relatively small number (less than 100) of chemicals.

B. Priority Setting

    During priority setting, EPA will determine in what order the 
chemicals placed in Category 2 during ``initial sorting'' will enter 
Tier 1 analysis. EPA will set priorities using existing exposure and 
effects data and statutory criteria. The exposure and effects data will 
consist of empirical data where available and may also employ models to 
estimate exposure or effects characteristics. EPA recognizes that 
existing endocrine specific effects data are incomplete or lacking for 
most chemicals. To address this inadequacy, EPA, in partnership with 
others, will conduct selected in vitro assays in a high-speed, 
automated fashion. This step is called ``high throughput pre-
screening'' (HTPS). EPA will use the data that it generates from HTPS 
for priority setting. HTPS data alone is insufficient to ascertain 
whether or not a chemical may be an endocrine disruptor. Priority 
setting will result in a phased approach to screening with the highest 
priority chemicals evaluated first, followed by medium priority 
chemicals, and then low priority chemicals. EPA has adopted a priority 
setting approach because the available resources and laboratory 
capacity necessary for the Endocrine Disruptor Screening Program will 
not allow simultaneous entry of hundreds to thousands of chemicals into 
the process.

C. Tier 1 Analysis

    Tier 1 analysis is designed to identify those chemicals that are 
not likely to interact with the estrogen, androgen, and thyroid hormone 
systems. During Tier 1 analysis, the Agency hopes to eliminate those 
chemicals that are unlikely to interact with the estrogen, androgen, 
and thyroid hormone systems. EPA does not believe that Tier 1 analysis 
will be adequate to determine whether a chemical may have an endocrine 
effect. Completion of Tier 1 analysis will result in either a decision 
to move the chemical into Tier 2 analysis, or an initial decision that 
no further analysis is needed, in which case EPA will place the 
chemical on hold (Category 1).
    Under EPA's Screening Program, Tier 1 analysis involves both in 
vitro and in vivo test systems. The Tier I assays were designed and 
selected as a battery. EPA believes that data from the entire battery 
are necessary to make the necessary decisions about the chemicals. The 
individual assays and the battery were selected on the basis of 
scientific relevance and state of scientific development. All of the 
assays will be validated prior to the Screening Program's 
implementation. Validation will be addressed by EPA in the future 
Federal Register document. EPA will also include several alternative 
assays in its validation activities. The Tier 1 in vivo and in vitro 
assays are listed below.
    1. In Vitro assays include an estrogen receptor binding or reporter 
gene assay, an androgen receptor binding or reporter gene assay, and a 
steroidogenesis assay with minced testis.
    2. In Vivo assays include a rodent 3-day uterotrophic assay, a 
rodent 20-day pubertal female assay with enhanced thyroid endpoints, a 
rodent 5 to 7-day Hershberger assay, a frog metamorphosis assay, and a 
fish gonadal recrudescence assay.

D. Tier 2 Analysis

    Tier 2 analysis is designed to determine whether a chemical may 
have an effect in humans similar to that of naturally occurring 
hormones and to identify, characterize, and quantify those effects for 
estrogen, androgen, and thyroid hormones. Like the Tier 1 battery, the 
Tier 2 analysis scheme is designed as a battery. A negative outcome in 
Tier 2 analysis will supersede a positive outcome in Tier 1 analysis. 
Furthermore, each Tier 2 assay includes endpoints that will permit a 
decision regarding whether or not a tested chemical may be an endocrine 
disruptor for estrogen, androgen, or thyroid effects. Conducting all 
five assays in the Tier 2 battery will provide the type of information 
necessary for endocrine disruptor hazard assessment. A decision to 
require less testing may be made by EPA based on scientifically 
relevant information showing that exposure is limited or that effects 
can be adequately characterized in a one generation assay.
    1. Tier 2 assays. Tier 2 assays include a two-generation mammalian 
reproductive toxicity study or a less comprehensive alternative 
mammalian reproductive toxicity assay, an avian reproduction toxicity 
assay, a fish life cycle toxicity assay, an opossum shrimp (Mysidacea) 
or other invertebrate life cycle toxicity assay, and an amphibian 
development and reproduction assay.
    2. Assay selection. EPA will provide guidance on the selection of 
Tier 2 assays, focusing upon:
    a. The determination of which of the five taxonomic groups should 
be included in the Tier 2 analysis of a specific chemical.
    b. The circumstances under which it may be appropriate to perform 
an alternative assay, with a particular focus on the selection of 
alternative mammalian assays.
    c. The selection of endpoints.
    d. The special case of chemicals that bypass Tier 1 analysis and go 
directly to Tier 2 analysis.
    e. The potential need for supplemental information to complete Tier 
2 analysis.

E. Evaluation of Results

     A weight-of-evidence approach will be used to evaluate Tier 1 and 
Tier 2 analysis results. The weight-of-evidence approach will include:

[[Page 42855]]

    1. The balance of positive and negative responses observed in both 
the in vitro and in vivo assays.
    2. The nature and range of the biological effects observed.
    3. The shape of the dose-response curves when available.
    4. The severity and magnitude of the effects induced.
    5. The presence or absence of responses in multiple taxa.
    The evaluation of Tier 1 data, and other scientifically relevant 
information (e.g., HTPS or literature data), will result in a decision 
that either the chemical needs no further analysis and can be moved to 
the hold category or a decision that the chemical needs to undergo Tier 
2 analysis to determine whether it may have an effect in humans that is 
similar to the effect produced by a naturally occurring hormone. 
Similarly, an evaluation of Tier 2 data will result in a decision 
either to move the chemical into the hold category or to move it into 
hazard assessment.

IV. Development of EPA Policies

    EPA currently is developing policies to implement the Endocrine 
Disruptor Screening Program. EPA will set forth these policies in 
another Federal Register document later this year. This document will 
provide interpretive and operational details, and address such issues 
as standardization and validation of the assays, statutory and 
regulatory mechanisms for requiring the development of data, data 
reporting requirements, data compensation, confidential business 
information, and the process for granting waivers from screening 
requirements.

List of Subjects

    Environmental protection.

Dated: July 31, 1998

    Approved by:

J. Charles Fox,
Assistant Administrator for Water.

Lynn R. Goldman,
Assistant Administrator for Prevention, Pesticides, and Toxic 
Substances.
[FR Doc. 98-21522 Filed 8-10-98; 8:45 am]
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