[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] ----------------------------------------------------------------------- ENVIRONMENTAL PROTECTION AGENCY [OPPTS-42206; FRL-6021-3] Endocrine Disruptor Screening Program AGENCY: Environmental Protection Agency (EPA). ACTION: Notice. ----------------------------------------------------------------------- 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: [[Page 42853]] 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] BILLING CODE 6560-50-F