03-18010. National Toxicology Program; Announcement of and Request for Public Comments on Substances Nominated to the National Toxicology Program (NTP) for Toxicological Studies and Study Recommendations Made by the NTP Interagency Committee for ...

Summary: The National Toxicology Program (NTP) continuously solicits and accepts nominations for toxicological studies to be undertaken by the program. Nominations of substances of potential human health concern are received from Federal agencies, the public, and other interested parties. These nominations are subject to several levels of review before selections for testing are made and toxicological studies are designed and implemented. Evaluation by the NTP Interagency Committee for Chemical Evaluation and Coordination (ICCEC) is the initial external review step in the NTP's formal selection process for NTP study nominations. On June 10, 2003, the ICCEC met to review 14 new nominations and make study recommendations. This announcement (1) Provides brief background information regarding the substances nominated to the NTP for study, (2) presents the ICCEC's study recommendations from its June 10, 2003 meeting, (3) solicits public comment on the nominations and study recommendations, and (4) requests the submission of additional relevant information for consideration by the NTP in its continued evaluation of these nominations.

Review of Study Nominations

Evaluation by the ICCEC is the initial external step in the NTP's formal selection process for NTP study nominations. At it's meeting on June 10, 2003, the ICCEC reviewed 14 new nominations for NTP studies. For 13 of these nominations, the ICCEC recommended one or more types of toxicological studies, and for one nomination, no studies were recommended at this time. The nominated substances with CAS numbers, nomination source, nomination rationale, and specific study recommendations are given in the accompanying tables.

The ICCEC is composed of representatives from the Agency for Toxic Substances and Disease Registry, U.S. Consumer Product Safety Commission, U.S. Department of Defense, U.S. Environmental Protection Agency, U.S. Food and Drug Administration's National Center for Toxicological Research, National Institutes of Health's (NIH) National Cancer Institute, National Center for Environmental Health, NIH's National Institute of Environmental Health Sciences (NIEHS), National Institute for Occupational Safety and Health, NIH's National Library of Medicine, and the Occupational Safety and Health Administration. The ICCEC meets once or twice annually to evaluate groups of new study nominations and to make recommendations with respect to both specific types of studies and testing priorities.

Request for Public Comment

Interested parties are invited to submit written comments or supplementary information on the nominated substances and study recommendations that appear in the accompanying tables. The NTP welcomes toxicology and carcinogenesis study information from completed, ongoing, or anticipated studies, as well as information on current U.S. production levels, use or consumption patterns, human exposure, environmental occurrence, or public health concerns for any of the nominated substances. The NTP is also interested in identifying appropriate new animal and non-animal models for mechanistic based research, including genetically modified rodents, and as such, solicits comments regarding the use of specific in vivo and in vitro experimental models to address scientific questions relevant to the nominated substances or issues under consideration. All information received will be considered by the NTP in its continued review of these nominations. Comments or information should be sent to Dr. Scott Masten (contact information below) by September 15, 2003. Persons responding to this request should include their name, affiliation, mailing address, phone, fax, e-mail address and sponsoring organization (if any) with the submission. Written submissions will be made available electronically on the NTP Web site as they are received.

An electronic copy of this announcement, Internet links to electronic versions of supporting documents for each nomination, and further information on the NTP and the NTP Chemical Nomination and Selection Process can be accessed through the NTP Web site: http://ntp-server.niehs.nih.gov.

Send comments or information to Dr. Scott A. Masten, Office of Chemical Nomination and Selection, NIEHS/NTP, PO Box 12233, MD A3-07, Research Triangle Park, North Carolina 27709; telephone: [phone]; Fax: [phone]; e-mail: [e-mail].

Background

The NTP actively seeks to identify and select for study chemicals and other agents for which sufficient information is not available to adequately evaluate potential human health hazards. The NTP accomplishes this goal through a formal open nomination and selection process. Substances considered appropriate for study generally fall into two broad yet overlapping categories: (1) Substances judged to have high concern as a possible public health hazard based on the extent of human exposure and/or suspicion of toxicity and (2) substances for which toxicological data gaps exist and additional studies would aid in assessing potential human health risks, e.g. by facilitating cross-species extrapolation or evaluating dose-response relationships. Input is also solicited regarding the nomination of studies that permit the testing of hypotheses to enhance the predictive ability of future NTP studies, address mechanisms of toxicity, or fill significant gaps in the knowledge of the toxicity of classes of chemical, biological, or physical substances. Substances may be studied to evaluate a variety of health-related effects, including but not limited to reproductive and developmental toxicity, genotoxicity, immunotoxicity, neurotoxicity, metabolism and disposition, and carcinogenicity. In reviewing and selecting nominated substances, the NTP also considers legislative mandates that require responsible private sector commercial organizations to evaluate their products for health and environmental effects. The possible human health consequences of anticipated or known human exposure, however, remain the over-riding factor in the NTP's decision to study a particular substance.

The review and selection of substances nominated for study is a multi-step process. A broad range of concerns are addressed during this process through the participation of representatives from the NIEHS, other Federal agencies, the NTP Board of Scientific Counselors—an external scientific advisory body, the NTP Executive Committee—the NTP Federal interagency policy body, and the public. This process is described in further detail in a March 2, 2000 Federal Register announcement (Volume 65, Number 42, pages 11329-11331). This multi-step evaluative process provides the NTP with direction and guidance to ensure that it's testing program addresses toxicological concerns relative to all areas of public health, and furthermore, that there is balance among the types of substances selected for study (e.g., industrial chemicals, consumer products, therapeutic agents). As such, it should be recognized that at any given time, the new study nominations under consideration do not necessarily reflect the overall balance of substances historically or currently being evaluated by the NTP in it's toxicology testing program. For further information on NTP toxicology studies (previous or in progress) visit the NTP Web site at http://ntp-server.niehs.nih.gov.

Dated: July 7, 2003.

Samuel Wilson,

Deputy Director, National Institute of Environmental Health Sciences.

Substances Nominated to the NTP for Toxicological Studies and Recommendations Made by the ICCEC on June 10, 2003

Table 1.—Substances Recommended for Study

Substance [CAS No.]	Nominated by	Nomination rationale	Recommendations for toxicological studies
Acrylamide [79-06-1] and Glycidamide [5694-00-8]	U.S. Food and Drug Administration	Inadequate information available to accurately assess human health risks from exposure to acrylamide in foodstuffs; a properly designed well-conducted, GLP-compliant bioassay with appropriate ancillary studies is needed to provide dose-response information and account for the food matrix through which humans are exposed	—Toxicological characterization. —Toxicokinetics. —Mechanistic (hemoglobin adducts). —Carcinogenicity. —Bioavailability from food and drinking water.
Antimony trisulfide [1345-04-6]	National Cancer Institute.	Significant human exposure in occupational settings and suspicion of carcinogenicity	Chronic toxicity/carcinogenicity.
Cadmium telluride [1306-25-8]	U.S. Department of Energy, Brookhaven National Laboratory, National Renewable Energy Laboratory, First Solar, Inc	Potential for widespread applications in photovoltaic energy generation; anticipated increase in human exposures; further data needed to address health and safety issues related to manufacture and use	—Toxicological characterization. —Chemical disposition (oral and inhalation routes).
Cedarwood oil, Virginia [8000-27-9]	National Cancer Institute	Widespread occupational and consumer exposure; lack of basic toxicology data	—Toxicological characterization. —Developmental toxicity.
Chondroitin sulfate [9007-28-7]	National Cancer Institute	Widespread long-term use as a dietary supplement and inadequate data to assess safety	—Chronic toxicity/carcinogenicity. —Carcinogenicity of chondroitin sulfate and glucosamine combined.
Dimethylethanolamine [108-01-0]	National Institute of Environmental Health Sciences	Potential for widespread human exposure through its use in industrial and consumer products; inadequate toxicological database; some ethanolamines can interfere with choline uptake and utilization and may also generate nitrosamines	—Metabolism.
Drugs positive for QT Interval Prolongation/Induction of Torsade Proarrhythmia [No CAS No.]	U.S. Food and Drug Administration	QT interval prolongation and torsade de pointes is a high priority cause for concern in drug development and regulatory safety evaluation; a clear definition of the strengths, limitations, and future performance characteristics of the canine telemetry model for pre-clinical safety assessment is needed	—Initiate a study program to develop in vitro and in vivo test systems for assessing QT interval prolongation.
Glucosamine [3416-24-8]	National Cancer Institute	Widespread long-term use as a dietary supplement and inadequate data to assess safety	—Chronic toxicity/carcinogenicity. —Carcinogenicity of chondroitin sulfate and glucosamine combined.
Nanoscale materials. [No CAS No.]	Rice University Center for Biological and Environmental Nanotechnology	Intense current and anticipated future research and development focus; further studies and development of appropriate toxicological methods are needed to adequately assess health effects	—Size—and composition—dependent biological disposition of nanocrystalline fluorescent semiconductor materials. —Toxicological characterization of high aspect ratio carbon nanomaterials. —Role of particle core and surface composition in the immunotoxicity of the above listed materials.
			—Phototoxicity of representative metal oxide nanoparticles.
trans—Resveratrol [501-36-0]	National Institute of Environmental Health Sciences	Widespread human exposure from natural dietary sources and use of dietary supplements; suspicion of toxicity based on estrogenic and genotoxic activity; insufficient data available to characterize safety	—Toxicological characterization. —Carcinogenicity. —Reproductive toxicity.
Tetrabromobisphenol A [79-94-7]	National Institute of Environmental Health Sciences	High production volume; widespread human exposure and suspicion of thyroid toxicity/tumorigenicity	—Toxicological characterization. —Neurodevelopmental toxicity. —Carcinogencity.
Tetrabromobisphenol A bis(2,3-dibromopropyl ether) [21850-44-2]	National Institute of Environmental Health Sciences	High production volume; little toxicity data available; suspicion of carcinogenic potential due to 2,3-dibromo-1-propanol substructure	—Toxicological characterization. —In vivo genotoxicity. —Metabolism. —Carcinogenicity.
Tungsten [7440-33-7]	National Center for Environmental Health	Important industrial materials; insufficient data to assess human health implications of elevated urinary tungsten levels	—Toxicological characterization. —Carcinogenicity. —Studies should focus on a representative soluble tungsten compound.

Table 2.—Substance for Which No Study Is Recommended at This Time

Substance [CAS No.]	Nominated by	Nominated for	Nomination rationale	Rationale for recommending no toxicological studies
4-Phenylcyclohexene [4994-16-5]	Private Individuals	—Toxicological characterization including genotoxicity and neurotoxicity	Present in indoor environments primarily from carpet emissions; concern that it has not been adequately tested for potential health effects	Low suspicion of hazard based on available human exposure and toxicity information.