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National Toxicology Program (NTP)

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Announcement of and Request for Public Comments on Substances Nominated to the National Toxicology Program (NTP) for Toxicological Studies and on Study Recommendations Made by the NTP Interagency Committee for Chemical Evaluation and Coordination (ICCEC)

Summary

The NTP continuously solicits and accepts nominations for toxicological Start Printed Page 40330studies 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 undergo several levels of review before selections for testing are made and toxicological studies are designed and implemented. Evaluation by the NTP ICCEC is the initial external review step in the NTP's formal selection process for NTP study nominations. On April 17, 2002 the ICCEC met to review 19 new nominations and make study recommendations. This announcement (1) provides brief background information regarding the substances nominated to NTP for study, (2) presents the ICCEC's study recommendations from its April 17, 2002 meeting, (3) solicits public comment on the nominations themselves and on the study recommendations by the ICCEC, 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

At it's meeting on April 17, 2002, the ICCEC reviewed 19 new nominations for NTP studies. For 14 of these nominations, one or more types of toxicological studies were recommended, and for 5 nominations, no studies were recommended at this time. The nominated substances with CAS numbers, nomination source, nomination rationale, specific study recommendations, and other pertinent information are given in the attached tables.

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. The ICCEC is composed of representatives from the Agency for Toxic Substances and Disease Registry, U.S. Consumer Product Safety Commission, Department of Defense, U.S. Environmental Protection Agency, U.S. Food and Drug Administration's National Center for Toxicological Research, National Cancer Institute, National Center for Environmental Health, National Institute of Environmental Health Sciences, National Institute for Occupational Safety and Health, 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 Comments

Interested parties are invited to submit comments or supplementary information on the nominated substances and study recommendations that appear in the attached tables. The NTP welcomes toxicology and carcinogenesis information from completed, ongoing, or planned studies, as well as information on current production levels, use 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 models for mechanistic based research, including transgenic or knockout mice, and welcomes comments regarding the use of specific animal models to address scientific questions relevant to the nominated substances and studies 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 by August 12, 2002. 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's 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, P. O. Box 12233, MD A3-07, Research Triangle Park, North Carolina 27709; telephone: (919) 541-5710; FAX: (919) 541-3647; email: masten@niehs.nih.gov.

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) Those substances of greatest concern for public health 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 National Institute of Environmental Health Sciences, 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 testing program. For further information on NTP toxicology studies (previous or in progress) visit Start Printed Page 40331the NTP web site at http://ntp-server.niehs.nih.gov.

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Dated: June 5, 2002.

Samuel Wilson,

Deputy Director, National Toxicology Program.

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Attachment

Substances Nominated to the NTP for Toxicological Studies and Recommendations Made by the ICCEC on April 17, 2002

Table 1.—Substances Recommended for Study

Substance [CAS No.]Nominated byNomination rationale; other informationRecommendations for toxicological studies
Abrasive blasting agents; Coal slag; Crushed glass; Garnet; Sand; Specular hematite; Steel gritNational Institute for Occupational Safety and Health; Occupational Safety and Health AdministrationHigh production volume and widespread occupational exposure; lack of adequate health effects information; data needed to establish safe exposure limits—Chronic inhalation toxicity in male rats; —Pulmonary tissue burden analysis.
5-Amino-o-cresol [2835-95-2]National Cancer InstituteWidely used in permanent hair dyes; some evidence of toxicity; lack of carcinogenicity data—Metabolism; —Developmental and reproductive toxicity; —Carcinogenicity.
tert-Butyl hydroperoxide [75-91-2]National Cancer InstituteHigh production volume industrial chemical; evidence for genotoxicity and tumor promotion activity; lack of carcinogenicity data—Carcinogenicity; —Consider mechanistic studies related to carcinogenicity of organic peroxides as a class.
Chloramine-T [127-65-1] and p-Toluenesulfonamide [70-55-3]Private IndividualInvestigational new animal drug for antimicrobial use in aquaculture; evidence for toxicity further studies needed to establish safe residue levelsIn vitro and in vivo genotoxicity; —Subchronic toxicity; and/or carcinogenicity studies may be considered when results of genotoxicity studies are available for review.
Cobalt metal dust [7440-48-4]Cobalt Development Institute; International Union, United Auto Workers; Occupational Safety and Health AdministrationWidespread occupational exposure; evidence for toxicity; insufficient data to assess chronic toxicity and carcinogenic potential—Toxicological characterization including carcinogenicity and developmental toxicity (inhalation studies).
Ephedrine alkaloid dietary supplements [no CAS No.]National Cancer Institute; National Institutes of Health Office of Dietary SupplementsWidely used dietary supplement; reports of adverse effects in consumers; lack of adequate toxicological information for multi-component dietary supplement formulations—Developmental and reproductive toxicity; —Subchronic toxicity; —Special emphasis on assessment of potential cardiovascular and central ervous systems effects; —Studies should use commercial ephedra products with and without caffeine and other additives.
Ethanone, 1-(1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthalenyl)-(Iso-E Super) [54464-57-2]Private IndividualHigh production volume fragrance material; widespread consumer exposure; lack of toxicity data—Toxicological characterization including genotoxicity.
Hexafluorosilicic acid [16961-83-4] and Sodium hexafluorosilicate [16893-85-9]Private Individuals (multiple nominations)Primary agents used to fluoridate public drinking water systems; lack of toxicity information; assumed complete dissociation to free fluoride under normal conditions of use not supported by experimental evidence—Chemical characterization studies to assess chemical fate under aqueous conditions; —Toxicological studies may be considered when results of chemical characterization studies are available for review.
Ketamine hydrochloride [1867-66-9]U.S. Food and Drug AdministrationApproved drug for anesthetic use in adults; off-label pediatric use thought to occur; causes severe lesions in developing rat brain; further studies needed to assess safety of pediatric use—Comprehensive neurotoxicity assessment and toxicokinetics in developing (post-natal) non-human primates.
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Mercury, ((o-carboxyphenyl)thio)ethyl-,sodium salt (Thimerosal) [54-64-8]U.S. Food and Drug AdministrationOrganomercurial preservative widely used in vaccines and other therapeutics; large exposed population; insufficient toxicity data—Toxicokinetics; —Neurodevelopmental toxicity; —Comparative studies with ethylmercury and methylmercury under different dosing regimens in non-human primates; —Coordinate with ongoing federally-sponsored research efforts.
Nitrogen trifluoride [7783-54-2]National Cancer InstituteRapidly increasing industrial demand; acute toxic effects well described; potential for toxicity based on oxidizing properties—Genotoxicity; —Metabolism.
Sodium metasilicate [6834-92-0]National Institute for Occupational Safety and HealthWidespread occupational exposure; evidence for biological activity; insufficient toxicity data—Subchronic toxicity (inhalation studies); —Respiratory hypersensitivity.
Turpentine [8006-64-2]International Union, United Auto WorkersWidespread occupational and consumer exposure; reports of kidney toxicity in exposed humans; insufficient chronic toxicity information—Chronic toxicity; —Carcinogenicity.
Welding fume: Gas metal arc welding with stainless steel electrode; Gas metal arc welding with mild steel electrode; Manual arc welding with stainless steel electrodeNational Institute for Occupational Safety and Health; International Union; United Auto WorkersWidespread Occupational exposure; evidence for toxicity of mixture and components; gaps in available health effects data—Acute and subchronic inhalation exposure studies to assess neurotoxicity, immunotoxicity, and pulmonary toxicity of all 3 welding fume types; —Chronic inhalation toxicity and carcinogenicity studies with one or more welding fume types.

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

Substance [CAS No.]Nominated byNominated forNomination rationale; other informationRationale for recommending no toxicological studies
Hexachloro-1,3-butadiene [87-68-3]Carcinogen Identification Committee (Advisory Body for California Environmental Protection Agency)—Carcinogenicity (at doses intermediate to those used in previous studies)Persistent industrial by-product widely dispersed in environment; some evidence for carcinogenicity; existing data insufficient to characterize carcinogenic hazardLow commercial production volume, insufficient evidence of significant human exposure, and availability of adequate toxicological data.
Infrasound [no CAS No.]National Institute of Environmental Health Sciences—Toxicological characterizationLow frequency sound ubiquitous in occupational and community settings; insufficient settings; insufficient data to address public concerns regarding potential health hazards at low exposure levelsInsufficient information on human exposures in community settings and questionable utility of additional studies in available animal models/test systems; Consider seeking additional expert opinion on human exposure and toxicity data needs.
Magnesium oxide [1309-48-4]National Cancer Institute—Biological disposition —Chronic inhalation toxicityHigh production volume industrial chemical; widespread occupational exposure; lack of chronic inhalation toxicity dataAdequate available toxicological data.
Methylolurea [1000-82-4]National Institute of Environmental Health Sciences—Toxicological characterizationHigh production volume industrial chemical; widespread use and potential for human exposure; lack of toxicity informationInclusion in the High Production Volume Chemical Challenge Program.
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4-Methylquinoline [491-35-0]Carcinogen Identification Committee (Advisory Body for California Environmental Protection Agency)—Comparative metabolism studies (with quinoline) —CarcinogenicityUbiquitous environmental contaminant; some evidence for carcinogenicity; existing data insufficient to characterize carcinogenic hazardLow commercial production volume, insufficient evidence of significant human exposure, and availability of adequate toxicological data.
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[FR Doc. 02-14821 Filed 6-11-02; 8:45 am]

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