[Federal Register Volume 69, Number 161 (Friday, August 20, 2004)]
[Notices]
[Pages 51691-51693]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-19136]



[[Page 51691]]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service


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

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 24, 2004, the ICCEC met to review 10 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 24, 2004 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. 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.

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 its meeting on 
June 24, 2004, the ICCEC reviewed 10 new nominations for NTP studies. 
For 7 of these nominations, the ICCEC recommended one or more types of 
toxicological studies, and for 3 nominations, the ICCEC deferred making 
specific study recommendations pending review of additional 
information. The nominated substances with Chemical Abstract Service 
(CAS) Registry numbers, nomination source, nomination rationale, and 
specific study recommendations are given in the accompanying tables.
    The ICCEC is composed of representatives from the U.S. Consumer 
Product Safety Commission, U.S. Department of Defense, U.S. 
Environmental Protection Agency (U.S. EPA), U.S. Food and Drug 
Administration's National Center for Toxicological Research, National 
Center for Environmental Health/Agency for Toxic Substances and Disease 
Registry, National Institutes of Health's (NIH) National Cancer 
Institute, 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, 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 
October 19, 2004. 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.
    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; e-mail: [email protected].

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 pharmacokinetics, 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, 
Federal agencies represented on the ICCEC, the NTP Board of Scientific 
Counselors--an external scientific advisory body, the NTP Executive 
Committee--the NTP Federal interagency policy body, and

[[Page 51692]]

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 its 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 its 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: August 10, 2004.
Samuel Wilson,
Deputy Director, National Institute of Environmental Health Sciences.

Substances Nominated to the NTP for Toxicological Studies and 
Recommendations Made by the NTP Interagency Committee for Chemical 
Evaluation and Coordination on June 24, 2004

                                  Table 1.--Substances Recommended for Study *
----------------------------------------------------------------------------------------------------------------
                                                                                       Recommendations for
    Substance [CAS number]        Nominated by         Nomination rationale           toxicological studies
----------------------------------------------------------------------------------------------------------------
Bitter orange extract [No CAS  Private            Consumer exposure through      Toxicological studies:
 No.].                          Individual.        increasing dietary            --Developmental toxicity
                                                   supplement use; suspicion of  --Physiological responses
                                                   toxicity; lack of adequate     (e.g., cardiovascular and
                                                   toxicity data.                 cerebrovascular)
                                                                                 --Subchronic toxicity
                                                                                 --Toxicokinetics (of
                                                                                  constituents)
                                                                                 --Studies alone and in
                                                                                  combination with caffeine
                                                                                 --Studies in rats and possibly
                                                                                  miniature pigs.
n-Buityl glycidyl ether [2426- National           Suspicion of toxicity based    Toxicological studies:
 08-6].                         Institute of       on structural features;       --Toxicological
                                Environmental      positive results in genetic    characterization including
                                Health Sciences.   toxicity studies;              reproductive toxicity,
                                                   substantial potential for      carcinogenicity, and analysis
                                                   human exposure and a lack of   of urinary metabolites
                                                   chronic toxicity data.        --Coordinate with voluntary
                                                                                  data development activities of
                                                                                  the U.S. EPA.
Di-(2-ethylhexyl)phthalate     U.S. Food and      Long-term risks associated     Toxicological studies: Tiered
 (DEHP) [118-71-7].             Drug               with medical exposures of      research programs to address:
                                Administration.    infants have not been         --Quantitative studies of
                                                   clearly elucidated;            toxicokinetics and
                                                   significant knowledge gaps     biotransformation following
                                                   on the toxicokinetics and      intravenous exposure in
                                                   effects in fetal and           neonatal male non-human
                                                   neonatal primates of           primates
                                                   intravenous exposure;         --Assessment of toxicokinetics,
                                                   further studies will better    reproductive and immune
                                                   define risks and benefits of   endpoints following acute and
                                                   utilizing non-DEHP-            subchronic intravenous
                                                   containing products.           exposure to neonatal male rats
                                                                                  and nonhuman primates.
Ionic liquids 1-Butyl-3-       University of      Widespread interest as         Toxicological studies:
 methylimida zo lium chloride   Alabama Center     replacements for volatile     --Toxicological
 [79917-90-1] 1-Butyl-1-        for Green          organic compounds (VOCs) in    characterization
 methylpyrrolidinium chloride   Manufacturing.     various applications; lack    --Coordinate research program
 [479500-35-1] N-                                  of toxicity data.              with the U.S. EPA.
 Butylpyridinium chloride
 [1124-64-7].
Perfluorinated compounds       U.S.               Presumed widespread human      Toxicological studies:
 class study [Mutliple CAS      Environmental      exposure; known toxicity of   --Tiered research program to
 Nos.].                         Protection         certain class members;         include pharmacokinetics,
                                Agency.            insufficient information to    mechanistic, reproductive
                                                   assess hazard/risk across      toxicity, and carcinogenicity
                                                   entire structural class.       studies (for specific
                                                                                  compounds, see supporting
                                                                                  document available at http://ntp-server.niehs.nih.gov/NomPage/noms.html)
Stachybotrys chartarum [67892- Private            Public concern regarding       Toxicological studies:
 26-2].                         Individual.        potential non-infectious      --Toxicological
                               National            adverse health effects of      characterization including
                                Institute of       fungal exposures in indoor     immunotoxicity.
                                Environmental      environments; inadequate
                                Health Sciences.   toxicological data available
                                                   evaluating potential
                                                   systemic toxicity from long-
                                                   term exposure to this
                                                   organism under relevant
                                                   exposure scenarios.
Tungsten trioxide [1314-35-8]  National Cancer    Important industrial raw       Toxicological studies:
 and fibrous tungsten           Institute.         materials; one of several     --Toxicoligical
 suboxides.                                        metals that may form toxic     characterization
                                                   fibrous ``whiskers'';         --Genotoxicity
                                                   carcinogenic potential of     --Characterize fiber stability
                                                   tungsten (vs. cemented         and biopersistence
                                                   tungsten carbide) is not      --In vitro toxicity to lung
                                                   adequately characterized.      cells
                                                                                 --Comparative intratracheal
                                                                                  toxicity studies with a known
                                                                                  hazardous fiber

[[Page 51693]]

 
                                                                                 --Further studies including
                                                                                  carcinogenicity will be
                                                                                  considered following
                                                                                  completion of above.
----------------------------------------------------------------------------------------------------------------


    * Note: A recommendation for ``toxicological characterization'' 
in this table includes studies for genotoxicity, subchronic 
toxicity, and chronic toxicity/carcinogenicity, as determined to be 
appropriate during the conceptualization and design of a research 
program to address toxicological data needs. Though other types of 
studies (e.g., metabolism, pharmacokinetics, immunotoxicity, 
reproductive/developmental toxicity) may be conducted as part of a 
complete toxicological characterization, these types of studies are 
not listed unless they were specifically recommended.


                   Table 2.--Substance for Which Specific Study Recommendations Were Deferred
----------------------------------------------------------------------------------------------------------------
                                                                                                Rationale for
    Substance [CAS number]         Nominated by      Nominated for    Nomination rationale    deferral/further
                                                                                             information needed
----------------------------------------------------------------------------------------------------------------
Butylparaben [94-26-8]........  National           --Toxicological    Widespread use in     Further review of
                                 Institute of       characterization   foods, cosmetics,     data on estrogen
                                 Environmental      including          and                   receptor binding,
                                 Health Sciences.   reproductive       pharmaceuticals;      pharmacokinetics,
                                                    toxicity studies.  potential             dose-response of
                                                                       reproductive          male reproductive
                                                                       toxicant; lack of     effects, and human
                                                                       adequate toxicity     exposure.
                                                                       data.
Decane [124-18-5].............  National Cancer    --Carcinogenicity  Widespread            Review of industry
                                 Institute.         studies.           industrial use and    voluntary data
                                                                       environmental         development
                                                                       occurrence as air     activities
                                                                       pollutant;            coordinated by the
                                                                       suspicion of          U.S. EPA.
                                                                       carcinogenicity but
                                                                       no adequate
                                                                       carcinogenicity
                                                                       study available.
Undecane [1120-21-4]..........  National Cancer    --Carcinogenicity  Widespread            Review of industry
                                 Institute.         studies.           industrial use and    voluntary data
                                                                       environmental         development
                                                                       occurrence as air     activities
                                                                       pollutant;            coordinated by the
                                                                       suspicion of          U.S. EPA.
                                                                       carcinogenicity but
                                                                       no adequate
                                                                       carcinogenicity
                                                                       study available.
----------------------------------------------------------------------------------------------------------------

[FR Doc. 04-19136 Filed 8-19-04; 8:45 am]
BILLING CODE 4140-01-P