[Federal Register Volume 65, Number 233 (Monday, December 4, 2000)]
[Notices]
[Pages 75727-75730]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-30715]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service


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

Summary

    The National Toxicology Program (NTP) routinely solicits, accepts 
and reviews for consideration nominations for toxicological studies to 
be undertaken by the Program on substances of potential human health 
concern. Nominations are solicited widely from Federal agencies, the 
public, and other interested parties and those received undergo several 
levels of review before toxicological studies are designed and 
implemented. The NTP Interagency Committee for Chemical Evaluation and 
Coordination (ICCEC) serves as the first level of review for NTP 
nominations. At the October 27, 2000 ICCEC meeting, 18 new nominations 
were reviewed and testing recommendations were made. As part of an 
effort to inform the public and to obtain input for consideration when 
selecting chemicals for evaluation, the NTP routinely seeks public 
comment on (1) substances nominated to the Program for toxicological 
studies and (2) the testing recommendations made by the ICCEC. This 
announcement provides brief background information about the nomination 
of substances for NTP study; presents the ICCEC's testing 
recommendations from the October 27, 2000 meeting; solicits public 
comment on those nominations and recommendations; and requests the 
submission of additional relevant information for consideration by the 
NTP in its subsequent evaluation of the nominations.

Background

    The NTP actively seeks to identify and select for study chemicals 
and agents with the highest potential for

[[Page 75728]]

adversely impacting public health. The nomination process is open to 
all interested parties and substances selected for study generally fall 
into two broad overlapping categories: (1) Those substances of greatest 
concern for public or occupational health based on the extent of human 
exposure and suspicion of toxicity; and (2) substances for which 
toxicological data gaps exist and additional studies would aid in 
assessing potential human health risks by facilitating cross-species 
extrapolation and evaluation of dose-response relationships. Particular 
assistance is also sought for 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 chemicals or classes of chemicals. 
Substances may be studied for a variety of health-related effects, 
including but not limited to reproductive and developmental toxicity, 
genotoxicity, immunotoxicity, metabolism and disposition, as well as 
carcinogenicity. Selections for NTP testing also consider legislative 
mandates that require responsible manufacturers to evaluate their own 
chemicals or agents for health and environmental effects. The possible 
human health consequences of anticipated or known human exposure, 
however, remain the over-riding factor in the decision to study a 
particular chemical or agent.
    The review and selection of substances nominated for study is a 
multi-level process. A broad range of concerns are addressed during 
this process through the participation of representatives from Federal 
agencies, the NTP Board of Scientific Counselors--an external 
scientific advisory body, the NTP Executive Committee--the NTP Federal 
interagency policy body, and a public comment period. This process is 
described in further detail in a March 2, 2000 Federal Register 
Announcement (Volume 65, Number 42, pages 11329-11331). As a result of 
this multi-step evaluative process for NTP nominations, the Program 
receives appropriate 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, etc.). As such, it must be recognized 
that for any given committee review, the substances being considered 
for new testing do not necessarily reflect the overall balance of 
substances historically or currently being evaluated by NTP in it's 
testing program. For further information on NTP studies (previous or in 
progress) visit the NTP web page at the URL listed at the end of this 
announcement.

Nominated Substances and ICCEC Review

    The NTP Interagency Committee for Chemical Evaluation and 
Coordination (ICCEC) is composed of representatives from the Agency for 
Toxic Substances and Disease Registry, Consumer Product Safety 
Commission, Department of Defense, Environmental Protection Agency, 
Food and Drug Administration's National Center for Toxicological 
Research, National Cancer Institute, National Institute of 
Environmental Health Sciences, National Institute for Occupational 
Safety and Health, National Library of Medicine, and the Occupational 
Safety and Health Administration. As part of the review and selection 
process for nominations, the ICCEC meets once or twice annually to 
review and evaluate the nominations and to make testing recommendations 
with respect to both specific types of studies and testing priorities. 
At its meeting on October 27, 2000, the ICCEC reviewed 18 new 
nominations for NTP studies. For 15 of these nominations, 
pharmacokinetic, toxicity, and/or carcinogenicity studies were 
recommended. A testing recommendation for three nominations was 
deferred pending receipt of (1) additional information or data from the 
nominator or other organizations on related studies completed, 
anticipated or in progress, or (2) additional information on 
production, exposure, use patterns, and regulatory needs. The nominated 
substances with CAS numbers, nomination source, types of studies 
recommended, study rationale and other information are given in the 
attached tables.

Request for Comment

    Interested parties are encouraged to provide comments or 
supplementary information on the nominated substances and 
recommendations identified in this announcement. The NTP would welcome 
receiving toxicology and carcinogenesis information from completed, 
ongoing, or planned studies, as well as information on current 
production levels, human exposure, use patterns, environmental 
occurrence, or public health concerns for any of the substances listed 
in the attached tables. Comments or information should be sent to Dr. 
Scott Masten at the address given below within 60 days of the 
publication date of this announcement. Persons responding to this 
request are asked to include their name, affiliation, mailing address, 
phone, fax, e-mail address and sponsoring organization (if any) with 
the submission. An electronic copy of this announcement as well as 
further information on the NTP and the NTP Chemical Nomination and 
Selection Process can be accessed through the NTP web site. The URL for 
the NTP homepage is http://ntp-server.niehs.nih.gov.
    Contact may be made by mail to Dr. Scott Masten, NIEHS/NTP, P. O. 
Box 12233, Research Triangle Park, North Carolina 27709; by telephone 
at (919) 541-5710; by FAX at (919) 558-7067; or by email to 
[email protected].

    Dated: November 20, 2000.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences.

Attachment--Substances Nominated to the NTP for Study and Testing 
Recommendations Made by the ICCEC on October 27, 2000

                                  Table 1.--Substances Recommended for Testing
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                                                                                       Study rationale; other
     Substance [CAS Number]          Nominated by         ICCEC recommendations              information
----------------------------------------------------------------------------------------------------------------
Aluminum complexes found in       Environmental       Long-term drinking water      Drinking water contaminants
 drinking water, Aluminum          Protection          studies to address            with a high health research
 fluoride, [7784-18-1], Aluminum   Agency; National    pharmacokinetics,             priority; known
 citrate, [31142-56-0].            Institute of        neurotoxicity, bone           neurotoxicity of aluminum;
                                   Environmental       development, and              need for better
                                   Health Sciences.    reproduction and              understanding of
                                                       developmental toxicity.       pharmacokinetics and
                                                                                     toxicity of aluminum
                                                                                     species occurring in
                                                                                     drinking water.
                                                      --Consider testing in
                                                       transgenic animal models of
                                                       neurodegenerative disease.

[[Page 75729]]

 
Bilberry fruit extract, [84082-   National Cancer     --In vitro and in vivo        Widespread human exposure
 34-8].                            Institute.          genotoxicity testing.         through use as a dietary
                                                                                     supplement; lack of
                                                                                     toxicity information.
Black cohosh, [84776-26-1]......  National Cancer     --Subchronic toxicity         Widespread human exposure
                                   Institute;          testing in young and aged     through use as a dietary
                                   National            female animals.               supplement; reported
                                   Institute of                                      estrogenic activity;
                                   Environmental                                     inadequate toxicity
                                   Health Sciences.                                  information.
                                                      --Two-generation
                                                       reproductive and
                                                       developmental toxicity
                                                       study.
Blue-Green algae (dietary         National Cancer     --Subchronic toxicity and     Widespread human exposure
 supplements and selected          Institute.          neurotoxicity studies of      through drinking water and
 toxins).                                              commercial blue-green algae   via contamination of algal
                                                       dietary supplements.          dietary supplements;
                                                                                     demonstrated acute toxicity
                                                                                     but only limited chronic
                                                                                     toxicity information
                                                                                     available.
                                                      --Consider testing specific
                                                       cyanobacterial toxins
                                                       pending results of Blue-
                                                       Green algae dietary
                                                       supplement and microcystin-
                                                       LR studies.
Cefuroxime, [55268-75-2]........  Food and Drug       --Genotoxicity testing        Prescription drug with
                                   Administration.     (Syrian hamster embryo in     widespread and potentially
                                                       vitro cell transformation     long-term use; lack of
                                                       assay; in vivo micronucleus   chronic toxicity data for
                                                       assay).                       any member of this class of
                                                                                     drugs.
Clarithromycin, [81103-11-9]....  Food and Drug       --Genotoxicity testing        Prescription drug with
                                   Administration.     (Syrian hamster embryo in     widespread and potentially
                                                       vitro cell transformation     long-term use; numerous
                                                       assay; in vivo micronucleus   known toxicities in short-
                                                       assay).                       term studies; lack of
                                                                                     chronic toxicity data.
D&C Red No. 27, [13473-26-2] and  Food and Drug       --In vitro percutaneous       Approved colorings for drugs
 D&C Red No. 28, [18472-87-2].     Administration.     absorption testing.           and cosmetics that can lead
                                                                                     to DNA damage; lack of
                                                                                     sufficient data on long-
                                                                                     term phototoxicity or
                                                                                     photocarcinogenicity.
                                                      --Photocarcinogenicity
                                                       testing dependent on
                                                       results of absorption
                                                       studies.
N,N-Dimethyl-p-toluidine, [99-97- National Cancer     --Subchronic toxicity         High production volume
 8].                               Institute.          testing pending review of     chemical with potential for
                                                       industry test plans and/or    widespread human exposure
                                                       data developed under EPA's    and limited chronic
                                                       High Production Volume        toxicity or carcinogenicity
                                                       Chemical Challenge Program.   data; genotoxic; suspicion
                                                                                     of carcinogenicity.
Lemon Oil, [8008-56-8] and Lime   Food and Drug       --Photogenotoxicity testing.  Widespread consumer exposure
 Oil, [8008-26-2].                 Administration.                                   as a fragrance component;
                                                                                     known phototoxicity; long-
                                                                                     term toxicity unknown.
                                                      --Photocarcinogenicity
                                                       testing dependent on
                                                       results of
                                                       phototogenotoxicity studies.
Local anesthetics that            Private             --Short-term in vitro/in      Widespread clinical use and
 metabolize to 2,6-xylidine or o-  Individual;         vivo mechanistic studies to   human exposure; potentially
 toluidine, Bupivacaine, [38396-   National            evaluate carcinogenic         metabolized to carcinogenic
 39-3], Prilocaine, [721-50-6].    Institute of        metabolite formation and      and neurotoxic
                                   Environmental       genotoxicity of               intermediates; little
                                   Health Sciences.    representative local          available quantitative
                                                       anesthetic compounds.         metabolism or genotoxicity
                                                                                     data.
Microcystin-LR, [101043-37-2]...  National Institute  --Toxicokinetic, subchronic,  Cyanobacteria and their
                                   of Environmental    reproductive toxicity,        toxins are drinking water
                                   Health Sciences.    chronic toxicity and          contaminants with a high
                                                       carcinogenicity studies       health research priority;
                                                       including doses relevant to   many have high acute
                                                       environmental                 toxicity and known
                                                       concentrations in drinking    hepatotoxicity and
                                                       water.                        hepatocarcinogenicity.
                                                      --Consider carcinogenicity
                                                       testing in Japanese Medaka
                                                       fish model.
Organotins occurring in drinking  Environmental       --Long-term single chemical   Drinking water contaminants
 water, Monomethyltin              Protection          and binary mixture drinking   with a high health research
 trichloride, [993-16-8],          Agency; National    water studies to address      priority; numerous
 Dimethyltin dichloride, [753-73-  Institute of        pharmacokinetics,             organotins have
 1], Monobutyltin trichloride,     Environmental       neurotoxicity,                demonstrated a broad
 [1118-46-3], Dibutyltin           Health Sciences.    immunotoxicity, and           spectrum of toxicity;
 dichloride, [683-18-1].                               reproductive and              chronic toxicity
                                                       developmental toxicity.       information on organotin
                                                                                     species primarily found in
                                                                                     drinking water is limited.
                                                      --Consider testing in
                                                       transgenic animal models of
                                                       neurodegenerative disease.
All-trans-retinyl palmitate, [79- Food and Drug       --Phototoxicity and           Widespread use in cosmetic
 81-2].                            Administration.     photocarcinogenicity          products; known biochemical
                                                       testing.                      and histological cutaneous
                                                                                     alterations; other
                                                                                     retinoids known to enhance
                                                                                     photocarcinogenesis.

[[Page 75730]]

 
S-Adenosylmethionine, [29908-03-  National Cancer     --In vitro genotoxicity       Widespread exogenous human
 0].                               Institute.          testing (Syrian hamster       exposure through use as a
                                                       embryo cell transformation    dietary supplement; limited
                                                       and DNA alkylation assays).   toxicity data available.
                                                      --Subchronic toxicity
                                                       testing dependent on
                                                       results of genotoxicity
                                                       studies.
Senna...........................  Food and Drug.....  --Carcinogenicity testing in  Data needed to complete
                                                       p53.                          safety
[8013-11-4].....................  Administration....  transgenic mouse model......  evaluation of stimulant
                                                                                     laxatives; transgenic
                                                                                     studies will complement
                                                                                     manufacturer sponsored
                                                                                     carcinogenicity studies.
----------------------------------------------------------------------------------------------------------------


    Table 2.--Substances for Which a Testing Recommendation is Deferred Pending Receipt and Consideration of
                                             Additional Information
----------------------------------------------------------------------------------------------------------------
                                                                                                 Additional
    Substance [CAS Number]        Nominated by      Nominated for    Nomination rationale    information needed
----------------------------------------------------------------------------------------------------------------
1,3-Dichloropropane, [142-28-   Environmental     --Short-term      Drinking water         Additional drinking
 9], 2,2-Dichloropropane, [594-  Protection        comprehensive     contaminants with      water occurrence
 20-7], 1,1-Dichloropropene,     Agency;           drinking water    high health research   data; production
 [563-58-6].                     National          toxicity          priority; very         volumes; potential
                                 Institute of      studies.          limited toxicity       sources of drinking
                                 Environmental                       data; known toxicity   water contamination;
                                 Health Sciences.                    and carcinogenicity    anticipated
                                                                     of structurally        regulatory value of
                                                                     similar compounds.     additional toxicity
                                                                                            data.
                                                  --Pharmacokineti
                                                   cs.
                                                  --Medaka studies
                                                  --Testing in
                                                   human bladder
                                                   cell
                                                   transformation
                                                   model.
Hydergine, [8067-24-1]........  National Cancer   --Genotoxicity    Ergot alkaloid         Dietary supplement
                                 Institute.        testing.          prescription drug      sales and use
                                                                     with recent increase   information;
                                                                     in ``off label'' and   regulatory agency
                                                                     dietary supplement     information needs.
                                                                     use in healthy
                                                                     individuals; lack of
                                                                     available
                                                                     information on
                                                                     toxicity and
                                                                     carcinogenicity.
Yohimbe bark extract, [85117-   National Cancer   --Micronucleus    Significant human      Dietary supplement
 22-2], Yohimbine, [146-48-5].   Institute.        assay.            exposure through use   use levels and
                                                                     as a dietary           patterns; regulatory
                                                                     supplement;            agency informaiton
                                                                     suspicion of           needs.
                                                                     carcinogenicity of
                                                                     yohimbine based on
                                                                     structural
                                                                     similarity to
                                                                     reserpine.
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[FR Doc. 00-30715 Filed 12-1-00; 8:45 am]
BILLING CODE 4140-00-M