[Federal Register Volume 64, Number 129 (Wednesday, July 7, 1999)]
[Notices]
[Pages 36704-36707]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-17119]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service


National Institute of Environmental Health Sciences; National 
Toxicology Program; Request for Comments on Chemicals Nominated to the 
National Toxicology Program (NTP) for Toxicological Studies--
Recommendations by the Interagency Committee for Chemical Evaluation 
and Coordination (ICCEC) for Study, No Studies, or Deferral To Obtain 
Additional Information

Summary

    The National Toxicology Program (NTP) routinely solicits, accepts 
and reviews for consideration nominations from Federal agencies, 
industry, the public, and other interested parties for toxicological 
studies to be undertaken by the Program. Nominations undergo several 
levels of review before toxicological studies are designed and 
implemented. The Interagency Committee for Chemical Evaluation and 
Coordination (ICCEC) serves as the first level of review for NTP 
nominations. At the June 1, 1999 meeting of the ICCEC, 13 nominations 
were reviewed. As part of an effort to earlier inform the public and 
obtain input into the selection of chemicals for evaluation, the NTP 
routinely seeks public input on (1) chemicals nominated to the Program 
for toxicological studies, and (2) testing recommendations made by the 
ICCEC. This announcement outlines the process for nomination and 
selection of agents for NTP study, presents the recommendations of the 
ICCEC from the June 1, 1999 meeting, and requests comment on these 
recommendations or the submission of additional information to be 
considered in the evaluation of these nominations.

Background

    The nomination and selection for study of chemicals and agents with 
the highest potential for adversely impacting public health are 
essential to the success of the NTP. From its inception, the NTP has 
had an open nomination process. Nominations are solicited from a 
variety of sources in academia, Federal and State regulatory and health 
agencies, industry, and unions, as well as from environmental groups 
and the general public. Particular assistance is sought with the 
selection of studies that permit testing of hypotheses to enhance the 
predictive ability of NTP studies, address mechanisms of toxicity, or 
identify significant gaps in knowledge of the toxicity of chemicals or 
classes of chemicals. Chemicals are selected for study based upon two 
broad criteria: (1) those chemicals of greatest concern for public or 
occupational health and (2) chemicals for which toxicological data is 
needed to fill major knowledge gaps, address mechanisms of toxicity, 
and reduce uncertainty in risk assessment by aiding species-to-species 
extrapolation and understanding dose-response relationships. Chemicals 
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. 
The possible public health consequences of exposure remain the over-
riding factor in the decision to study a particular chemical or agent. 
Selections for government testing are based on the principle that 
responsible industries will evaluate their own chemicals or agents for 
health and environmental effects as mandated by Congress under 
legislative authorities. Increased efforts continue to be focused on: 
(1) improving the quality of the nominations of chemicals,

[[Page 36705]]

environmental agents, or issues for study; (2) broadening the base and 
diversity of nominating organizations and individuals; and (3) 
increasing nominations for endpoints of toxicity other than 
carcinogenesis.
    Nominated chemicals are first reviewed by a multi-disciplinary 
NIEHS committee to determine whether the nominated agent has undergone 
adequate toxicological testing or has been previously considered by the 
NTP. For chemicals not eliminated from consideration or deferred at 
this stage, the available literature is examined in detail to prepare 
Toxicological Summaries which evaluate and summarize the relevant data 
for each chemical. Included in each Toxicological Summary are chemical 
and physical information, production levels, use and exposure 
categories and levels, regulatory status, toxicological effects, and 
rationale for the nomination. The Toxicological Summaries are 
distributed to the Interagency Committee for Chemical Evaluation and 
Coordination (ICCEC), 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, Occupational Safety and Health Administration, National 
Cancer Institute, National Institute of Environmental Health Sciences, 
National Institute for Occupational Safety and Health, and the National 
Library of Medicine. ICCEC members are assigned as reviewers for each 
chemical after consideration of the nature of its uses and exposure so 
that, to the extent possible, appropriate regulatory concerns will be 
addressed. Members are requested to identify their agency's interests, 
if any, in the chemical, and to search databases unique to their 
agencies for further information on the nominated chemicals and 
structurally related substances. During the evaluation process, the NTP 
works actively with regulatory agencies and interest groups to 
supplement the information about chemicals nominated and to ensure that 
the chemical selection process meets regulatory agency needs.
    At its meeting to consider the nominated chemicals, the ICCEC 
assigns testing priorities, and also may make recommendations for study 
in addition to those requested by the nominator. Summaries of the ICCEC 
recommendations and any public comments received on these chemicals are 
then presented to the NTP Board of Scientific Counselors (the Program's 
external scientific advisory committee) for review and comment in an 
open public session. The ICCEC recommendations, NTP Board of Scientific 
Counselors recommendations, and public comments are incorporated into 
recommendations that are then submitted to the NTP Executive Committee, 
the Federal interagency policy oversight body. For each chemical 
nominated for the various types of studies, the NTP Executive Committee 
reviews and approves action to move forward to test, defer testing, or 
remove from testing consideration, and recommends testing priorities. 
The selection of a chemical or agent by the Executive Committee does 
not automatically commit the NTP to its evaluation. The priority of the 
chemicals and the proposed studies are assessed during the nomination 
process and reassessed during the study design process. During any of 
these stages, a chemical or study may be withdrawn if applicable 
research data is identified, higher priority studies are identified, or 
if a study proves impractical. A broad range of regulatory and 
toxicological concerns are addressed during the nomination and 
selection process through the participation of representatives from 
Federal agencies concerned with public health issues. In addition, 
representatives from non-government organizations, including industry, 
labor, and public interest, sit on the NTP Board of Scientific 
Counselors, and thus have input into chemical selection decisions.
    Following Executive Committee action, each selected chemical is 
assigned to an NIEHS, FDA, or NIOSH staff scientist (project leader) 
who assesses the data compiled during the chemical evaluation process 
and other information obtained from detailed searches of the published 
literature and public comments. The project leader also consults with 
industrial or commercial sources on such issues as mode of production, 
uses, worker exposure, planned or ongoing testing, and availability of 
the chemical for study. The project leader together with a study design 
team develops a study plan to address the research needs. The study 
plan is reviewed and modified as necessary before being carried out via 
the most appropriate mechanisms. Results of toxicological studies of 
selected chemicals are routinely peer-reviewed. The results are 
published as NTP Technical Reports and/or in the open scientific 
literature. Test results are also available from the NTP subsequent to 
peer-review but prior to publication.

Request for Comment

    At their meeting on June 1, 1999, the ICCEC reviewed 13 agents 
nominated for NTP study. For 9 of these agents, metabolism, toxicity, 
or carcinogenicity studies were recommended, no additional study was 
recommended for 2 chemicals, and studies of 2 other chemicals were 
deferred pending receipt of additional data from other organizations or 
from related studies anticipated or in progress by the NTP, or 
information on production, exposure, and use patterns. Additionally, 
the ICCEC reviewed 7 chemicals recommended for study in previous ICCEC 
meetings. Following review of initial NTP studies and additional data 
received from the public or elsewhere, these 7 chemicals were withdrawn 
as priority candidates for study.
    Chemicals with CAS numbers, nomination source, types of studies 
under consideration, and rationale and other information are given in 
the attached tables. Interested parties are encouraged to provide 
comments or supplementary information on the chemicals and 
recommendations that appear in this announcement. The Program 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, or 
environmental occurrence for any of the chemicals listed in this 
announcement. To provide comments or information, please contact Dr. 
William Eastin at the address given below by September 7, 1999.
    Contact may be made by mail to: Dr. William Eastin, NIEHS/NTP, P. 
O. Box 12233, Research Triangle Park, North Carolina 27709; by 
telephone at (919) 541-7941; by FAX at (919) 541-3687; or by email at 
[email protected]. The URL for the NTP homepage is http://ntp-
server.niehs.nih.gov.

    Dated: June 24, 1999.
Samuel H. Wilson,
Deputy Director, NIEHS.

[[Page 36706]]

Attachment--Chemicals Nominated to the NTP for Study, and Testing 
Recommendations made by the ICCEC on June 1, 1999

------------------------------------------------------------------------
                                                        Study rationale;
  Chemical [CAS       Nominated by          ICCEC             other
     Number]                           recommendations     information
------------------------------------------------------------------------
                    Chemicals Recommended for Testing
------------------------------------------------------------------------
Aloe vera gel      NCI                --Cell            --Widespread use
[8001-97-6]                            transformation    as a dietary
[94349-62-9]                           assay             supplement and
                                      --Phototoxicity    cosmetic.
                                      --Tumor           --Inadequate
                                       promotion in      toxicity
                                       Tg.AC mice        information.
Ammonium           NCI                --In vitro        --Representative
 molybdate                             chromosome        soluble
[12027-67-7]                           aberration        molybdenum
[12054-85-2]                           assay             compound.
[13106-76-8]                          --In vitro        --Potential for
                                       micronucleus      worker and
                                       assay             general
                                      --Subchronic       population
                                       toxicity          exposure.
                                       (inhalation      --Inadequate
                                       studies)          toxicity
                                                         information.
5,6-Benzoflavone   NCI                --Toxicological   --Potential use
[6051-87-2]                            characterizatio   as
                                       n                 chemopreventive
                                      --Reproductive     agent.
                                       toxicity         --Lack of
                                      --Carcinogenicit   industry
                                       y                 sponsorship.
                                                        --Testing
                                                         dependent on
                                                         confirmation
                                                         from nominator
                                                         that
                                                         recommended
                                                         studies are
                                                         needed for
                                                         further
                                                         development as
                                                         therapeutic
                                                         agent.
1,3-Dichloro-2-    NIEHS              --Toxicological   --High
 butene                                characterizatio   production
[926-57-8]                             n                 industrial
                                      --Metabolism       chemical with
                                       studies           potential for
                                      --Carcinogenicit   worker
                                       y (inhalation     exposure.
                                       studies)         --Structural
                                                         similarity to
                                                         known
                                                         carcinogen.
                                                        --Inadequate
                                                         toxicity
                                                         information.
Ginseng and        NCI                --Genotoxicity    --Widespread use
 ginsenosides                         --Reproductive     as a dietary
[50647-08-0]                           toxicity          supplement.
                                      --Neurotoxicity   --Inadequate
                                      --Carcinogenicit   toxicity
                                       y                 information.
                                                        --Subchronic
                                                         testing will
                                                         determine if
                                                         ginseng or a
                                                         specific
                                                         ginsenoside
                                                         will be subject
                                                         to
                                                         carcinogenicity
                                                         testing.
Indole-3-carbinol  NCI                --Reproductive    --Widespread and
[700-06-1]                             toxicity          rapidly
                                      --Toxicological    increasing use
                                       characterizatio   as a dietary
                                       n                 supplement.
                                      --Carcinogenicit  --Potential use
                                       y                 as
                                                         chemopreventive
                                                         agent.
Kava kava extract  NCI                --Genotoxicity    --Widespread use
[9000-38-8]                           --Reproductive     as a dietary
[84696-40-2]                           toxicity          supplement.
                                      --Neurotoxicity   --Reported human
                                      --Subchronic       toxicity.
                                       toxicity         --Inadequate
                                      --Carcinogenicit   toxicity
                                       y                 information.
Milk thistle       NCI                --Genotoxicity    --Widespread use
 extract                              --Metabolism       as a dietary
[84604-20-6]                           studies           supplement.
                                      --Reproductive    --Reported
                                       toxicity          hepatoprotectiv
                                      --Subchronic       e and anti-
                                       toxicity          carcinogenic
                                                         action.
                                                        --Inadequate
                                                         toxicity
                                                         information.
3-Picoline         NIEHS              --Subchronic      --High
[108-99-6]                             toxicity          production
                                      --Carcinogenicit   industrial
                                       y (pending        chemical with
                                       results of        potential for
                                       subchronic        worker and
                                       studies)          general
                                                         population
                                                         exposure.
                                                        --Inadequate
                                                         toxicity
                                                         information.
------------------------------------------------------------------------
              Chemicals for Which No Testing is Recommended
------------------------------------------------------------------------
1-Bromo-3-         NIEHS              --Toxicological   --Available data
 chloropropane                         characterizatio   indicate low
[109-70-6]                             n                 toxicity.
                                      --Carcinogenicit  --Low potential
                                       y                 for human
                                                         exposure.
N,N-               NCI                --Subchronic      --Available data
 Diethylhydroxyla                      toxicity          indicate low
 mine                                                    toxicity.
[3710-84-7]                                             --Low potential
                                                         for human
                                                         exposure.
------------------------------------------------------------------------
              Chemicals Deferred for Additional Information
------------------------------------------------------------------------
1,3,5-Triazine-    NCI                --Carcinogenicit  --Reconsider as
 1,3,5                                 y                 part of class
(2H,4H,6H)-                                              study of
 triethanol                                              formaldehyde-
[4719-04-4]                                              releasing
                                                         compound.

[[Page 36707]]

 
s-Trioxane         NIEHS              --Toxicological   --Reconsider as
[110-88-3]                             characterizatio   part of class
                                       n                 study of
                                      --Carcinogenicit   formaldehyde-
                                       y                 releasing
                                                         compounds.
------------------------------------------------------------------------
              Chemicals to be Withdrawn from Consideration
------------------------------------------------------------------------
Arsenic Trioxide   NIEHS; Private     --Mechanistic     --Lack of an
[1327-53-3]         Individual         studies           appropriate
                                      --Carcinogenicit   animal model
                                       y                 for human
                                                         carcinogenicity
                                                         .
2,3-Butanedione    NCI                --Genotoxicity    --Rapid and near
[431-03-8]                            --Metabolism       complete
                                       studies           metabolism to
                                      --Carcinogenicit   carbon dioxide.
                                       y
t-Butylcatechol    NCI/FDA            --Toxicological   --Toxicity in
[98-29-3]                              characterizatio   subchronic
                                       n                 studies at
                                      --Metabolism       doses as high
                                       studies           as 12,500 ppm
                                      --Carcinogenicit   in the diet was
                                       y                 limited to
                                                         forestomach
                                                         lesions.
Camphor            NCI                --Teratogenicity  --Teratogenicity
[464-49-3]                            --Reproductive     studies
[76-22-2]                              toxicity          completed
                                      --Carcinogenicit  --Toxicity in
                                       y                 subchronic
                                                         dermal studies
                                                         limited to
                                                         hyperplasia at
                                                         the site of
                                                         application.
Fluasterone        NCI                --Toxicological   --Difficulty in
[112859-71-9]                          characterizatio   obtaining
                                       n                 sufficient
                                      --Carcinogenicit   material for
                                       y                 study.
                                                        --Industry
                                                         sponsor has
                                                         responsibility
                                                         for
                                                         toxicological
                                                         evaluation of
                                                         this chemical
                                                         if pursued as a
                                                         chemotherapeuti
                                                         c agent.
Luminol            Private            --Toxicological   --Lack of
[521-31-3]          Individual         characterizatio   absorption from
                                       n                 skin.
                                      --Carcinogenicit  --Rapid
                                       y                 metabolism and
                                                         elimination of
                                                         oral doses as
                                                         nontoxic
                                                         metabolites.
Propylene Glycol   NCI                --Carcinogenicit  --Availability
 Monomethyl Ether                      y                 of industry-
[107-98-2]                                               sponsored
                                                         reproductive
                                                         toxicity and
                                                         carcinogenicity
                                                         studies.
------------------------------------------------------------------------


[FR Doc. 99-17119 Filed 7-6-99; 8:45 am]
BILLING CODE 4140-01-P