[Federal Register Volume 79, Number 92 (Tuesday, May 13, 2014)]
[Notices]
[Pages 27323-27324]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-10892]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Request for Information: The National Toxicology Program 
Interagency Center for the Evaluation of Alternative Toxicological 
Methods Requests the Nomination of Reference Chemicals

SUMMARY: The National Toxicology Program (NTP) Interagency Center for 
the Evaluation of Alternative Toxicological Methods (NICEATM) requests 
the nomination of reference chemicals, with supporting data, to be used 
to validate in vitro metabolizing systems with the potential to 
interact with estrogen receptors (ERs) or androgen receptors (ARs). 
Specifically, a list of chemicals is needed to characterize the 
usefulness and limitations of in vitro metabolizing systems for use in 
conjunction with ER and AR transactivation tests.

DATES: The deadline for receipt of information is June 2, 2014.

ADDRESSES: Nominated reference chemicals and associated data should be 
submitted electronically in Microsoft[supreg] Excel or Word formats to 
[email protected]. A Microsoft[supreg] Excel template for data 
submission is available at http://ntp.niehs.nih.gov/go/41493.

FOR FURTHER INFORMATION CONTACT: Dr. Warren S. Casey, Director, 
NICEATM; email: [email protected]; telephone: (919) 316-4729.

SUPPLEMENTARY INFORMATION:

Background

    Endocrine-active substances (EAS) are chemicals that interfere with 
normal endocrine hormone function by mimicking, blocking, or increasing 
their actions, thereby possibly causing adverse health effects. United 
States legislation (e.g., 7 U.S.C. 136, 110 Stat 1613) requires that 
chemicals be tested for their ability to disrupt the hormonal systems 
of mammals; prospective international legislative proposals may have 
similar requirements. Chemicals found to test positive in vitro as EAS 
may be in vivo endocrine disruptors. The lack of in vitro tools that 
mimic in vivo metabolism is the main obstacle to implementation of in 
vitro tools for EAS toxicity testing. Improved understanding of 
metabolic capabilities and limitations of in vitro toxicity testing is 
critical to:

 Ensure that no potentially active metabolites are missed
 Allow better interpretation of results
 Accurately predict species-specific characteristics of 
absorption, metabolism, and excretion

    While there is a growing body of international in vitro test 
guidelines addressing EAS mechanisms and modes of action, there are few 
or no standardized methods to incorporate metabolic and toxicokinetic 
aspects into these EAS in vitro tests to date. In vitro assays for EAS 
should incorporate metabolic enzyme systems to better address the 
relevance of EAS tests to in vivo adverse outcome pathways.
    The Organization for Economic Co-operation and Development (OECD) 
Validation Management Group-Non-Animal (VMG-NA) expert working group 
develops internationally accepted non-animal test guidelines to support 
various international regulatory needs for the hazard identification of 
potential EAS. These test guidelines describe methods and approaches 
capable of identifying potential EAS without the use of animals. 
Consistent with its purpose of evaluating alternative methods for 
testing chemicals and chemical products, NICEATM participates in the 
VMG-NA.
    Test guidelines for in vitro assays for ER activity have been 
evaluated and accepted by international regulatory authorities; test 
guidelines for in vitro AR activity assays are currently in 
development. However, none of these in vitro EAS assays account for 
whole animal metabolism. Further development of specific tests is 
needed to optimize the use of in vitro metabolism with EAS assays. 
Identification of appropriate reference chemicals to check the 
metabolic capacity of any proposed test method is key to continued 
assay development. For this purpose, the VMG-NA is developing a robust 
list of chemicals that, when metabolized, act as ER or AR agonist or 
antagonists.

Request for Information

    On behalf of the VMG-NA, NICEATM requests nominations of chemicals 
that can be used to characterize and validate in vitro metabolizing 
systems for use in conjunction with in vitro tests for ER and AR 
transactivation. Responses are requested from all interested parties, 
including the research community, health professionals, educators, 
policy makers, industry, and the public. Considerations for selection 
of appropriate chemicals include the ability of a chemical to act as an 
ER or AR agonist or antagonist and:

 Potential for metabolism to make a chemical either more potent 
(bioactivation) or less potent (detoxification)
 Likelihood of metabolism occurring in relevant routes of 
exposure and target organs
 Likelihood of metabolism occurring over a range of doses: 
Information on the ratio of the half maximal effective or inhibitory 
concentration (EC50 or IC50, respectively) of parent to daughter 
metabolites will be useful and there is a particular need for 
information pertaining to substances where biotransformation yields a 
very small or very large ratio of EC50/IC50 of parent to daughter 
metabolites
 Stability, preferably with real-time curves and consequent 
exposure significance of likely metabolites
 Diversity of likely and predominant biotransformative pathways
 Diversity of chemical types, use classes, and consequent 
applicability domains

    The reference chemicals will be used to check the metabolic 
capacity of the in vitro model, including characterization of the 
general metabolic capacity of the cell lines. To ensure relevant use in 
a regulatory context, it will be necessary, where possible, to make 
correlations to:
    (a) Relevant in vivo metabolic modeling (accounting for absorption, 
distribution, metabolism, and excretion, etc.) of plasma/blood 
metabolites in vertebrate animals (e.g., rat, fish, human).
    (b) Data from the uterotrophic, Hershberger, and/or other relevant 
assays with a demonstrated high confidence in prediction of 
bioactivation of estrogenic or androgenic agonist and antagonist 
pathways, such that the true systemic in vivo metabolic response is 
addressed as accurately as possible.
    When reporting the in vitro dose response for potential reference 
chemicals, the concentrations of solvent and/or carrier proteins used 
in the assay buffers to solubilize the reference chemicals should be 
described to facilitate an understanding of potential differences among 
new in vitro assays with regard to free concentrations of parent 
chemical and metabolites versus nominal dosages within each testing 
system.
    Nominated reference chemicals and associated data should be 
submitted electronically in Microsoft[supreg] Excel or Word formats to 
[email protected]. Data submitted can include, but need

[[Page 27324]]

not be limited to, citations of reports in the published literature, 
data from past or ongoing validation studies, data in databases, or 
unpublished data. A template for data submission is available at http://ntp.niehs.nih.gov/go/41493.
    Responses to this request are voluntary. NICEATM does not intend to 
publish a summary of responses received or any other information 
provided. No proprietary, classified, confidential, or sensitive 
information should be included in your response. Please note that the 
U.S. Government will not pay for the preparation of any information 
submitted or for its use of that information.
    Those submitting information should include name, affiliation, 
mailing address, phone, fax, email address, and sponsoring organization 
(if any) with the submission. The deadline for receipt of the requested 
information is June 2, 2014.

Background Information on NICEATM

    NICEATM conducts data analyses, workshops, independent validation 
studies, and other activities to assess new, revised, and alternative 
test methods and strategies and provides support for the Interagency 
Coordinating Committee on the Validation of Alternative Methods 
(ICCVAM). The ICCVAM Authorization Act of 2000 (42 U.S.C. 285l-3) 
provides authority for ICCVAM and NICEATM to conduct activities 
relevant to the development of alternative test methods. Information 
about NICEATM and ICCVAM is found at http://ntp.niehs.nih.gov/go/niceatm and http://ntp.niehs.nih.gov/go/iccvam.

    Dated: May 7, 2014.
John R. Bucher,
Associate Director, National Toxicology Program.
[FR Doc. 2014-10892 Filed 5-12-14; 8:45 am]
BILLING CODE 4140-01-P