[Federal Register Volume 75, Number 124 (Tuesday, June 29, 2010)]
[Notices]
[Pages 37443-37445]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-15777]
[[Page 37443]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Toxicology Program (NTP); NTP Interagency Center for the
Evaluation of Alternative Toxicological Methods (NICEATM); Availability
of Interagency Coordinating Committee on the Validation of Alternative
Methods Test Method Evaluation Reports on Two Nonradioactive Versions
of the Murine Local Lymph Node Assay for Assessing Allergic Contact
Dermatitis Hazard Potential of Chemicals and Products, and Expanded
Uses of the Local Lymph Node Assay for Pesticide Formulations and Other
Products; Notice of Transmittal to Federal Agencies
AGENCY: National Institute of Environmental Health Sciences (NIEHS),
National Institutes of Health (NIH), HHS.
ACTION: Availability of Reports; Notice of Transmittal.
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SUMMARY: NICEATM announces availability of Interagency Coordinating
Committee on the Validation of Alternative Methods (ICCVAM) Test Method
Evaluation Reports (TMERs) recommending two nonradioactive versions of
the Local Lymph Node Assay (LLNA) for assessing allergic contact
dermatitis (ACD) hazard potential of chemicals and products and
expanded uses of the LLNA for pesticide formulations and other
products. Related ICCVAM Test Method Recommendations in each report
have also been transmitted to Federal agencies for their review and
response to ICCVAM in accordance with the provisions of the ICCVAM
Authorization Act of 2000. The LLNA: 5-Bromo-2'-deoxyuridine-Enzyme-
Linked Immunosorbent Assay (BrdU-ELISA) and LLNA: Daicel Adenosine
Triphosphate (DA) do not use radioactive reagents and therefore provide
advantages in terms of reduced hazardous waste disposal and broader
availability for use by laboratories that cannot use radioactive
reagents. ICCVAM concludes that the accuracy and reliability of the
LLNA: BrdU-ELISA and LLNA: DA support use of these test methods to
identify substances as potential skin sensitizers or nonsensitizers.
Based on an updated evaluation, ICCVAM is also recommending expanded
use of the LLNA to evaluate the ACD hazard potential of pesticide
formulations and other products.
FOR FURTHER INFORMATION CONTACT: Dr. William S. Stokes, Director,
NICEATM, NIEHS, P.O. Box 12233, Mail Stop: K2-16, Research Triangle
Park, NC, 27709, (telephone) 919-541-2384, (fax) 919-541-0947, (e-mail)
[email protected]. Courier address: NICEATM, NIEHS, Room 2034, 530
Davis Drive, Morrisville, NC 27560.
SUPPLEMENTARY INFORMATION:
Background
ICCVAM previously evaluated the validation status of the LLNA as a
stand-alone alternative method to the guinea pig maximization test
(GPMT) and the Buehler test (BT) for assessing the ACD hazard potential
of products and chemicals (NIH Publication No. 99-4494; available at
http://iccvam.niehs.nih.gov/methods/immunotox/llna.htm). Based on this
evaluation, ICCVAM recommended the LLNA as a valid substitute for the
guinea pig test methods for most testing situations in 1999. The
Environmental Protection Agency, the Food and Drug Administration, and
the U.S. Consumer Product Safety Commission (CPSC) subsequently
accepted the method as a valid substitute for the GPMT and BT. The
Organization for Economic Co-operation and Development (OECD)
subsequently adopted the LLNA as OECD Test Guideline 429 in 2002. Using
the LLNA instead of guinea pig tests reduces and refines (less pain and
distress) animal use for ACD safety testing.
In 2007, the CPSC nominated several new versions and applications
of the LLNA to ICCVAM for evaluation of their scientific validity
(http://iccvam.niehs.nih.gov/methods/immunotox/llnadocs/CPSC_LLNA_nom.pdf). The nomination requested that ICCVAM assess (1) the
validation status of the LLNA limit dose procedure (i.e., the reduced
LLNA); (2) the modified LLNA test method protocols that do not require
the use of radioactive materials; (3) the use of the LLNA to test
mixtures, aqueous solutions, and metals; and (4) the use of the LLNA to
determine ACD potency categories for hazard classification. NICEATM
published a Federal Register notice (72 FR 27815) requesting public
comments on (1) the appropriateness and relative priority of the CPSC-
nominated LLNA activities, (2) the nomination of scientists to serve on
an international independent scientific peer review panel, and (3) the
submission of data from LLNA testing that related to the CPSC-nominated
LLNA activities as well as corresponding data from human and other
animal studies. ICCVAM assigned these activities a high priority after
considering comments from the public and endorsement from the
Scientific Advisory Committee on Alternative Toxicological Methods
(SACATM). NICEATM and ICCVAM compiled comprehensive draft background
review documents (BRDs), released them for public comment in January
2008 (73 FR 1360), and convened a public meeting of the panel on March
4-6, 2008 to peer review the draft documents. The panel evaluated the
information in the BRDs as to whether it supported draft ICCVAM test
method recommendations for test method uses and limitations, updated
standardized test method protocols, and proposed future studies. The
panel considered public comments made at the meeting, as well as public
comments submitted in advance of the meeting, before concluding their
deliberations. The panel's report was made available in May 2008 (73 FR
29136) for public comment. The draft ICCVAM BRDs, draft ICCVAM test
method recommendations, the panel's report, and all public comments
were made available to SACATM for comment at its meeting on June 18-19,
2008 (73 FR 25754).
After considering the conclusions and recommendations of the panel,
comments from SACATM, and public comments, ICCVAM forwarded final
recommendations for the updated LLNA test method protocol, the reduced
LLNA, and LLNA performance standards to Federal agencies in September
2009 (74 FR 50212). ICCVAM concluded that the updated LLNA test method
protocol will further reduce animal use by 20% compared to the original
version of the LLNA and also provide for more consistent and reliable
results. The reduced LLNA will reduce animal use by 40% for each test
compared to the traditional, multi-dose LLNA. ICCVAM also recommended
LLNA test method performance standards that can be used to efficiently
evaluate the validity of modified versions of the LLNA that are
mechanistically and functionally similar to the traditional LLNA.
Federal agencies subsequently responded with their support and
concurrence with the ICCVAM recommendations. Agency responses are
available on the NICEATM-ICCVAM Web site.
NICEATM subsequently obtained additional data and/or information
and revised the draft documents for both the traditional and
nonradioactive LLNA methods. ICCVAM released the revised draft
documents to the public for comment and announced a second meeting of
the panel (74 FR 8974). The panel reconvened in public session on April
28-29, 2009 to review the ICCVAM-revised draft documents and
[[Page 37444]]
finalize its conclusions and recommendations on the current validation
status of the nonradioactive test methods and the expanded uses of the
LLNA for pesticide formulations and other products. The panel's report
was made available for public comment in June 2009 (74 FR 26242). The
revised draft ICCVAM BRDs, revised draft ICCVAM test method
recommendations, the panel's report, and all public comments were made
available to SACATM for comment on June 25-26, 2009 (74 FR 19562).
After considering the conclusions and recommendations of the panel,
comments from SACATM, and public comments, along with the
recommendations of an OECD Expert Consultation on the LLNA convened in
October and December 2009, ICCVAM finalized and forwarded test method
recommendations to Federal agencies for their consideration, in
accordance with the ICCVAM Authorization Act of 2000 (42 U.S.C. 285l-
3(e)(4)). Agency responses to the ICCVAM test method recommendations
will be made available on the NICEATM-ICCVAM website as they are
received.
The ICCVAM TMERs, The LLNA: BrdU-ELISA, A Nonradioactive
Alternative Test Method to Assess the Allergic Contact Dermatitis
Potential of Chemicals and Products (NIH Publication 10-7552), and The
LLNA: DA, A Nonradioactive Alternative Test Method to Assess the
Allergic Contact Dermatitis Potential of Chemicals and Products (NIH
Publication 10-7551), describe ICCVAM's recommendations for using the
LLNA: BrdU-ELISA and LLNA: DA for regulatory hazard identification
purposes. The reports also provide ICCVAM-recommended LLNA: BrdU-ELISA
and LLNA: DA test method protocols, the final BRDs, and the peer review
reports of the panel. The ICCVAM-recommended LLNA: BrdU-ELISA test
method protocol is based on the protocol developed by Takeyoshi et al.
(2001). The ICCVAM-recommended LLNA: DA test method protocol is based
on the protocol developed by Idehara et al. (2008). Both test method
protocols incorporate all relevant aspects of the recently updated
ICCVAM-recommended traditional LLNA test method protocol (ICCVAM,
2009). The protocols also include reduced LLNA: BrdU-ELISA and LLNA: DA
procedures that should always be considered and used where determined
appropriate in order to further reduce animal use.
The ICCVAM Test Method Evaluation Report, Using the Murine Local
Lymph Node Assay for Testing Pesticide Formulations, Metals, Substances
in Aqueous Solutions, and Other Products (NIH Publication 10-7512)
provides ICCVAM's updated evaluation and recommendations for use of the
LLNA to evaluate the ACD hazard potential of pesticide formulations,
metals, substances in aqueous solutions, and other products. The
evaluation considered new data that became available subsequent to the
original ICCVAM LLNA evaluation in 1999. The report also includes the
peer review reports of the panel.
ICCVAM's evaluation of the LLNA for skin sensitization potency
categorization is currently nearing completion, and final ICCVAM
recommendations will be forwarded to Federal agencies later this year.
Background Information on ICCVAM, NICEATM, and SACATM
ICCVAM is an interagency committee composed of representatives from
15 Federal regulatory and research agencies that require, use,
generate, or disseminate toxicological information. ICCVAM conducts
technical evaluations of new, revised, and alternative methods with
regulatory applicability and promotes the scientific validation and
regulatory acceptance of toxicological test methods that more
accurately assess the safety and hazards of chemicals and products that
refine, reduce, and replace animal use. The ICCVAM Authorization Act of
2000 established ICCVAM as a permanent interagency committee of the
NIEHS under NICEATM (42 U.S.C 285l-3). NICEATM administers ICCVAM and
provides scientific and operational support for ICCVAM-related
activities. NICEATM and ICCVAM work collaboratively to evaluate new and
improved test methods applicable to the needs of U.S. Federal agencies.
NICEATM and ICCVAM welcome the public nomination of new, revised, and
alternative test methods for both validation studies as well as
technical evaluations. Additional information about ICCVAM and NICEATM
can be found on the NICEATM-ICCVAM Web site (http://iccvam.niehs.nih.gov).
SACATM was established January 9, 2002, and is composed of
scientists from the public and private sectors (67 FR 11358). SACATM
provides advice to the Director of the NIEHS, ICCVAM, and NICEATM
regarding the statutorily-mandated duties of ICCVAM and activities of
NICEATM. Additional information about SACATM, including the charter,
roster, and records of past meetings, can be found at http://ntp.niehs.nih.gov/go/167.
References
ICCVAM. 2010. ICCVAM Test Method Evaluation Report on The LLNA:
BrdU-ELISA, A Nonradioactive Alternative Test Method to Assess the
Allergic Contact Dermatitis Potential of Chemicals and Products. NIH
Publication Number 10-7552. Research Triangle Park, NC: National
Institute of Environmental Health Sciences.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report on The LLNA: DA,
A Nonradioactive Alternative Test Method to Assess the Allergic Contact
Dermatitis Potential of Chemicals and Products. NIH Publication Number
10-7551. Research Triangle Park, NC: National Institute of
Environmental Health Sciences.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report on Using the
Murine Local Lymph Node Assay for Testing Pesticide Formulations,
Metals, Substances in Aqueous Solutions, and Other Products. NIH
Publication Number 10-7512. Research Triangle Park, NC: National
Institute of Environmental Health Sciences.
ICCVAM. 2009. Recommended Performance Standards: Murine Local Lymph
Node Assay. NIH Publication Number 09-7357. Research Triangle Park, NC:
National Institute of Environmental Health Sciences. Available at:
http://iccvam.niehs.nih.gov/methods/immunotox/llna_PerfStds.htm.
ICCVAM. 2009. ICCVAM Test Method Evaluation Report. The Reduced
Murine Local Lymph Node Assay: An Alternative Test Method Using Fewer
Animals to Assess the Allergic Contact Dermatitis Potential of
Chemicals and Products. NIH Publication Number 09-6439. Research
Triangle Park, NC: National Institute of Environmental Health Sciences.
Available at: http://iccvam.niehs.nih.gov/methods/immunotox/LLNA-LD/TMER.htm.
ICCVAM. 1999. The Murine Local Lymph Node Assay: A Test Method for
Assessing the Allergic Contact Dermatitis Potential of Chemicals/
Compounds. The Results of an Independent Peer Review Evaluation
Coordinated by ICCVAM and NICEATM. NIH Publication Number 99-4494.
Research Triangle Park, NC: National Institute of Environmental Health
Sciences. Available at: http://iccvam.niehs.nih.gov/methods/immunotox/llna.htm.
Idehara K, Yamagishi G, Yamashita K, Ito M. 2008. Characterization
and evaluation of a modified local lymph node assay using ATP content
as a non-radio isotopic endpoint. Journal of Pharmacological and
Toxicological Methods 58(1): 1-10.
Takeyoshi M, Yamasaki K, Yakabe Y, Takatsuki M, Kimber I. 2001.
Development of non-radio isotopic endpoint of murine local lymph node
[[Page 37445]]
assay based on 5-bromo-2'-deoxyuridine (BrdU) incorporation. Toxicology
Letters 119(3): 203-208.
Dated: June 16, 2010.
John R. Bucher,
Associate Director, National Toxicology Program.
[FR Doc. 2010-15777 Filed 6-28-10; 8:45 am]
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