[Federal Register Volume 76, Number 145 (Thursday, July 28, 2011)]
[Notices]
[Pages 45254-45256]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-18639]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Report and Recommendations on the Usefulness and Limitations of
the Murine Local Lymph Node Assay for Potency Categorization of
Chemicals Causing Allergic Contact Dermatitis in Humans
AGENCY: Division of the National Toxicology Program (DNTP), National
Institute of Environmental Health Sciences (NIEHS), National Institutes
of Health (NIH), HHS.
ACTION: Availability of Report and Recommendations; Notice of
Transmittal.
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SUMMARY: The NTP Interagency Center for the Evaluation of Alternative
Test Methods (NICEATM) announces availability of an Interagency
Coordinating Committee on the Validation of Alternative Methods
(ICCVAM) test method evaluation report (TMER) that includes
recommendations on the usefulness and limitations of the local lymph
node assay (LLNA) for categorizing the potency of substances with the
potential to cause allergic contact dermatitis (ACD) as strong skin
sensitizers. Strong skin sensitizers are substances considered to have
a significant potential for causing ACD.
ICCVAM recommends that a specific potency criterion for positive
results from ACD safety testing using the LLNA can be used to further
categorize some chemicals and products as strong skin sensitizers.
However, since this criterion only identified approximately half of
strong human skin sensitizers, ICCVAM concluded that failure to meet
this criterion cannot be used as the basis for determining that a
substance is not a strong skin sensitizer. Therefore, the potency
criterion should only be used in a screening approach where chemicals
that meet the criterion could be categorized as strong skin
sensitizers, but chemicals that do not meet the criterion would require
additional testing or information to determine that they are not strong
skin sensitizers.
The report and recommendations have been transmitted to Federal
agencies for their review and response to ICCVAM in accordance with the
provisions of the ICCVAM
[[Page 45255]]
Authorization Act of 2000 (42 U.S.C. 285l-2).
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
In 1999, ICCVAM evaluated the validation status of the LLNA as a
stand-alone alternative test 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; http://iccvam.niehs.nih.gov/methods/immunotox/llna_PeerPanel98.htm). Based on
this evaluation, ICCVAM recommended the LLNA as a valid substitute for
traditional guinea pig test methods for most testing situations. The
U.S. Environmental Protection Agency, the U.S. 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 Organisation for Economic Co-operation and Development (OECD)
also adopted the LLNA as OECD Test Guideline 429 in 2002. Using the
LLNA instead of guinea pig tests reduces and refines (decreases or
eliminates 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 for
regulatory testing purposes (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 as a stand-alone assay to determine ACD potency
categories for hazard classification and labeling. 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 draft BRDs as to whether it supported draft ICCVAM
recommendations for (1) Test method usefulness and limitations, (2)
updated standardized test method protocols, and (3) 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 reduced LLNA (NIH Publication No. 09-6439;
http://iccvam.niehs.nih.gov/methods/immunotox/LLNA-LD/TMER.htm), LLNA
performance standards, and the updated LLNA test method protocol (NIH
Publication No. 09-7357; http://iccvam.niehs.nih.gov/methods/immunotox/llna_PerfStds.htm) to Federal agencies in September 2009 (74 FR
50212). Agency responses are available on the NICEATM-ICCVAM Web site.
NICEATM subsequently obtained additional data and/or information
and revised the draft BRDs for both the traditional and nonradioactive
LLNA methods. ICCVAM released the revised draft BRDs and the revised
draft ICCVAM test method recommendations 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 to 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 on two nonradioactive versions of the LLNA, LLNA: 5-
Bromo-2'-deoxyuridine-Enzyme-Linked Immunosorbent Assay (BrdU-ELISA)
(NIH Publication No. 10-7552; http://iccvam.niehs.nih.gov/methods/immunotox/llna-ELISA/TMER.htm) and LLNA: Daicel Adenosine Triphosphate
(DA) (NIH Publication No. 10-7551; http://iccvam.niehs.nih.gov/methods/immunotox/llna-DA/TMER.htm), and expanded uses of the LLNA for
pesticide formulations and other products (NIH Publication No. 10-7512;
http://iccvam.niehs.nih.gov/methods/immunotox/llna-app.htm) to Federal
agencies in June 2010 (75 FR 37443). Agency responses to these ICCVAM
test method recommendations are available on the NICEATM-ICCVAM Web
site.
The ICCVAM TMER, Usefulness and Limitations of the Murine Local
Lymph Node Assay for Potency Categorization of Chemicals Causing
Allergic Contact Dermatitis in Humans (NIH Publication No. 11-7709),
describes ICCVAM's recommendations for using LLNA test results to
categorize the potency of some substances identified as having the
potential to cause ACD in humans as strong skin sensitizers. Strong
sensitizers are those substances considered to have a significant
potential for causing hypersensitivity. ICCVAM recommends that a
specific potency criterion for positive results from ACD safety testing
using the LLNA can be used to further categorize some chemicals and
products as strong skin sensitizers. However, since this criterion only
identified approximately half of the strong human skin sensitizers
tested, failure to meet this criterion cannot be used as the basis for
determining that a substance is not a strong skin sensitizer.
Therefore, the potency criterion should only be used in a screening
approach where chemicals that meet the criterion
[[Page 45256]]
could be categorized as strong skin sensitizers, but chemicals that do
not meet the criterion would require additional testing or information
to determine that they are not strong skin sensitizers.
The ICCVAM evaluation found that only 52% of the strong human skin
sensitizers in the validation database would be identified as strong
skin sensitizers using the LLNA potency criterion in the 2009 United
Nations Globally Harmonized System of Classification and Labelling of
Chemicals (GHS). Accordingly, chemicals that do not meet the criterion
would require additional testing or information to determine that a
substance is not a strong human skin sensitizer.
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 and safety testing information.
ICCVAM conducts technical evaluations of new, revised, and alternative
safety testing methods with regulatory applicability and promotes the
scientific validation and regulatory acceptance of toxicological and
safety testing methods that more accurately assess the safety and
hazards of chemicals and products and that reduce, refine (decrease or
eliminate pain and distress), or replace animal use. The ICCVAM
Authorization Act of 2000 (42 U.S.C. 285l-3) established ICCVAM as a
permanent interagency committee of the NIEHS under NICEATM. NICEATM
administers ICCVAM, provides scientific and operational support for
ICCVAM-related activities, and conducts independent validation studies
to assess the usefulness and limitations of new, revised, and
alternative test methods and strategies. NICEATM and ICCVAM welcome the
public nomination of new, revised, and alternative test methods and
strategies applicable to the needs of U.S. Federal agencies. Additional
information about NICEATM and ICCVAM can be found on the NICEATM-ICCVAM
Web site (http://iccvam.niehs.nih.gov).
SACATM was established in response to the ICCVAM Authorization Act
[Section 285l-3(d)] and is composed of scientists from the public and
private sectors (67 FR 11358). SACATM advises ICCVAM, NICEATM, and the
Director of the NIEHS and NTP regarding statutorily mandated duties of
ICCVAM and activities of NICEATM. SACATM provides advice on priorities
and activities related to the development, validation, scientific
review, regulatory acceptance, implementation, and national and
international harmonization of new, revised, and alternative
toxicological test methods. 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. 2011. ICCVAM Test Method Evaluation Report: Usefulness and
Limitations of the Murine Local Lymph Node Assay for Potency
Categorization of Chemicals Causing Allergic Contact Dermatitis in
Humans. NIH Publication No. 11-7709. Research Triangle Park, NC:
National Institute of Environmental Health Sciences. Available at:
http://iccvam.niehs.nih.gov/methods/immunotox/llna-ELISA/LLNA-pot/TMER.htm.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report on the Murine
Local Lymph Node Assay: BrdU-ELISA, a Nonradioactive Alternative Test
Method to Assess the Allergic Contact Dermatitis Potential of Chemicals
and Products. NIH Publication No. 10-7552. Research Triangle Park, NC:
National Institute of Environmental Health Sciences. Available at:
http://iccvam.niehs.nih.gov/methods/immunotox/llna-ELISA/TMER.htm.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report on the Murine
Local Lymph Node Assay: DA, a Nonradioactive Alternative Test Method to
Assess the Allergic Contact Dermatitis Potential of Chemicals and
Products. NIH Publication No. 10-7551. Research Triangle Park, NC:
National Institute of Environmental Health Sciences. Available at:
http://iccvam.niehs.nih.gov/methods/immunotox/llna-DA/TMER.htm.
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 No. 10-7512. Research Triangle Park, NC: National Institute
of Environmental Health Sciences. Available at: http://iccvam.niehs.nih.gov/methods/immunotox/LLNA-app/TMER.htm.
ICCVAM. 2009. Recommended Performance Standards: Murine Local Lymph
Node Assay. NIH Publication No. 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 No. 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 No. 99-4494.
Research Triangle Park, NC: National Institute of Environmental Health
Sciences. Available at: http://iccvam.niehs.nih.gov/methods/immunotox/llna_PeerPanel98.htm.
Dated: July 14, 2011.
John R. Bucher,
Associate Director, National Toxicology Program.
[FR Doc. 2011-18639 Filed 7-27-11; 8:45 am]
BILLING CODE 4140-01-P