[Federal Register Volume 76, Number 9 (Thursday, January 13, 2011)]
[Notices]
[Pages 2388-2390]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-669]
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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); Federal
Agency Responses to Interagency Coordinating Committee on the
Validation of Alternative Methods (ICCVAM) Recommendations on Two
Nonradioactive Versions of the Murine 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; Notice of Availability
AGENCY: National Institute of Environmental Health Sciences (NIEHS),
National Institutes of Health (NIH), HHS.
ACTION: Notice of Availability.
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SUMMARY: U.S. Federal agency responses to ICCVAM test method
recommendations on two nonradioactive versions of the LLNA for
assessing the ACD hazard potential of chemicals and products and for
expanded uses of the LLNA for pesticide formulations and other products
are now available on the NICEATM-ICCVAM Web site at http://iccvam.niehs.nih.gov/methods/immunotox/llna.htm. ICCVAM recommended the
nonradioactive LLNA: 5-bromo-2-deoxyuridine-enzyme-linked immunosorbent
assay
[[Page 2389]]
(BrdU-ELISA) and LLNA: Daicel Adenosine Triphosphate (DA), and expanded
uses for the LLNA. In accordance with the ICCVAM Authorization Act (42
U.S.C. 285l-3(e)(4)), ICCVAM forwarded recommendations to Federal
agencies and made these recommendations available to the public (75 FR
37443). Agencies have now notified ICCVAM in writing of their findings
and ICCVAM is making these responses available to the public.
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 recommended the LLNA as a valid safety test for
assessing the ACD hazard potential of many chemicals and products (NIH
Publication No. 99-4494; available at http://iccvam.niehs.nih.gov/methods/immunotox/llna_PeerPanel98.htm). ICCVAM also concluded that
the LLNA, when used as an alternative method to the guinea pig
maximization test (GPMT) or the Buehler test (BT), could also
significantly reduce animal use and improve animal welfare. Based on
this evaluation, the U.S. Environmental Protection Agency (EPA 2003),
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 (http://iccvam.niehs.nih.gov/methods/immunotox/llna_PeerPanel98.htm). The Organisation for Economic Co-
operation and Development (OECD) subsequently adopted the LLNA in 2002
as international OECD Test Guideline 429 (OECD, 2002). The
International Organization for Standardization (ISO) adopted the LLNA
as ISO standard 10993-10 in 2002 (ISO, 2002).
ICCVAM recommended an updated LLNA test method protocol in 2009
that further reduced animal use for each safety test by 20-40% (ICCVAM,
2009). Federal agencies endorsed this updated protocol (75 FR 25866).
OECD Test Guideline 429 was subsequently updated in 2010 to incorporate
the updated revisions (OECD, 2010a). The ISO standard was also updated
in 2010 (ISO, 2010).
Compared to the LLNA, the LLNA: BrdU-ELISA and LLNA: DA do not use
radioactive reagents and therefore provide additional 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 their use to determine whether substances have the
potential to cause ACD. The protocols also include reduced LLNA: BrdU-
ELISA and LLNA: DA procedures that should always be considered and used
where determined appropriate because they can further reduce animal use
by 40% compared to multi-dose procedures. The ICCVAM evaluation and
complete recommendations for the LLNA: BrdU-ELISA and LLNA: DA are
provided in the 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, available at http://iccvam.niehs.nih.gov/methods/immunotox/llna-ELISA/TMER.htm) and the
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, available at http://iccvam.niehs.nih.gov/methods/immunotox/llna-DA/TMER.htm). The OECD subsequently adopted the
LLNA: BrdU-ELISA and LLNA: DA as international test guidelines (OECD,
2010b, 2010c).
ICCVAM also concluded that available data support the use of the
LLNA for safety testing of a broader range of chemicals and products,
including pesticide formulations, metals with the exception of nickel,
substances in aqueous solutions, and other chemicals and products,
unless there are unique physicochemical properties associated with
these materials that may interfere with the accuracy of the LLNA.
Aqueous solutions should be tested in an appropriate vehicle that
maintains sufficient contact of the test article with the skin. The
ICCVAM evaluation and complete recommendations for expanded uses of the
LLNA are provided in 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, available at http://iccvam.niehs.nih.gov/methods/immunotox/LLNA-app/TMER.htm).
ICCVAM evaluated the new versions and applications of the LLNA in
response to a 2007 nomination from CPSC (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) 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. ICCVAM
recommendations on an updated LLNA test method protocol that included
the reduced LLNA were communicated to Federal agencies and each of the
15 ICCVAM agencies concurred with the ICCVAM recommendations for the
reduced LLNA. ICCVAM has completed the evaluation of the LLNA for its
validity for potency categorization of chemicals causing ACD in humans.
Final ICCVAM recommendations will be forwarded to Federal agencies in
2011.
Agency Responses to ICCVAM Recommendations
In June 2010, ICCVAM forwarded final test method recommendations
for the LLNA BrdU-ELISA, LLNA: DA and the expanded uses of the LLNA to
U.S. Federal agencies for consideration (74 FR 50212), in accordance
with the ICCVAM Authorization Act of 2000 (42 U.S.C. 285l-3(e)(4)). The
Act requires agencies to review ICCVAM test method recommendations and
notify ICCVAM in writing of their findings no later than 180 days after
receipt of recommendations. The Act also requires ICCVAM to make ICCVAM
recommendations and agency responses available to the public. Agency
responses are to include identification of relevant test methods for
which the ICCVAM test method recommendations may be added or
substituted, and indicate any revisions or planned revisions to
existing guidelines, guidances, or regulations to be made in response
to these recommendations.
Federal agency responses include acceptance decisions and agreement
with the test method recommendations for the LLNA: BrdU-ELISA, LLNA: DA
and the expanded uses of the LLNA. Several agencies also indicated that
they would communicate the ICCVAM recommendations to stakeholders and
encourage their appropriate use. Agency responses are available at
http://iccvam.niehs.nih.gov/methods/immunotox/llna.htm.
[[Page 2390]]
Background Information on ICCVAM and NICEATM
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
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 established ICCVAM as a permanent interagency committee of the
NIEHS under NICEATM (42 U.S.C. 285l-3(a)). NICEATM administers ICCVAM,
provides scientific and operational support for ICCVAM-related
activities, and conducts independent validation studies to assess the
usefulness and limitation of new, revised, and alternative test
methods. 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 validation studies and technical
evaluations. Additional information about ICCVAM and NICEATM can be
found on the NICEATM-ICCVAM Web site (http://iccvam.niehs.nih.gov).
References
EPA. 2003. Health Effects Test Guidelines: OPPTS 870.2600--Skin
Sensitization. EPA 712-C-03-197. Washington, DC: U.S. Environmental
Protection Agency. Available: http://www.epa.gov/ocspp/pubs/frs/publications/Test_Guidelines/series870.htm.
ICCVAM 2010 ICCVAM Test Method Evaluation Report. 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. 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-D/TMER.htm.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report on Using the LLNA
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. 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.
ISO. 2002. Biological evaluation of medical devices--10993 Part 10:
Tests for irritation and delayed-type hypersensitivity. Available for
purchase at: http://www.iso.org/iso/home.htm.
ISO. 2010. Biological evaluation of medical devices--10993 Part 10:
Tests for irritation and skin sensitization. Available for purchase at:
http://www.iso.org/iso/home.htm.
OECD. 2002. Test Guideline 429. Skin Sensitization: Local Lymph Node
Assay, adopted April 24, 2002. In: OECD Guidelines for Testing of
Chemicals. Paris: OECD.
OECD. 2010a. Test Guideline 429. Skin Sensitization: Local Lymph Node
Assay, adopted July 22, 2010. In: OECD Guidelines for Testing of
Chemicals. Paris: OECD. Available at: http://dx.doi.org/10.1787/9789264071100-en.
OECD. 2010b. Test Guideline 442B. Skin Sensitization: Local Lymph Node
Assay: BrdU-ELISA, adopted July 22, 2010. In: OECD Guidelines for
Testing of Chemicals. Paris: OECD. Available at: http://dx.doi.org/10.1787/9789264090996-en.
OECD. 2010c. Test Guideline 442A. Skin Sensitization: Local Lymph Node
Assay: DA, adopted July 22, 2010. In: OECD Guidelines for Testing of
Chemicals. Paris: OECD. Available at: http://dx.doi.org/10.1787/9789264090972-en.
Dated: January 5, 2011.
John R. Bucher,
Associate Director, National Toxicology Program.
[FR Doc. 2011-669 Filed 1-12-11; 8:45 am]
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