[Federal Register Volume 75, Number 180 (Friday, September 17, 2010)]
[Notices]
[Pages 57027-57029]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-23262]


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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 (ICCVAM) Test Method Evaluation Reports: In Vitro Ocular Safety 
Testing Methods and Strategies, and Routine Use of Topical Anesthetics, 
Systemic Analgesics, and Humane Endpoints for Ocular Safety Testing; 
Notice of Transmittal to Federal Agencies

AGENCY: National Institute of Environmental Health Sciences (NIEHS), 
National Institutes of Health (NIH).

ACTION: Availability of ICCVAM Test Method Evaluation Reports (TMERs); 
Notice of Transmittal.

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SUMMARY: NICEATM announces availability of ICCVAM TMERs that provide 
recommendations regarding proposed in vitro ocular safety testing 
methods, testing strategies, and the routine use of anesthetics, 
analgesics, and humane endpoints for ocular safety testing to avoid or 
minimize any pain and distress. The reports and recommendations have 
been transmitted to Federal agencies for their review and response to 
ICCVAM in accordance with the ICCVAM Authorization Act of 2000. In the 
first report, ICCVAM recommends pain management procedures that should 
always be used to avoid or minimize pain and distress when it is 
determined necessary to conduct the

[[Page 57028]]

rabbit eye test for regulatory safety purposes. In the second report, 
ICCVAM recommends that the Cytosensor microphysiometer (CM) test method 
can be used as a screening test to identify some types of substances 
that may cause permanent or severe eye injuries. ICCVAM also recommends 
that the CM test method can be used to determine if some types of 
substances will not cause sufficient injury to require hazard labeling 
for eye irritation. ICCVAM evaluated four other in vitro test methods 
for their usefulness and limitations for identifying substances with 
the potential to cause reversible and nonsevere ocular injuries, but 
concluded that the performance of these methods must be improved before 
they can be used for regulatory safety testing to classify such 
substances. The report includes ICCVAM recommendations for future 
studies that could potentially improve these test methods. In the third 
report, ICCVAM recommends further studies to characterize the 
usefulness and limitations of a non-animal in vitro testing strategy 
that uses three in vitro test methods. In the fourth report, ICCVAM 
recommends that a proposed low volume rabbit eye test (LVET) should not 
be used for regulatory testing due to performance issues when compared 
to the current standard rabbit eye test.

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) 
<a href="/cdn-cgi/l/email-protection#402e29232521342d002e292528336e2e29286e272f36"><span class="__cf_email__" data-cfemail="97f9fef4f2f6e3fad7f9fef2ffe4b9f9feffb9f0f8e1">[email protected]</span></a>. Courier address: NICEATM, NIEHS, Room 2034, 530 
Davis Drive, Morrisville, NC 27560.

SUPPLEMENTARY INFORMATION: 

Background

    In October 2003, the U.S. Environmental Protection Agency (EPA) 
requested ICCVAM to: (1) Evaluate the current validation status of the 
bovine corneal opacity and permeability (BCOP), hen's egg test-
chorioallantoic membrane (HET-CAM), isolated chicken eye (ICE), and 
isolated rabbit eye (IRE) test methods; (2) identify in vivo ocular 
toxicity reference data to support the validation of in vitro test 
methods; (3) explore ways of alleviating pain and suffering from 
current in vivo ocular safety testing; and (4) review the state of the 
science and the availability of in vitro test methods for assessing 
mild or moderate ocular irritants. The highest priority activity, an 
evaluation of the BCOP, HET-CAM, ICE, and IRE test methods for their 
ability to identify potential ocular corrosives, was completed in 2006 
(NIH Publication No. 07-4517; available at http://iccvam.niehs.nih.gov/methods/ocutox/ivocutox/ocu_tmer.htm). ICCVAM recently completed 
additional test method evaluations relevant to the original EPA 
nomination and a subsequent EPA request for ICCVAM to evaluate a 
proposed in vitro testing strategy for identifying the ocular hazard 
potential of antimicrobial cleaning products (AMCPs).
    NICEATM and ICCVAM compiled comprehensive draft background review 
documents (BRDs) and released them for public comment in March 2009 (74 
FR 14556). ICCVAM convened a public panel meeting on May 19-21, 2009, 
to review the draft documents and assess whether the information they 
contained 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 its deliberations. The panel's 
report was made available in July 2009 (74 FR 33444) for public 
comment. The draft ICCVAM BRDs, draft ICCVAM test method 
recommendations, the panel's report, and all public comments were made 
available to ICCVAM's Scientific Advisory Committee on Alternative 
Toxicological Methods (SACATM) for comment at its meeting on June 25-
26, 2009 (74 FR 19562).
    After considering the conclusions and recommendations of the panel, 
comments from SACATM, and public comments, ICCVAM forwarded final test 
method recommendations to U.S. Federal agencies for their 
consideration. Agency responses to the ICCVAM test method 
recommendations will be made available on the NICEATM-ICCVAM Web site 
(http://www.iccvam.niehs.nih.gov) as they are received.
    The ICCVAM TMER, Recommendations for Routine Use of Topical 
Anesthetics, Systemic Analgesics, and Humane Endpoints to Avoid or 
Minimize Pain and Distress in Ocular Safety Testing (NIH Publication 
No. 10-7514) provides ICCVAM's evaluation and recommendations for the 
routine use of topical anesthetics, systemic analgesics, and humane 
endpoints to avoid or minimize pain and distress in ocular safety 
testing. ICCVAM concludes that balanced preemptive pain management 
procedures should always be provided when it is determined necessary to 
conduct the rabbit eye test for regulatory safety assessments. ICCVAM 
also identifies clinical signs and ocular lesions that are considered 
predictive of an ocular corrosive or severe irritant response and, 
therefore, can be routinely used as humane endpoints to end studies 
early when deemed appropriate. The report also includes a test method 
protocol that incorporates the ICCVAM-recommended procedures, the final 
BRD, and the panel's peer review report.
    The ICCVAM TMER, Current Validation Status of In Vitro Test Methods 
Proposed for Identifying Eye Injury Hazard Potential of Chemicals and 
Products (NIH Publication No. 10-7553) provides ICCVAM's updated 
evaluation and recommendations for the use of five in vitro ocular test 
methods (i.e., BCOP, CM, HET-CAM, ICE, and IRE) for their ability to 
identify nonsevere ocular irritants and substances not labeled as 
irritants. ICCVAM concludes that the CM test method can be used as a 
screening test to identify test substances within a defined limited 
applicability domain that may cause permanent or severe eye injuries. 
ICCVAM also recommends that the CM can be used to determine if 
substances within an even more restricted applicability domain will not 
cause sufficient injury to require hazard labeling for eye irritation. 
The performance of the remaining four in vitro test methods must be 
improved before they can be used in regulatory safety testing for 
classifying substances not labeled as irritants. None of these in vitro 
test methods were considered adequately predictive of all ocular hazard 
categories to support their use as a complete replacement for the 
current standard rabbit eye test. This report also includes updated 
ICCVAM-recommended BCOP, CM, HET-CAM, ICE, and IRE test method 
protocols, final BRDs for the BCOP, CM, HET-CAM, and ICE test methods, 
and the panel's peer review report.
    ICCVAM also discovered during these evaluations that an estimated 
30% of chemicals identified as eye hazards by current U.S. regulations 
will not be labeled as eye hazards by the United Nations Globally 
Harmonized System for Classification and Labelling of Chemicals (GHS), 
which some Federal agencies are or will be considering for 
implementation. The reduced hazard labeling that will result from 
implementing the GHS was based on analyzing actual testing data for 
over 250 chemicals. Of concern is that over 50% of the chemicals that 
will no longer be labeled using GHS criteria produced eye injuries 
expected to interfere with normal vision. Accordingly, the report

[[Page 57029]]

includes an optional GHS hazard category that could be used to provide 
at least equivalent hazard labeling as current U.S. regulations in 
order to support continued protection of consumers and workers.
    The ICCVAM TMER, Current Validation Status of a Proposed In Vitro 
Testing Strategy for U.S. Environmental Protection Agency Ocular Hazard 
Classification and Labeling of Antimicrobial Cleaning Products (NIH 
Publication No. 10-7513) provides ICCVAM's evaluation and 
recommendations regarding the use of a proposed in vitro testing 
strategy to classify and label AMCPs for eye irritation. ICCVAM 
concludes that the data are insufficient to adequately demonstrate that 
the proposed in vitro testing strategy can classify test substances to 
all four EPA ocular hazard categories. ICCVAM recommends further 
studies to characterize the usefulness and limitations of the non-
animal in vitro testing strategy that uses the three in vitro test 
methods. This report also includes updated ICCVAM-recommended BCOP, CM, 
and EpiOcular \TM\ test method protocols, the final summary review 
document (SRD), and the panel's peer review report.
    The ICCVAM TMER, Recommendation to Discontinue Use of the Low 
Volume Eye Test for Ocular Safety Testing (NIH Publication No. 10-7515) 
provides ICCVAM's evaluation and recommendations on the usefulness of 
the LVET as an in vivo reference test method. ICCVAM concludes that the 
proposed LVET should not be used for regulatory safety testing due to 
performance issues.

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, or 
generate toxicological and safety testing information for chemicals, 
products, and other substances. 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 health hazards of chemicals and products while reducing, 
refining (decreasing or eliminating pain and distress), or replacing 
animal use. The ICCVAM Authorization Act of 2000 (42 U.S.C. 285l-2, 
285l-5 [2000], available at http://iccvam.niehs.nih.gov/docs/about_docs/PL106545.pdf) 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 coordinates international 
validation studies of new and improved 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 as well as technical evaluations. 
Additional information about NICEATM and ICCVAM can be found on the 
NICEATM-ICCVAM Web site (http://www.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. 2006. ICCVAM Test Method Evaluation Report: In Vitro Ocular 
Toxicity Test Methods for Identifying Severe Irritants and Corrosives. 
NIH Publication No. 07-4517. Research Triangle Park, NC: NIEHS. 
Available: http://iccvam.niehs.nih.gov/methods/ocutox/ivocutox/ocu_tmer.htm.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report: Recommendations for 
Routine Use of Topical Anesthetics, Systemic Analgesics, and Humane 
Endpoints to Avoid or Minimize Pain and Distress in Ocular Safety 
Testing. NIH Publication No. 10-7514. Research Triangle Park, NC: 
NIEHS. Available: http://iccvam.niehs.nih.gov/methods/ocutox/OcuAnest-TMER.htm.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report: Current Validation 
Status of In Vitro Test Methods Proposed for Identifying Eye Injury 
Hazard Potential of Chemicals and Products. NIH Publication No. 10-
7553. Research Triangle Park, NC: NIEHS. Available: http://iccvam.niehs.nih.gov/methods/ocutox/MildMod-TMER.htm.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report: Current Validation 
Status of a Proposed In Vitro Testing Strategy for U.S. Environmental 
Protection Agency Ocular Hazard Classification and Labeling of 
Antimicrobial Cleaning Products. NIH Publication No. 10-7513. Research 
Triangle Park, NC: NIEHS. Available: http://iccvam.niehs.nih.gov/methods/ocutox/AMCP-TMER.htm.
ICCVAM. 2010. ICCVAM Test Method Evaluation Report: Recommendation to 
Discontinue Use of The Low Volume Eye Test for Ocular Safety Testing. 
NIH Publication No. 10-7515. Research Triangle Park, NC: NIEHS. 
Available: http://iccvam.niehs.nih.gov/methods/ocutox/LVET.htm.

    Dated: September 10, 2010.
John R. Bucher,
Associate Director, National Toxicology Program.
[FR Doc. 2010-23262 Filed 9-16-10; 8:45 am]
BILLING CODE 4140-01-P


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