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Despite progress in development of alternative test methods that do not use live animals, nearly
all ocular safety testing has been conducted using the Draize rabbit eye test. ICCVAM recommends
that pain management procedures should always be used when it is determined
necessary to use the Draize rabbit eye
test for regulatory safety assessments. The report on the ICCVAM evaluation of the use of
anesthetics, analgesics, and humane
endpoints in ocular safety testing includes a test method protocol that describes how to use
topical anesthetics (similar to those used in human eye surgeries) and systemic
analgesics prior to and after test article administration in order
to avoid or minimize animal pain and distress.
The report also identifies specific clinical signs and lesions that can be
used as humane endpoints to allow the investigator to end a study early in order to reduce or terminate
animal pain and distress.
Background on the ICCVAM Evaluation of Topical Anesthetics, Systemic Analgesics, and Humane Endpoints
The Draize rabbit eye test has been in use since 1944 to evaluate the risk of substances to cause
irritation or corrosion to the eyes. This test presents the potential for pain and distress in
rabbits after application of a test substance. Alternative approaches have been proposed and
developed to reduce the number of animals used or refine (decrease or eliminate pain and distress)
this test.
In 2005, experts at an international symposium titled "Minimizing Pain and Distress in
Ocular Toxicity Testing" (see below) made the following recommendations:
- Topical anesthetics and systemic analgesics should routinely be administered before ocular
testing to avoid or minimize pain and distress that might occur during and after the initial
application of test substances
- Systemic analgesics should routinely be administered when there is evidence of potentially
painful ocular damage or when there are clinical signs indicative of pain or distress
- Specific ocular injuries identified by the experts that would not be expected to reverse
within 21 days could be used as humane endpoints to end a study early
NICEATM and the ICCVAM Interagency Ocular Toxicity Working Group (OTWG) prepared a draft background review document
(BRD) on the use of topical
anesthetics, systemic analgesics, and humane endpoints to avoid or minimize pain and distress during
ocular safety testing. Data in these documents were used as the basis for developing draft ICCVAM
recommendations. The draft BRD and draft ICCVAM recommendations were reviewed in May 2009 by an
independent international peer review panel. ICCVAM considered the peer review panel's comments, as
well as comments from the public and from the Scientific Advisory Committee on Alternative
Toxicological Methods, before finalizing its recommendations for Federal agencies.
ICCVAM recommended that pain management procedures should always be used when it is determined
necessary to use the Draize rabbit eye
test for regulatory safety assessments. Pain management should include:
- Treating the animals with a topical anesthetic and a systemic analgesic before applying test substances
- Following a routine schedule of systemic analgesia after applying test substances
- Scheduled observation, monitoring, and recording of animals for clinical signs of pain and/or distress
- Scheduled observation, monitoring, and recording of the nature, severity, and progression of all eye injuries
ICCVAM also recommended that ocular safety testing protocols include a pain management procedure and
schedule. The ICCVAM recommendations also identified specific ocular lesions and combinations of lesions
that should be used as humane endpoints to terminate the study before the end of the scheduled 21-day
observation period.
The ICCVAM recommendations are included in the 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 (2010). The recommendations were tranmitted to Federal
agencies in September 2010. Agency responses,
received within 180 days of transmittal as required by the ICCVAM Authorization Act, indicated
acceptance or endorsement of the ICCVAM recommendations.
View transmittal letters, agency responses,
and summary of all September 2010 ICCVAM recommendations on ocular test methods transmitted to
Federal agencies
Read the Test Method Evaluation Report
Read the Peer Review Panel Report
[PDF]
Presentation at the 2010 Society of Toxicology Meeting
NICEATM staff and ICCVAM Committee and OTWG members presented a poster summarizing the ICCVAM recommendations on the
routine use of topical anesthetics, systemic analgesics, and humane endpoints in ocular safety testing at the 2010 meeting of the Society of Toxicology.
"ICCVAM Recommendations for the Routine Use of Topical Anesthetics, Systemic Analgesics, and Humane Endpoints to Refine Ocular Toxicity Testing"
J Merrill, M Wind, D Lowther, W Chambers, T McMahon, J Chen, M Hashim, M Lewis, W Stokes
View Abstract [PDF]
View Poster [PDF]
View all NICEATM-ICCVAM posters presented at the 2010 SOT meeting
Federal Register Notices with Announcements Relevant to the ICCVAM Evaluation
of Routine Use of Topical Anesthetics, Systemic Analgesics, and Humane Endpoints in Ocular Safety Testing
Federal Register Notice:
Recommendations on In Vitro Ocular Safety Testing Methods and Strategies and Routine Use of
Topical Anesthetics, Systemic Analgesics, and Humane Endpoints for Ocular Safety Testing
View Federal Register notice
(76 FR 20672, April 13, 2011) [PDF]
Federal Register Notice:
Availability of 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
View Federal Register notice
(75 FR 57027, September 17, 2010) [PDF]
Federal Register Notice:
Independent Scientific Peer Review Panel Report: Evaluation of the Validation Status of Alternative Ocular Safety Testing
Methods and Approaches: Notice of Availability and Request for Public Comments (74 FR 33444, July 13, 2009)
View Federal Register notice [PDF]
View comments submitted on Federal Register notice
Federal Register Notice:
Announcement of an Independent Scientific Peer Review Panel on Alternative Ocular Safety
Testing Methods; Availability of Draft Background Review Documents (BRD); Request for Comments (74 FR 14566, March 31, 2009)
View Federal Register notice [PDF]
Federal Register Notice:
Request for Data on the Use of Topical Anesthetics and Systemic Analgesics for In Vivo Eye Irritation Testing (72 FR 26396, May 9, 2007)
View Federal Register Notice [PDF]
View comments submitted on Federal Register Notice
Using data generated during required safety testing,
NICEATM conducted analyses evaluating the effect of topical application of a tetracaine hydrochloride ophthalmic anesthetic solution
on the irritancy potential of test substances evaluated using a sequential testing scheme. The results of these analyses were
presented by NICEATM at two major scientific meetings in 2007.
View the NICEATM 2007 SOT Poster [PDF]
View the NICEATM Sixth World Congress Poster [PDF]
View abstract
of platform presentation, "Alternatives for Ocular Toxicity Testing: ICCVAM and NICEATM Recent and Planned Initiatives", given by Dr. William Stokes at
the Sixth World Congress [PDF]
Symposium on Minimizing Pain and Distress in Ocular Toxicity Testing
In May 2005, ICCVAM, NICEATM, and the European Centre for the Validation of Alternative Methods (ECVAM), organized a
Symposium on Minimizing Pain and Distress in Ocular Toxicity Testing. The symposium was sponsored by ICCVAM,
NICEATM, ECVAM, and the European Cosmetic, Toiletry and Perfumery Association. The goals of this symposium were to:
- Review current understanding of the sources and mechanisms of pain and distress in ocular toxicity testing
- Identify current best practices for preventing, recognizing, and alleviating ocular pain and distress
- Identify additional research, development, and validation studies necessary to support scientifically
valid ocular toxicity testing procedures that avoid pain and distress
The participants in the symposium made the following recommendations:
- Topical anesthetics and systemic analgesics should routinely be administered before ocular
testing to avoid or minimize pain and distress that might occur during and after the initial
application of test substances
- Systemic analgesics should routinely be administered when there is evidence of potentially
painful ocular damage or when there are clinical signs indicative of pain or distress
- Specific ocular injuries identified by the experts that would not be expected to reverse
within 21 days could be used as humane endpoints to end a study early
View information about the Symposium
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