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Use of Anesthetics, Analgesics, and Humane Endpoints in Ocular Safety Testing

Despite progress in development of alternative test methods that do not use live animals, nearly all ocular safety testing has been conducted using the rabbit eye test. ICCVAM recommends that alternative in vitro test methods should be considered and used where appropriate for eye safety testing. When it is determined necessary to use the rabbit eye test for regulatory safety assessments, ICCVAM recommends that pain management procedures should always be used.

The report on the ICCVAM evaluation 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 avoid or minimize animal pain and distress.

In 2012, the Organisation for Economic Cooperation and Development issued an update to Test Guideline 405 for the rabbit eye test that incorporates these ICCVAM recommendations. The adoption of the updated Test Guideline 405 means that these procedures may now be used in the 34 member countries of the OECD, refining animal use for eye safety testing in many more countries.

Background on the ICCVAM Evaluation of Topical Anesthetics, Systemic Analgesics, and Humane Endpoints

List of relevant references

The 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" recommended that:

  • 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

ICCVAM prepared a draft background review document and draft recommendations on the use of topical anesthetics, systemic analgesics, and humane endpoints to avoid or minimize pain and distress during ocular safety testing. These 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.

Peer Review Panel Report (July 2009)

Summary of the Peer Review Panel meeting

ICCVAM recommended that pain management procedures should always be used when it is determined necessary to use the 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.

Recommendations and Agency Responses

The ICCVAM recommendations were communicated to Federal agencies in letters from Dr. Linda Birnbaum, Director, NIEHS. These letters and responses received from Federal agencies are available below.

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, now known as EURL 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

More information about the Symposium