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Ocular Toxicity

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In Vitro Test Methods for Detecting Ocular Corrosives and Severe Irritants

In October 2007, ICCVAM forwarded its first recommendations for the use of in vitro methods for ocular safety testing to Federal agencies. ICCVAM recommended that two methods, the Bovine Corneal Opacity and Permeability (BCOP) test method and the Isolated Chicken Eye (ICE) test method, can be used in a tiered testing strategy to determine ocular hazards, with specific limitations for certain chemical classes and/or physical properties. Substances that test positive in these assays can be classified as ocular corrosives or severe irritants without further testing in animals. The report also recommends that these in vitro test methods should be considered before using animals for ocular testing and used when determined appropriate. These recommendations, once accepted by Federal agencies, will result in a reduction of the number of animals used for safety testing to determine corrosive or severely irritating damage to the eye.

ICCVAM evaluated two other in vitro test methods, the Isolated Rabbit Eye (IRE) test method and the Hen's Egg Test - Chorioallantoic Membrane (HET-CAM) test method. Before these two methods can be recommended for use as screening tests for the identification of ocular corrosives and severe irritants, the protocol and decision criteria for the identification of ocular corrosives and severe irritants need to be optimized and undergo further validation.

Nomination History and Evaluation

In October 2003, the U.S. Environmental Protection Agency (EPA) submitted several nominations to ICCVAM to reduce, replace, and refine the use of rabbits for ocular irritation testing. Such safety testing is required by Federal agencies to determine whether consumer products or other substances may cause temporary or permanent damage to the eye.

In response to the nominations, ICCVAM initiated evaluation of four in vitro ocular toxicity test methods as potential screening methods for eye corrosion or severe irritation: the BCOP test method, the ICE test method, the IRE test method, and the HET-CAM test method. NICEATM compiled data and information on each test method into four draft Background Review Documents (BRDs). ICCVAM, in collaboration with NICEATM, convened an independent Expert Panel in January 2005 to determine the validation status of these methods. The Expert Panel Report: Evaluation of the Current Validation Status of In Vitro Test Methods for Identifying Ocular Corrosives and Severe Irritants, was made available in March 2005. Submission of additional data after the Expert Panel Meeting led to release of addenda to the BRDs. The Expert Panel was subsequently reconvened in September 2005 to reconsider their evaluation. An Addendum to the Expert Panel Report, incorporating additional data and analyses, was made available in November 2005.

ICCVAM considered the expert panel report and its addendum, public comments, the comments of the Scientific Advisory Committee on Alternative Toxicological Methods, and the draft BRDs and their addenda in finalizing its recommendations on the validation status of these four test methods. These are contained in the ICCVAM Test Method Evaluation Report: In Vitro Ocular Toxicity Test Methods for Identifying Severe Irritants and Corrosives.

In October 2007, the ICCVAM Test Method Evaluation Report, as well as the supporting final BRDs, were forwarded to Federal agencies for their consideration of regulatory acceptance as required by the ICCVAM Authorization Act of 2000 (42 U.S.C. 285l-3). These are the first alternative nonanimal test methods for ocular safety testing reviewed by ICCVAM and transmitted to agencies. Agencies' response to the test method recommendations, which are due in April 2008, will be posted on the NICEATM-ICCVAM website as they are received.

In Vitro Test Methods for Detecting Nonsevere Ocular Irritants

In addition to the evaluation discussed above, the October 2003 EPA nomination recommended the review of the validation status of the in vitro methods for identifying nonsevere ocular irritants (i.e., those that induce reversible ocular damage) and non-irritants. In June 2007, NICEATM requested the submission of data from substances tested for ocular irritancy in humans, rabbits, and/or in vitro. NICEATM welcomes the submission of all relevant data, which will be compiled and added to the database maintained by NICEATM and utilized where appropriate in the evaluation of in vitro ocular irritation test methods. Data received will also be considered and used where applicable for future evaluation activities.

Nonanimal Assessment Approach for Evaluating Eye Irritation Potential of Antimicrobial Cleaning Products

In January 2008, NICEATM received an EPA-sponsored submission of a nonanimal approach using in vitro test methods to assess the eye irritation potential of antimicrobial cleaning products. This proposed testing strategy will utilize the BCOP, the Cytosensor Microphysiometer, and the EpiOcular in vitro test methods to determine the EPA toxicity category and labeling requirements for these substances. NICEATM and ICCVAM are conducting a preliminary evaluation of the submission to determine its completeness and adherence to ICCVAM guidelines.

Effects of Topical Anesthetic Pre-treatment on In Vivo Ocular Irritation Hazard Classification

In May 2007, NICEATM requested the submission of data from completed studies on the use of topical anesthetics and/or systemic analgesics for in vivo ocular irritancy testing. These data will be used to evaluate the validation status of the use of topical anesthetics and/or analgesics to reduce pain and distress for in vivo testing situations. ICCVAM and NICEATM also requested the submission of information and data from in vivo methods, procedures, and/or strategies that may reduce or eliminate the pain and suffering associated with current in vivo eye irritation methods.

In vivo tests used to evaluate the risk of substances to cause irritation or corrosion to the eyes present the potential for pain and distress in rabbits after application of a severely irritating or corrosive substance. In October 2003, the EPA requested that ICCVAM review ways to alleviate pain and suffering that might arise during current in vivo tests. ICCVAM has recommended with high priority that NICEATM review the data currently available on the use of topical anesthetics and/or systemic analgesics to reduce animal pain and distress.

Scientific Symposia on Ocular Toxicity

Two Scientific Symposia on ocular toxicity topics were held in May 2005. Both symposia were sponsored by ICCVAM, NICEATM, the European Centre for the Validation of Alternative Methods (ECVAM), and the European Cosmetic, Toiletry and Perfumery Association, and were organized by ICCVAM, NICEATM and ECVAM.

Symposium I: Mechanisms of Chemically-Induced Ocular Injury and Recovery identified research needed to address current knowledge gaps and to advance the development and validation of ocular toxicity test methods for regulatory testing that provide for protection of human health while reducing, refining (less pain and distress), and/or replacing the use of animals. The participants in Symposium I made the following recommendations:

  • Data collected from objective, quantitative endpoints and biomarkers should be used to assess the severity of chemically-induced ocular injuries in animal safety studies and human accidental exposures.
  • The routine collection of this data can be expected to:
    • Provide insights into chemical-specific mechanisms of ocular injury and recovery
    • Support the development and validation of more predictive mechanism-based in vitro test models
    • Improve the accuracy and reliability of ocular hazard assessments
    • Aid in identifying predictive, mechanism-based earlier humane endpoints

Symposium II: Minimizing Pain and Distress in Ocular Toxicity Testing, reviewed current understanding of the sources and mechanisms of pain and distress in ocular toxicity testing; identified current best practices for preventing, recognizing, and alleviating ocular pain and distress; and identified additional research, development, and validation studies necessary to support scientifically valid ocular toxicity testing procedures that avoid pain and distress. The participants in Symposium II made the following recommendations:

  • Pre-treatment with topical or general anaesthesia should be used routinely to avoid pain from topical application of test substances
  • Systemic analgesics should be administered prior to test article application and continued until injuries resolve or the study is terminated
  • Ocular injuries predictive of severe or irreversible ocular damage should be used as earlier humane endpoints
  • Objective, quantitative measurements should be collected during ocular studies to assist in identifying earlier, more humane endpoints. Data from these measurements are also critical to the development and validation of more predictive in vitro methods.

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