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Regulatory agencies require testing of chemicals and products to
protect workers and consumers from potential eye injury hazards. This type of test represents one of
the four most commonly conducted product safety tests. Evaluation of test methods that identify
such hazards and also reduce, refine, and replace animal use is a high priority for NICEATM and ICCVAM.
ICCVAM activities in the area of ocular toxicity include the following evaluations:
- Routine use of topical anesthetics, systemic analgesics, and
humane endpoints to avoid or minimize pain and distress during in vivo ocular irritation testing
- Validation status of in vitro test methods for
assessing the potential of test substances to cause severe or permanent injury to the eye
- Validation status of in vitro test methods for
assessing the potential of test substances to cause reversible and nonsevere injury to the eye, or
for identifying substances as not requiring ocular hazard labeling
- Validation status of a testing strategy that proposes the use of three in vitro
test methods to assess the eye injury hazard potential for antimicrobial cleaning products
- Data analysis in support of proposed classification criteria that will
provide the same or greater level of eye hazard classification as current U.S. Federal Hazardous
Substances Act (FHSA) regulations, while using 50% to 83% fewer animals.
Click on heading links below for more information on ICCVAM evaluations of ocular toxicity test methods,
as well as links to relevant ICCVAM documents,
Federal Register notices, and peer review information.
View summary of ICCVAM recommendations on ocular test methods transmitted to
Federal agencies - September 2010
Regulations under the U.S. Federal Hazardous Substances Act (FHSA) provide procedures to determine
the eye hazard classification and labeling requirements for chemicals and products to which
consumers may be exposed. The current procedure requires a minimum of 6 animals per test and may
require up to 3 sequential tests for each substance, thus requiring 6, 12, or 18 animals to reach a
hazard classification decision. ICCVAM is proposing classification criteria that will
provide the same or greater level of eye hazard classification as current U.S. Federal Hazardous
Substances Act (FHSA) regulations, while using 50% to 83% fewer animals. The draft recommendations
are based on an analysis conducted in collaboration with NICEATM. NICEATM invites the submission of
written comments on the draft ICCVAM recommendations and the extent to which the analysis supports
these recommendations.
Thanks to the recent endorsement of several alternative testing methods, Federal public health
agencies and regulated industries now have important new tools for assessing potential ocular hazards presented by chemicals
and products. The new test methods were the topic of a January 2011 workshop organized by
NICEATM and ICCVAM. The workshops provided information on current best practices for safety testing to determine whether
chemicals and products may cause eye injuries using methods and approaches that reduce, refine, and replace animal use.
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 conduct the Draize rabbit eye
test. 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 specific procedures to
be used to avoid or minimize animal pain and distress.
ICCVAM has made recommendations on the use of five in vitro test methods for identifying
substances with the potential to cause reversible and nonsevere eye injuries:
- The bovine corneal opacity and permeability (BCOP) test method
- The Cytosensor microphysiometer (CM) test method
- The hen's egg test - chorioallantoic membrane (HET-CAM) test method
- The isolated chicken eye (ICE) test method
- The isolated rabbit eye (IRE) test method
ICCVAM recommends that the Cytosensor microphysiometer (CM) test method can be used as a
screening test to identify some types of water-soluble substances that may cause permanent or severe eye injuries.
ICCVAM also recommends that the CM test method can be used to determine if a limited range of
substances will not cause sufficient injury to require hazard labeling for eye irritation. ICCVAM
concluded that the performance of the other four test methods must be improved before they can
be used used in regulatory safety testing to identify substances with the potential to cause
reversible, nonsevere eye injuries or that do not require hazard labeling for eye irritation.
The
2010 report on the ICCVAM evaluation of these test methods includes recommendations
for future studies that could potentially
improve these test methods.
ICCVAM previously recommended that the BCOP and ICE test methods may be used
to identify substances that may cause severe or permanent eye injuries
(see
“In Vitro Test Methods for Detecting Ocular Corrosives and Severe Irritants”, below).
In 2008, NICEATM received a submission, sponsored by the U.S. Environmental Protection
Agency (EPA), for a testing strategy to assess the eye irritation
potential of antimicrobial cleaning products without using live animals.
This proposed testing strategy utilized the BCOP, CM, and EpiOcular
test methods to determine the EPA hazard category and labeling requirements for these substances.
ICCVAM conducted an evaluation of the proposed strategy and recommended further studies to
characterize its usefulness and limitations. As part of this evaluation, ICCVAM recommended that the
low volume eye test (LVET), a test method that was used to generate data supporting the
validity of the proposed testing strategy, should not be used for future regulatory testing.
Histopathology in Ocular Safety Testing
A continuing priority for NICEATM and ICCVAM is to identify and
promote research, development, translation, and validation activities for alternative test methods
with the potential to replace the rabbit eye test for identification of substances that are
potential ocular hazards. The current major obstacle to replacing animals for eye hazard testing is
the lack of in vitro methods that can accurately identify chemicals and products that are capable of
causing severe or permanent eye injuries.
To this end, one activity proposed in the 2009
NICEATM-ICCVAM Five-Year
Implementation Plan was a workshop on
the use of histopathology in ocular safety testing to determine if this additional information
might improve the in vitro prediction of severe and irreversible injuries. However, several recent evaluations and publications
have failed to demonstrate the usefulness of histopathology as an additional endpoint for currently accepted
in vitro methods. Thus, a workshop does not appear warranted at this
time.
View a NICEATM summary of the current status of the usefulness of histopathology evaluation
as an additional endpoint in in vitro eye hazard testing methods (November 2011)
[PDF]
In 2006, ICCVAM forwarded its first recommendations for the use of in vitro test
methods for ocular safety testing to Federal agencies.
ICCVAM recommended that the BCOP and ICE test methods
can be used as part of a weight-of-evidence approach to
identify substances that may cause permanent or severe eye injuries, 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 safety
testing and used when determined appropriate. The ICCVAM recommendations were accepted by Federal agencies,
and the two in vitro test methods may now be used
instead of animal tests for certain regulatory testing purposes.
The use of these tests will eliminate
eye safety testing in animals of most substances likely to
cause the most severe pain and discomfort.
Subsequent to the U.S. acceptance of the ICCVAM recommendations, the Organisation for Economic
Co-operation and Development (OECD) formally adopted guidelines describing the use of the BCOP and
ICE test methods. These guidelines, designated Test Guidelines 437 and 438, respectively, were based
on the ICCVAM recommendations. Acceptance of Test Guidelines 437 and 438 permits the use of these
test methods internationally to identify substances that may cause permanent or severe eye injuries
without the need for animal testing.
Two Scientific Symposia on ocular toxicity topics were held in 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 (decreasing or eliminating animal 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:
- 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
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