[Federal Register Volume 65, Number 166 (Friday, August 25, 2000)]
[Notices]
[Pages 51828-51830]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-21784]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-00673; FRL-6736-5]
Pesticides; Protocols for Testing the Efficacy of Disinfectants
Against Hepatitis B Virus (HBV); Notice of Availability
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of availability.
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SUMMARY: The Agency is announcing the availability of guidance titled
``Protocol for Testing the Efficacy of Disinfectants Used to Inactivate
Hepatitis B Virus and Corresponding Label Claims.'' Through this
guidance, EPA expresses its view that the appropriate and preferred
test relies on in vitro duck assays which use duck hepatitis B virus as
a surrogate for human hepatitis B virus (HHBV) to evaluate the efficacy
of disinfectants used to inactivate HHBV. Use of such assays will
greatly minimize the use of animals for testing. The Agency is also
making available its responses to comments on the draft protocols that
were made available for public comment.
FOR FURTHER INFORMATION CONTACT: Ibrahim Barsoum, Antimicrobials
Division (7510C), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460; telephone number: (703) 308-6417; fax
number: (703) 308-8481; e-mail address: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
This action is directed to the public in general. This action may
be of particular interest to those persons who manufacture or formulate
pesticides. Potentially affected categories and entities may include,
but are not limited to:
------------------------------------------------------------------------
Examples of
Categories NAICS potentially
affected entities
------------------------------------------------------------------------
Pesticide Producers 32532 Pesticide
manufacturers
Pesticide
formulators
------------------------------------------------------------------------
Since other entities may also be interested, the Agency has not
attempted to describe all the specific entities that may be affected by
this action. If you have any questions regarding the information in
this notice, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document from the Office of Pesticide Programs' Home Page at http://www.epa.gov/pesticides/. You can also go directly to the listings from
the EPA Internet Home Page at http://www.epa.gov/. To access this
document, on the Home Page select ``Laws and Regulations,''
``Regulations and Proposed Rules,'' and then look up the entry for this
document under the `` Federal Register--Environmental Documents. '' You
can also go directly to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. Fax-on -demand. You may request a faxed copy of the guidance, as
well as supporting information, by using a faxphone to call (202) 401-
0527. Select item 6067 for the document titled ``Protocol for Testing
the Efficacy of Disinfectants Used to Inactivate Hepatitis B Virus and
Corresponding Label Claims.'' Select item 6068 for the document titled
``Responses to Public Comments on Protocols for Testing the Efficacy of
Disinfectants Used to Inactivate Hepatitis B Virus.'' You may also
follow the automated menu.
3. In person. The Agency has established an official record for
this action under docket control number OPP-00673. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
II. Background
A. What Guidance Does this Notice Provide?
EPA has authority through the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) to register pesticide products, including
antimicrobial pesticide products, for sale and distribution in the
United States. FIFRA section 3(c)(5) requires that the composition of a
pesticide product is such as to warrant the claims made for it, i.e.,
that a product work as claimed. Although registrants must maintain data
demonstrating efficacy in their files and must submit these data to the
Agency upon request, EPA does not routinely review efficacy data prior
to registration of most insecticides, fungicides, herbicides, and non-
public health antimicrobial pesticides. However, for public health
pesticide products (i.e., those that work against pests in situations
where they pose public health threats) the Agency reviews efficacy data
prior to registration. The Agency believes that the potential
consequences of performance failure for public health products warrant
this extra precautionary step in the review process. Moreover, for
public health products intended to control bacteria, fungi and viruses,
the user is typically unable to determine whether the product is
working, due simply to the microscopic size of these organisms.
[[Page 51829]]
Subdivision G of the Pesticide Assessment Guidelines describes the
efficacy tests routinely used to validate the claims made by
antimicrobial public health pesticide products. These guidelines are
available from the National Technical Information Service, 5285 Port
Royal Road, Springfield, VA 22161 (1-800-553-6847).
For the past several years, EPA has been engaged in a process to
identify scientifically and statistically adequate test protocols for
evaluating the efficacy of disinfectants used to inactivate human
hepatitis B virus (HHBV). In May 28, 1986 (51 FR 19174), the Agency
published a Notice of Amendment to Policy regarding certain virucidal
claims. Specifically, the Notice stated that virucidal claims for HBV
would be permissible only for sterilizer products until such time that
acceptable protocols to demonstrate virus isolation and disinfectant
product efficacy could be developed.
In 1990, the Agency received and approved a chimpanzee testing
protocol to support HBV efficacy claims for hard, environmental surface
disinfection products. While the data were being generated using the
approved protocol, a General Accounting Office (GAO) Report was issued
(August 1990) that criticized the Agency for accepting test methods
without criteria or a systematic review process. In response to this
criticism, the Agency initiated a process whereby new protocols would
undergo external review by scientific experts. In 1995, as a result of
this change in process, the chimpanzee protocol was subjected to
external review by experts working in various scientific institutions,
including the Food and Drug Administration (FDA), Center for Disease
Control (CDC), National Institutes of Health (NIH), and two university
medical schools. The experts were asked to review the data generated
using the EPA-approved protocol as well as similar data developed by
Bond et al. 1983, at CDC. After careful review of all comments
received, the Agency concluded that the chimpanzee data submitted by
the applicant, when considered together with the data developed by Bond
et al. 1983, were sufficient to support a label claim of disinfection
against HBV.
During the 1995 external review process for the chimpanzee
protocol, several experts urged the Agency to accept data developed
using a surrogate virus, thus making available an alternative to
chimpanzee testing. One expert stated that it would be unjustified to
permit the use of any type of animal for germicidal testing and that
such testing could be avoided though the use of properly designed in
vitro methods. As a result of these concerns, the Agency began to seek
alternative means of testing the product performance of disinfectant
products intended for inactivation of HBV. One of the steps in this
process was consultation with the FIFRA Scientific Advisory Panel (SAP)
in September 1997. At that meeting the questions posed to the Panel
were as follows:
1. If the Agency decides to replace the chimpanzee test used in
testing the efficacy of disinfectants against human hepatitis B-type
virus, what test methodologies could be used as a replacement? Two
possibilities that have been proposed to the Agency are the duck
hepatitis B Virus Test (DHVT) and the Morphological Alteration and
Disintegration Test (MADT). Could one or both of these tests be used to
test for efficacy against HHVB?
2. If a surrogate test system (i.e., the DHVT) is found to be
acceptable for efficacy testing using HVB, would the results be
sufficient to allow the registrant to make a label claim that the
product was efficacious against HHBV, even though it was tested against
a surrogate virus (i.e., duck hepatitis B virus) and not the human
virus?
Briefly, the SAP's responses to these questions were as follows.
The Panel concurred with the notion that it is unethical to continue to
require testing using a species of primates, chimpanzees, where
alternative methods are available, and observed that there is a long
history of using surrogate microbes to assess the efficacy of
disinfection/sterilization technologies against various classes of
microorganisms. The Panel stated that the duck hepatitis B virus (DHBV)
constitutes an appropriate HHBV surrogate and added that an advantage
to this surrogate is that the DHBV can be utilized in both in vivo and
in vitro settings. In particular, the Panel stated that the DHBV
approach would allow for sufficient numbers of test samples to be used
for each set of experimental conditions so that statistically
significant results can be obtained. The Panel discussed the
possibility that DHBV may be more resistant to germicidal chemical
activity but, in essence, felt that even if this were true it was not a
serious issue, given that hepatitis B-type viruses have been
demonstrated to be sensitive to the activity of a wide spectrum of
liquid chemical germicides including low level disinfectants. While the
panel did not discuss the MADT alternative at great length or exclude
the possibility of its use, it did observe that the test is only
subjective. The Panel stated its belief that registrants who use DHBV
could make a label claim of product efficacy to either the specific
virus or in the alternative to perhaps the whole virus family as a
group. The example of claims against Mycobacterium tuberculosis by
testing against Mycobacterium bovis was cited as precedent for the use
of a surrogate in disinfectant efficacy testing. If tests validate that
a surrogate virus is less or equally susceptible to inactivation by
disinfectants, then logically any product which demonstrates efficacy
against the surrogate virus should be allowed a label claim against
HHBV.
The responses of the SAP to these questions provided invaluable
guidance to the Agency in its pursuit of scientifically adequate test
protocols for evaluating the efficacy of disinfectants used to
inactivate HHBV. The Antimicrobials Division of the Office of Pesticide
Programs sponsored a workshop in July 1998 to discuss alternative
models for testing disinfectants against HHBV. The workshop was
attended by representatives from academia, research centers, testing
laboratories, and industry. Presentations were given by experts in
hepatitis on various animal models of HBV infection followed by
technical presentations on in vitro and in vivo duck models of
infection that might be used in testing disinfectants for use against
HHBV. Presentations were followed by a discussion on criteria to be
used in decision making about surrogate model(s) and proposed labeling
claims of registered products. Many participants in the workshop
proposed that EPA leave the label claim broad, such as ``effective
against HBV'' or ``hepadnavirucidal'' and not add information about the
test organism. Submitted protocols were evaluated and discussed by all
participants. At the end of the workshop an outline was presented,
showing the Agency's implementation plans for allowing products to be
registered with HHBV label claims using surrogate animal models.
Subsequently, the Agency published an FR Notice on December 30, 1998
(63 FR 71924) (FRL-6051-4) announcing the availability of and
requesting comments on two protocols for testing the efficacy of
disinfectants against HHBV. These protocols were for an in vitro assay
using duck hepatocytes and DHBV and an in vivo assay using ducklings
and DHBV.
The Agency received 12 sets of comments in response to that Notice.
Comments were received from consultants, an animal rights organization,
university scientists, the regulated industry, the California
[[Page 51830]]
Department of Pesticide Regulation, and private organizations. These
comments in their entirety are available in the public docket (OPP-
00673). Many of the comments were similar in content, and pertained to
general issues concerning Agency policy or specific sections within the
protocols themselves. To facilitate review and consideration of the
comments, the Agency has grouped comments addressing similar issues
together.
After the Agency reviewed the comments, it reached three
conclusions:
1. It is the Agency's position that duck HBV serves as an adequate
surrogate for human HBV and that the in vitro assay is sufficiently
sensitive to preclude the need for any in vivo testing. The Agency is
adopting, where possible, policies and data requirements that minimize
animal testing, and when animal testing must be conducted, EPA is
committed to reducing the number of animals needed for testing,
reducing the pain and suffering of the test animals, and whenever
scientifically-defensible, replacing animals with validated non-animal
test systems. Therefore, relying heavily on the recommendations of the
SAP, the Agency expects to rely on the use of the in vitro duck
protocol as the method for evaluating the efficacy of disinfectants
used to inactivate HHBV. Notwithstanding its commitment to maximize the
reduction or elimination ofanimal testing where feasible, the Agency
recognizes that some testing may already have been initiated or
completed using the duck in vivo methodology as of the date of this
Notice. On a case-by-case basis, the Agency will generally accept these
data, if deemed valid, to support a registration.
2. Label claims against either the Hepadnavirus family or, more
specifically, HHBV will be permitted when supported by adequate
efficacy claims as described below. In addition, the following label
claim language will be deemed acceptable: ``effective against HBV.''
The Agency believes that these label claims can be supported by
appropriate DHBV efficacy tests, since the surrogate DHBV has been
shown to be a reliable predictor of resistence to chemical disinfection
for the Hepadnavirus family as a whole.
3. To ensure that the in vitro duck method has been adequately
validated, data should be provided from at least two independent
laboratories for each product tested (two batches per product per
laboratory). The validation of a protocol requires the use of a common
positive control disinfectant to be tested concurrently with all new
products. The recommended control is alkyldimethylammonium chloride
(BTC-835, Onyx Chemical Co.) (AOAC Official Methods of Analysis,
Chapter 6, p. 136, 15th Edition, 1990). This agent should serve as both
an intra-laboratory and an inter-laboratory control and will be used
for analyzing the reproducibility of the efficacy data results for that
particular protocol. In order to obtain the necessary inter-laboratory
data, all submissions must additionally be subjected to confirmatory
testing, with the common positive control, at a second laboratory test
facility. It is critical for the Agency to know that a test method is
repeatable; i.e., that there is an appropriately small standard
deviation of log reduction (LR) values found when the test is repeated
on different occasions in the same laboratory as well as when the test
is conducted in different laboratories. The use of the common positive
control and the generation of confirmatory data in a second testing
facility will achieve these goals. A more detailed document outlining
the criteria for validation is available electronically under the
section titled ``Related Documents'' section of the electronic version
of this Notice (``Protocol for Testing the Efficacy of Disinfectants
Used to Inactivate Hepatitis B Virus''). This document may also be
requested by mail directly from the Agency (refer to FOR FURTHER
INFORMATION CONTACT section of this Notice).
B. Guidance Documents
The guidance discussed in this notice is intended to provide
guidance to EPA personnel and to pesticide applicants and registrants.
This notice is not binding on EPA, applicants and registrants, and EPA
may depart from the guidance where circumstances warrant and without
prior notice. Registrants and applicants may propose altenatives to the
protocols described in this notice and the Agency will assess them on a
case-by-case basis.
List of Subjects
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests.
Dated: August 17, 2000.
Marcia E. Mulkey,
Director, Office of Pesticide Programs.
[FR Doc. 00-21784 Filed 8-24-00]
BILLING CODE 6560-50-S