65 FR 166 pgs. 51828-51830 - Pesticides; Protocols for Testing the Efficacy of Disinfectants Against Hepatitis B Virus (HBV); Notice of Availability
Type: NOTICEVolume: 65Number: 166Pages: 51828 - 51830
Docket number: [OPP-00673; FRL-6736-5]
FR document: [FR Doc. 00-21784 Filed 8-24-00]
Agency: Environmental Protection Agency
Official PDF Version: PDF Version
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.
SUMMARY:
The Agency is announcing the availability of guidancetitled "Protocol for Testing the Efficacy of Disinfectants Used to Inactivate Hepatitis B Virusand Corresponding Label Claims." Through this guidance, EPAexpresses 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 willgreatly minimize the use of animals for testing. The Agency is also making available itsresponses 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: barsoum.ibrahim@epa.gov.
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 interestto those persons who manufacture or formulate pesticides. Potentially affected categories andentities may include, but are not limited to:
| Categories | NAICS | Examples of 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 thespecific entities that may be affected by this action. If you have any questions regarding theinformation in this notice, consult the person listed under FOR FURTHERINFORMATION CONTACT.
B. How Can I Get Additional Information, Including Copies of this Document and OtherRelated Documents?
1. Electronically . You may obtain electronic copies of thisdocument from the Office of Pesticide Programs' Home Page athttp://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 documentunder the " Federal Register -EnvironmentalDocuments. " 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 recordfor 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. 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 thePanel 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 concurredwith 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 historyof using surrogate microbes to assess the efficacy of disinfection/sterilization technologiesagainst 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 thissurrogate is that the DHBV can be utilized in both in vivo and in vitro settings. In particular, thePanel stated that the DHBV approach would allow for sufficient numbers of test samples to beused for each set of experimental conditions so that statistically significant results can beobtained. The Panel discussed the possibility that DHBV may be more resistant to germicidalchemical activity but, in essence, felt that even if this were true it was not a serious issue, giventhat hepatitis B-type viruses have been demonstrated to be sensitive to the activity of a widespectrum of liquid chemical germicides including low level disinfectants. While the panel didnot discuss the MADT alternative at great length or exclude the possibility of its use, it didobserve that the test is only subjective. The Panel stated its belief that registrants who useDHBV could make a label claim of product efficacy to either the specific virus or in thealternative 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 forthe use of a surrogate in disinfectant efficacy testing. If tests validate that a surrogate virus isless or equally susceptible to inactivation by disinfectants, then logically any product whichdemonstrates efficacy against the surrogate virus should be allowed a label claim againstHHBV.
The responses of the SAP to these questions provided invaluable guidance to the Agencyin its pursuit of scientifically adequate test protocols for evaluating the efficacy of disinfectantsused to inactivate HHBV. The Antimicrobials Division of the Office of Pesticide Programssponsored a workshop in July 1998 to discuss alternative models for testing disinfectants againstHHBV. The workshop was attended by representatives from academia, research centers, testinglaboratories, and industry. Presentations were given by experts in hepatitis on various animalmodels of HBV infection followed by technical presentations on in vitro and in vivo duckmodels 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 registeredwith 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 werereceived from consultants, an animal rights organization, university scientists, the regulatedindustry, the California Department of Pesticide Regulation, and private organizations. Thesecomments in their entirety are available in the public docket (OPP-00673). Many of thecomments were similar in content, and pertained to general issues concerning Agency policy orspecific sections within the protocols themselves. To facilitate review and consideration of thecomments, 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 HBVserves as an adequate surrogate for human HBV and that the in vitro assay is sufficientlysensitive 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 beconducted, EPA is committed to reducing the number of animals needed for testing, reducingthe pain and suffering of the test animals, and whenever scientifically-defensible, replacinganimals 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 theefficacy 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 beeninitiated or completed using the duck in vivo methodology as of the date of this Notice. On acase-by-case basis, the Agency will generally accept these data, if deemed valid, to support aregistration.
2. Label claims against either the Hepadnavirus family or, more specifically, HHBV will bepermitted when supported by adequate efficacy claims as described below. In addition, thefollowing label claim language will be deemed acceptable: "effective against HBV." TheAgency 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 chemicaldisinfection for the Hepadnavirus family as a whole.
3. To ensure that the in vitro duck method has been adequately validated, data should beprovided from at least two independent laboratories for each product tested (two batches perproduct per laboratory). The validation of a protocol requires the use of a common positivecontrol disinfectant to be tested concurrently with all new products. The recommended controlis alkyldimethylammonium chloride (BTC-835, Onyx Chemical Co.) (AOAC Official Methodsof 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 ofthe 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 thecommon positive control, at a second laboratory test facility. It is critical for the Agency toknow that a test method is repeatable; i.e., that there is an appropriately small standard deviationof log reduction (LR) values found when the test is repeated on different occasions in the samelaboratory as well as when the test is conducted in different laboratories. The use of thecommon positive control and the generation of confirmatory data in a second testing facility willachieve these goals. A more detailed document outlining the criteria for validation is availableelectronically under the section titled "Related Documents" section of the electronic versionof this Notice ("Protocol for Testing the Efficacy of Disinfectants Used to Inactivate Hepatitis BVirus"). This document may also be requested by mail directly from the Agency (refer to FORFURTHER INFORMATION CONTACT section of this Notice).
B. Guidance Documents
The guidance discussed in this notice is intended to provide guidance to EPApersonnel and to pesticide applicants and registrants. This notice is not binding onEPA, applicants and registrants, and EPA may depart from the guidance where circumstanceswarrant 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, Agriculturalcommodities, 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