Draft For Public Comments

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### PROCESS FOR ESTABLISHING & IMPLEMENTING ALTERNATIVE **APPROACHES TO TRADITIONAL IN VI**  **VO ACUTE TOXICITY**  **STUDIES**

12/15/2014

Office of Pesticide Programs U.S. Environmental Protection Agency Washington DC, 20460Draft For Public Comments

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**I. B**  **ACKGROUND** EPA’s Office of Pesticide Programs (OPP) has developed a strategic vision 1 for implementing the 2007 NRC report on Toxicity Testing in the 21 st Century2 . This strategic vision has multiple components involving a combination of computational and predictive modeling approaches, in vitro techniques, and limited, targeted in vivo testing , to supplement or replace the existing toxicity tests required in 40 C.F .R. part 158 3 (40CFR158) in support of pesticide registration
. In May 2011, the agency

so ught exp ert a dvi ce and input from its the Federal Insecticide, Fungicide and Rodenticide Act ( FIFRA ) Sc i e nti f ic Adviso ry Pane l (S AP ) on OPP's vision and scientific iss ues associated with adopting integrated approaches to testing and assessment (IATA) and strategies for using new computational and molecular tools. The Panel concurred that OPP’s strategic vision clearly

articulated a sound scientific basis for utilizing the NRC’s recommendations regarding “21 st Century Toxicity Testing” in a manner that makes the risk assessment process more efficient and informative. And, the Panel commented that utilizing data from rapidly

and inexpensively

performed in silico and in vitro technologies appears to be the most logical way

to address the need to improve efficiency
. As part of the implementation of the strategic vision, OPP developed a document called

“ GUID ING PRINCIPLES for DATA REQUIREMENTS 4 ” which describes some of the key principles in moving towards smarter testing approaches . In 2013, OPP ’ s policy on the “Use of An Alternative Testing Framework for Classification of Eye Irritation Potential of EPA Pesticide Products ” was another early step toward this vision
. As science is rapidly advanc ing and new technologies are emerging , including some alternatives assays with Organization for Economic Co
- operation and Development (OECD) guidelines , there is increasing potential for the use of alternative method s in regulatory ris k assessment
. OPP plans to continue to expand its acceptance of alternative methods for acute toxicity testing
. The agency ’s goals for alternative testing approaches include: assessing a broader range and potentiall y more human
- relevant

1 http://www.epa.gov/pesticides/science/testing
- assessment.html#pesticide 2 http://dels.nas.edu/resources/static
- assets/materials
- based
- on - reports/reports
- in
- brief/Toxicity_Testing_final.pdf 3 http://www.ecfr.gov/cgi
- bin/text
- idx?tpl=/ecfrbrow se/Title40/40cfr158_main_02.tpl 4 http://www.epa.gov/pesticides/regulating/data
- require
- guide
- principle.pdfDraft For Public Comments

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adverse effects, fa ster and less expensive data generation and review, and reducing use of laboratory

animals in regulatory

testing. Th is document describes a transparent, stepwise process for evaluating and implementing alternative methods of testing for acute oral , dermal, inhalation toxicity, along with skin and eye irritation and skin sensitization ( often referred to as the “six pack studies”) 5

. In cluded in this document is a discussion of the three major phases of this process, and the implications for reporting i nformation under section 6(a)(2) of FIFRA. Having such a process and a clear articulation of the related reporting requirements addresses a challenge that has previousl y been associated with adopting alternative methods. Successfully putting this process i nto place will require an open dialogue with stakeholders , other regulatory organizations, and the scientific community
. **II. STEPWISE**  **PROCESS FOR EVALUATING & IMPLEMENTING**  **ALTERNATIVE METHODS** 
T he following text describes the major components of a transparent , stepwise process for evaluating and implementing in vitro or other alternative methods in OPP’s regulatory decision making with respect to acute toxicity tests . These components include :

1. **Evaluation** 2. **Transition** 3. **Implementation** OPP expects the alterative methodologies considered appropriate for this stepwise process to be well established by

the scientific community with respect to reproducibility and domain of applicability ; these methods may or may not have OECD guidelines. This process is fo cused on the utility of methods for regulatory application and is thus designed for well
- established me thods (for example, methods that have been ring
- tested)
. M ethods still in development or poorly characterized with respect to performance require further research and evaluation that is

5 This document does not apply to in vitro or alternative method s used for other purposes such as quantitative structure activity relationships, mechanistic or pharmacokineti c data used to support mode of action, adverse outcome pathways, or pharmacokinetic models.Draft For Public Comments

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out of the scope of this process . T he process does not prescribe a specific timeframe for each stage as the anal ys is required at each stage may differ among various methods. **A. Evaluation**  **Phase of Alternative Method(s)**  The purpose of the evaluation phase is to determine whether an alternative method(s) could be used for regulatory

purposes. The first step in the process is to identify an alternative method or sy stem (array) of methods that have the potential to be used in place of a traditional acute toxicity test. Organizations or coalitions of stakeholders interested in pursuing an evaluation of an alternative method for regulatory applicability are welcome to contact OPP for a consultation. Alternativel y, EPA may

identify promising alternatives.
T he objectives of the evaluation are to determine the reliability of the alternative method , evaluate the method in the context of regulatory use , an d identify

uncertainties
. So me considerations during the evaluation phase are: 1) the degree to which the method has been vetted by an international validation process ( e.g ., ASTM International 6 ) and/or the availability of an OECD guideline ; 2) whether the method is appropriate for sin gle chemicals , mixtures, or both; 3) the ty pes of chemicals which can be used with the method i.e ., the domain of applicability ; 4) whether the method can be used alone as a replacement for an in vivo study or the method must be used in combination with others as part of an integrated approach on testing and assessment (IATA) 7 process ;

6 http://www.astm.org/ABOUT/full_overvie w. html 7 **IATA (Integrated Approach to Testing and Assessment)**  : Integrate existing knowledge based on classes of chemicals with the results of biochemical and cellular assays, computational predictive methods, exposure studies, and other sources of information to identify requirements for targeted testing or develop assessment conclusions. In some cases, the application of IATA could lead to the refinement, reduction, and/or replacement of selected conventional tests (e.g., animal toxicity tests). IATA also has the potential to further enhance the understanding of mo de/mechanism of action including the consideration of relevant adverse outcome pathways (AOPs) that provide biological linkages between molecular initiating events to adverse outcomes in individual organisms and populations that are the bases for human health and ecological risk assessments (NAFTA, 2012). Extracted from http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=ENV/JM/MONO(2014)19&doclanguage= enDraft For Public Comments

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5) additional strengths and uncertainties associated with the assay such as feasibility , sensitivity

and specificity, ease of interpretation, costs, etc .; and, 6) whether information derived from the assay(s) is suitable for labeling and regulatory decisions (including whether the method(s) provide information relevant to risk assessment in addition to information for labeling decisions)
. Once a proposed alternative method(s) is accep ted as a suitable candidate, the evaluation process would consist of a number of steps. First, existing data generated using the alternative method(s) will be collated and organized ( for example in a spreadsheet or database). The data could be previously

g enerated or generated explicitly for the purpose of informing an evaluation of regulatory

applicability . This data compilation could be accomplished in various way s. For example, a coalition of interested companies could work with a neutral party to collec t and aggregate data so that confidential business information (CBI) would be concealed. Once the data are compiled, OPP anticipates performing an anal ys is , through which OPP and interested stakeholders would cooperativel y evaluate the utility of these data in the context of regulatory

decision making under FIFRA ( e.g. , approval of uses, application methods, labeling requirements for signal words and personal protective equipment). Part of this analy sis will include comparison with existing dat a generated through EPA’s approved test methods ( i.e ., consistent with existing test guidance). This anal ysis would consider how EPA would use data from the alternative method to classify products for acute toxicity labeling (Categories I

– IV ) 8

. Throughout the course of an evaluation, the agency will engage diverse stakeholders including states, non - government organizations (NGOs) and other federal agencies. The agency will seek peer review of the evaluation when necessary
. OPP’s goal for the evaluation phase is to end with a determination that an alternative method (s) is suitable for regulatory

purposes . Such a determination would come in the form of an EPA publication of a draft policy document (e.g., waiver guidance) for public comment on the proposed approach method and the appropriateness of the alternative method for a stated

8 http://www2.epa.gov/pesticide
- registration/label
- review
- manualDraft For Public Comments

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regulatory

purpose , including the establishment of a correlation between method results and a toxic effect si milar to those measured b y current guidelines
. The draft policy document would also discuss any

requirements the agency may have with respect to needing in vivo data. For example, depending on the method(s) proposed, a certain amount of in vivo oral acute toxicity data may be necessary

to support ecological risk assessments. At this point, with the publication of the draft policy , the agency will provide notice of its expectation and timeframes for reporting under section 6(a)(2) of FIFRA.
In some cases, the method(s) may be found not useful for regulatory purposes. Sometimes, areas for additional method development that have the potential to make the method more useful for regulatory

purposes may

be identified. For example, some alternative assays are d eveloped for use with a single chemical ; because acute toxicity testing is conducted on both single technical ingredients and formulations ( i.e., mixtures) , additional testing may be necessary

to evaluate the applicability

of a particular method for mixtures ( i.e., formulations)
. In other cases, the agency may recommend modifications to the test methods or the overall alternative approach.

**B. Transition**  **Phase**
In this phase, OPP would accept data generated from the alternative method(s ) , which w ere conducted following the draft policy document , and submitted along with corresponding data from its in vivo method counterpart (or citation to previously submitted in v ivo studies )
. This would provide the broader registrant community with the opportunity to practice conducting the method(s) and the agency additional experience in assess ing the data
. During the transition, the public will have the opportunity to provide comments on the draft policy document. The agency will use the public comments to revise the draft policy where appropriate. The agency is also aware of the importance of national and international harmonization and will continue to work with state and int ernational regulators on use of the alternative method.

**C. Implementation** Draft For Public Comments

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After addressing any potential issues identified through public comment s, a final science policy will be completed and released
. Subsequentl y , data generated from the accepted alternative approach may

be submitted to fulfill the requirement of its standard in vivo counterpart. D ata generated with the method will be reportable under section 6(a)(2) , if relevant, regardless o f when the data were generated (see Section III below)
. **III. APPLICABILITY OF FIFRA 6(a)(2) REQUIREMENTS**  FIFRA section 6(a)(2) provides that “ [i] f at any time after the registration of a pesticide the registrant has additional factual information regarding unreasonable adverse effects on the environment of the pesticide, he shall submit such information to the Administrator. ” This does not mean that the reported information will necessarily lead to regulatory

decisions or label amendments: Information is reportable under sectio n 6(a)(2) if it simply “ pertain[s ] or relate[s

] to unreasonable adverse effects on the environment; it does not have to indicate, establish, or prove the existence of such effects. ” 43 Fed.Reg. 37611, 37612 (Aug. 28, 1978 ) ( emphasis in the original). EPA alway s considers new information submitted pursuant to section 6(a)(2) in the context of the full range of data previously submitted in support of the registration, applying a weight of the evidence approach to the multiple lines of available evidence . L ike wise, OPP will review any information arising through the development of a new test method in relation to other pertinent information about the pesticide. The process described above for evaluating and implementing alternative methods for in vivo acute toxicity

studies includes comparing existing data previousl y generated by EPA’s test methods with data generated using an alternative test methodology ( e. g. , OECD Skin Irritation)
. Part of the focus of this comparison is simply to understand both the degree to which there is correlation between the standard in vivo and the alternative methods and the degree to which determinations regarding adverse effects can be made with the alternative method(s)
. P esticide registrants cooperating in this evaluation would already have submitted to EPA any information required to be reported under section 6(a)(2) arising from previous testing generated using EPA’s test guidelines ( i.e., in vivo test results) for registered pesticides . As a result, the scope of the new information arising from the evaluation that could potentially be reportable under sectionDraft For Public Comments

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6(a)(2) would be limited to information arising from the alternative methods or from any new correlation established between the alternative method ologies and the methods upon which EPA currentl y relies
. At the beginning of the process, the results of the alternative test ing methods are unlikel y to be of interest to EPA, because the degree to which those results correspond to EPA’s regulatory criteria is unknown . 9 Through its evaluation process , the agency will determine whether the alternative method (s) may meet OPP’s regulatory needs. If the evaluation is successful in developing a reasonabl y reliable correlation between the different test methods, then the results of alternative test methods would be more likel y to be of regulatory utility to EPA
. For example, i f a reasonabl y reliable correlation between the alternative assay and EPA’s skin irritation criteria were developed, registrants who possess or k now of information that, in the context of the new policy , would raise concerns about the continued registration of a product or about the appropriate terms and conditions of the registration of a product, would be required to report that information to EP A (§ 159.195(a)). This would apply to data previously

developed using existing test methods ( e.g., th e in vivo methods ) , as well as to data generated during initial research of new test methods
. Itwould appl y to all registrants i.e., those who are not cooperating in the anal ys is , as well as cooperating registrants.
In formation submitted pursuant to section 6(a)(2) will not necessaril y dictate regulatory decisions or label amendments. For the case of acute toxicity studies, an in vitro test result corresponding to a higher hazard category than that associated with an acceptable in vivo test result would not necessarily require a label change nor would an in vitro result corresponding to a lower hazard category necessarily lead to a lab el change
. EPA will consider reported data in the context of the full range of data previously submitted in support of the registration, applying a weight of the evidence approach.

9 Even in the absence of a reasonably reliable correlation between the OECD methods and EPA’s methods , it is possible

– though unlikely

– that testing under the OECD methods could produc e information reportable under FIFRA section 6(a)(2). For example, if a product or class of products that routinely show low levels of toxicity in [some EPA method] were to consistently show unexpectedly high levels of toxicity under an alternative method , a reasonable person might view the divergence in results as raising questions about which method adequately reflects the true risk of the product(s). It would be important for EPA to have such information, even if there was little short
- term

likelihood of either a regulatory response or a scientific explanation for the divergence.