
\* MERGEFORMAT
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                               
                                                                               
                                                  OFFICE OF CHEMICAL SAFETY AND
                                                                                               POLLUTION PREVENTION

MEMORANDUM

Date:  February 2, 2016

SUBJECT: Response to Public Comments: Process for Establishing and Implementing Alternative Approaches to Traditional In Vivo Acute Toxicity Studies

PC Code:  NA
DP Barcode:  xxx
Decision No.:  NA
Registration No.:  NA
Petition No.:  NA
Regulatory Action:  NA
Risk Assessment Type:  NA
Case No.:  NA
TXR No.:  NA
CAS No.:  NA
MRID No.: NA
40 CFR:  40 CFR§180.342

FROM:		Evisabel Craig
			Chris Schlosser
			Health Effects Division (7509P)	
	

THROUGH:		Anna Lowit, Senior Scientist
			Health Effects Division (7509P)

TO:			Jennifer McLain, Deputy Director
			Antimicrobials Division (xxx)
                                       
In early 2015, the EPA published a draft document delineating the proposed process for establishing and implementing alternative approaches to traditional in vivo acute toxicity studies. Members of the private sector, non-governmental organizations and the general public had the opportunity to provide comments to further strengthen and improve the draft document. The EPA has taken into consideration all comments received and made appropriate changes to the revised document.  The following memorandum constitutes a formal response to the aforementioned comments.
Overall Positive Comments

During the public comment period, EPA received an array of comments from the private sector, non-governmental organizations and private individuals. Overall, the majority of comments received by EPA were positive and supportive of the proposed guidance along with the direction that the agency is headed with respect to expanding the implementation of alternative approaches. A few comments asked for clarifications or revisions of the document, and responses to these are summarized below. Comments have been summarized and responses organized based on the section of the document they pertain to.

Collaboration

ACC, CLA and NC3R  -  suggest that EPA work with other federal agencies (FDA, CPSC, etc.) and OECD in the development of test guidelines for any specific alternative method being proposed to ensure consistency and harmonization. 

EPA is already working with other federal, state and international agencies and will continue to do so to ensure consistency and harmonization of test guidelines, and has included language to that effect on page 7 of the Process guidance.

Syngenta  -  state that the proposed approach needs to be part of the NAFTA regulatory cooperation process to be successful.   

The Agency is aware of the importance of international cooperation. OPP has already been collaborating with PMRA on the use of alternative approaches for the acute 6-pack battery.  However, this guidance is drafted in the context of FIFRA section 6(a)(2), which is a US-specific statute. Interested parties are encouraged to contact Canada PMRA regarding their efforts on alternative methods to in vivo toxicity testing.

Other Alternative Methods

Biocides Panel - Acknowledge that there are existing alternative approaches to the six studies requirement including waiving and bridging, as discussed in EPA's Guidance for Waiving or Bridging of Mammalian Acute Toxicity Tests for Pesticides and Pesticide Products (Acute Oral, Acute Dermal, Acute Inhalation, Primary Eye, Primary Dermal, and Dermal Sensitization) (dated March 1, 2012).  

A citation of the aforementioned bridging guidance document has been added.

CLA, PETA/PCRM  -  -  would like to have in silico methods included, not just in vitro. 

A reference to in silico methods has been included.




Evaluation Phase

ARDF and Syngenta  -  Text places too much emphasis on comparing new alternative methods to current "in vivo" standards.  The draft guidance should do more to: 1. move away from apical endpoints and towards pathways-based approaches; 2. incorporate more guidance on integrated testing strategies-how they could be developed and applied to the chemicals under consideration.

As guidelines for in vivo studies are referenced in the current data regulations at 40 CFR part 158, any developed alternative approaches will most often be compared to these standards already in place to determine the suitability of the alternative approach in replacing the required studies, except in cases where the alternative approach has been shown to be more predictive of human effects than the in vivo laboratory animal study.  These comparisons do not preclude use of adverse outcome pathways as scientific foundation for developing or evaluating alternative approaches for use as stand-alone replacements or as part of an integrated approach on testing and assessment (IATA) process or integrated testing strategy (ITS).  

With respect to developing integrated testing strategies, the agency expects IATAs/ITS to be developed on a case-by-case basis for various endpoints or effects; this level of detail is beyond the scope of the  "Process For Evaluating & Implementing Alternative Approaches to Traditional In Vivo Acute Toxicity Studies for FIFRA Regulatory Use" document.


Syngenta  -  Provide clarification on who is responsible for data generation, is it voluntary? Also, it is not clear in the current document how something is determined to be useful for regulatory purposes.    

In the near future, the Agency's expectation is that data to be used will likely come from existing sources of data (e.g. industry or in-house research and development).  Data may come from any source and participation in this initiative is voluntary. However, the Agency notes that limited participation by industry may lead to slower adoption of alternatives methods and/or narrow adoption with respect to chemical space of applicability.  Considerations to determine whether data are useful for regulatory purposes are discussed in section IIA (e.g. the degree to which a method has been validated by an international validation process).

CLA - suggest EPA consider test methods which have been vetted through an international validation process (i.e., OECD) in order to ensure consistency in test methods and data interpretation, particularly when conducting any evaluation correlating in vitro to in vivo results. 

The Agency notes that OECD does not validate methods, per se.  The role of the OECD is develop guidelines from well-established methods.  There are validation organizations around the world who work collaboratively to achieve validation (https://ntp.niehs.nih.gov/pubhealth/evalatm/iccvam/international-partnerships/index.html).  The issue identified in this comment is addressed in point 1 under "considerations during the evaluation phase" in the draft guidance. The Agency concurs that well-established methods will be the focus during the evaluation phase.

PETA/PCRM - suggest the EPA add language stating that the agency should be consulted prior to the data being generated to ensure the study is conducted in a manner that meets any applicable standards for evaluating the method. Add language clarifying suitability of methods for all classes vs. class-specific methods, and if class-specific methods are acceptable. 

The Agency expects to use data that has already been generated.  For new data generation, EPA encourages and welcome open dialogue.  The Agency often reviews study protocols and invites the submission of protocols. The suitability of a method, whether class-specific or across many classes, will be assessed during the evaluation phase as stipulated in point 3 of the evaluation phase section.

Transition Phase

ARDF  -  Do not extend public comments into the transition phase, work with state and international regulators early in the process. Discourage use of "in vivo" studies as early as possible. 

The previously titled transition phase has been renamed "the proposal and public comment phase". As discussed in IIA, throughout the course of an evaluation, the Agency will engage diverse stakeholders including states, NGOs, international partners and other federal agencies.

Syngenta and PETA/PCRM - No length of time or volume of data required was identified for the transition phase. Concerns were raised regarding cost for potential registrants who must utilize more than one test method for one endpoint for an indeterminate period of time. Suggestions include that methods that already have been substantially evaluated (for example at OECD) and/or undergone peer review, be subject to an abbreviated transition phase. Also, it is suggested that the EPA set up some form of outreach (ideally including incentives such as fast-track review) that would encourage companies to submit data so that, with a greater volume of submittals, the transition period could hopefully be shortened.

The previously titled transition phase has been renamed "the proposal and public comment phase". The Agency will work diligently after the public comment period closes to issue a revised policy in a timely manner to ensure rapid application. Typical comment periods are 30-90 days but extensions may be granted whenever appropriate. Upon finalization of the policy, it will be the choice of the submitter to use the alternative approach or the traditional in vivo test. The statement encouraging data submission during the comment period seemed to confuse readers so it has been removed. However, consistent with EPA's regulations, companies may submit data generated with an alternative method at any time. 

EPA appreciates the suggestion of incentives and encourages the commenters to provide specific ideas to the agency.

Implementation Phase

PETA/PCRM  -  Provide discussion on the phase-out of in vivo methods in the event that one or more acute in vitro methods are deemed acceptable by the agency. We would hope that a "test on animals only as a last resort" policy could be developed.

Our 2013 document, Guiding Principles for Data Requirements, states that "The goal is to ensure there is sufficient information to reliably support registration decisions that are protective of public health and the environment while avoiding the generation and evaluation of data that do not materially influence the scientific certainty of a regulatory decision. It is important to only require data that adequately inform regulatory decision making and thereby avoid unnecessary use of time and resources, data generation costs, and animal testing."

6a2

CLA - Clarity is also sought regarding the timing of if and when FIFRA §6(a)(2) reporting will be required for a new method, and whether the requirement for reporting would apply to specific individual methods or to multiple approaches combined in an integrated fashion.

As stated in section C (implementation phase) and section III (page 7), data generated with an alternative method for which the Agency has issued a final policy detailing how the data generated with the method (or a set of methods) should be interpreted with respect to EPA labeling requirements will be reportable under section 6(a)(2). In the evaluation phase of the process, the results of the alternative testing methods are unlikely to be of interest to EPA, because the degree to which those results correspond to EPA's regulatory criteria is unknown.  Through its evaluation process, the Agency will determine whether the alternative method(s) may meet OPP's regulatory needs. Whether the requirement for reporting would apply to specific individual methods or to multiple approaches combined in an integrated fashion will depend on the particular policy at hand. The critical factor is whether the Agency has determined how to interpret the data with respect to EPA's regulatory criteria. If the interpretation is dependent on using results from a set of methods combined in an integrated fashion, only such data are reportable. However, if the Agency issues criteria for interpreting data from individual methods with respect to EPA's regulatory criteria, whether or not those individual methods may also be combined in an integrated fashion, data from the individual methods would be reportable.   

Syngenta - Should an agreement of not changing already approved label/registration, like EDSP program used, be included for participants evaluating alternative assays? We're interested in the comments on PRF of effects. Currently, our criteria state that, when used as a screen, in vitro results are not referable. In this case referability is entirely dependent on the in vivo data. When used as a stand-alone assay an in vitro test would be referable. We need to understand exactly how the EPA's comments would affect this. 

FIFRA section 6(a)(2) provides that "if 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 is required irrespective of whether the study is in vitro, in vivo, used as a screen or as a stand-alone assay. The 2009 "Endocrine Disruptor Screening Program; Policies and Procedures for Initial Screening" document, section K states that "Under FIFRA section 6(a)(2), pesticide product registrants are required to submit adverse effects information about their products to the EPA", which corresponds to the discussion in "Process for Evaluating & Implementing Alternative Approaches to Traditional In Vivo Acute Toxicity Studies for FIFRA Regulatory Use."

ARDF  -  Establish a framework for "systematic review" instead of a "weight-of-evidence" approach in order to provide a scientific method for data integration. 

In recent years, the National Academy of Sciences has encouraged the Agency to move towards systematic review processes to enhance the transparency of scientific literature reviews that support chemical-specific risk assessments to inform regulatory decision making.  According to the National Research Council, systematic reviews "have several common elements: transparent and explicitly documented methods, consistent and critical evaluation of all relevant literature, application of a standardized approach for grading the strength of evidence, and clear and consistent summative language. "  EPA's Office of Chemical Safety and Pollution Prevention is currently developing systematic review policies and procedures. Weight of evidence analysis is the Agency's process for evaluating the strength of the scientific evidence along with integrating such evidence as a component of systematic review.  

ARDF and NC3R  -  Is a safe harbor from 6A2 possible?  Is it possible to elaborate on how this will be done - are there plans to establish a framework? (In considering data for 6a2).

EPA believes that it would be inconsistent with its FIFRA mandate to create a "safe harbor" that would allow registrants to withhold information "if the registrant knows, or reasonably should know, that if the information should prove to be correct, EPA might regard the information alone or in conjunction with other information about the pesticide as raising concerns about the continued registration of a product or about the appropriate terms and conditions of registration of a product prevent unreasonable adverse effects of pesticides." (§ 159.195(a)). However, EPA emphasizes that information submitted pursuant to section 6(a)(2) will not necessarily dictate regulatory decisions or label amendments. 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.    

General Comments

PETA/PCRM  -  On page 3, footnote 5 indicates that the document does not apply to in vitro or alternative methods used to develop adverse outcome pathways. We are not sure what this refers to as the assays involved in evaluating skin sensitization, for example, i.e., DPRA, KeratinoSens, and hCLAT, all measure events along the AOP for this endpoint. We would ask that the OPP provide more clarification on this footnote.

Footnote 5 has been removed.
