Page **1** of **6** UNITED STATES ENVIRONMENTAL PROTECTI ON AGENCY

WASHI NGTON, 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 V**  **ivo 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 Schloss er Health Effects Division (7509P) **THROUGH:** Anna Lowit , Senior Scientist

Health Effects Division (7509P) **TO:** Jennifer McL ai n, Deputy Director

Antimicrobial s Division (xxx) In earl y 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. T he following memorandum constitutes a formal response to the aforementioned comments.Page **2** of **6**

**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 b y 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 su**  **ccessful.** 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 sec tion 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 I**

**nhalation, Primary Eye, Primary Dermal, and Dermal Sensitization) (dated March 1, 2012).**  **1** A citation of the afore mentioned bridging guidance document has been added. **CLA , PETA/PCRM** 
**– would like to have**  **in silico methods included**  **, not just in vitro.** A reference to i n silico methods ha s been included.

1 Available at http://www2.epa.gov/sites/production/files/documents/acute
- data
- waiver
- guidance.pdf
.Page **3** of **6**

**Evaluation Phase ARDF**  **and Syngenta**
**– Text places too much e** **mp hasis on**  **comparing new alternative methods to curren**  **t “in vivo” standards. T he 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 d ata 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 th e required studies , except in cases where the a lternative 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 approac hes for use as stand
- alone replacements or as part of an integrated approach on testing and assessment (IATA) process or integrated testing strategy (I TS)
. 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 & Imple menting Alternative Approaches t o Traditional In Vivo Acute Toxicity Studies f or F IFRA Regul atory

Use 

### ” document. **Syngenta**
**– Provide clarification on who is responsible for data generation, is it voluntary?**  **Also, i t 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 e xisting 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 b y an international validation process)
. **CLA -**  **sugge st 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 valid ate 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 “consideratio ns during the evaluation phase” in the draft guidance. The A gency concurs that well
- established methods will be the focus during the evaluation phase
.Page **4** of **6**

**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 man y 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 p**  **hase, work with state and international**  **regulators early in the process. Discourage use of “in vivo” studies as early as possible.**  The previousl y titled transition phase has been renamed “ the proposal and public comment phase ”
. As discussed in IIA, throu ghout the course of an evaluation, the A gency 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 a**  **n indeterminate period of time. S uggest**  **ions include that**  **methods that already hav e 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 submitt als**  **, the transition period could**  **hopefully be shortened.** The previousl y titled transition phase has been renamed “ the proposal and public comment phase ”
. The A gency will work dili gently

after the public comment period closes to issue a revised policy in a timely manner to ensure rapid application. Ty pical comment periods are 30
- 90 day s 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. Th e statement encouraging data submission during the comment period seemed to confuse readers so it has been removed. However, consistent with EPA’s regulations, co mpanies 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 .** Page **5** of **6**

Our 2013 document, Guiding Pri nciples 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 adequatel y inform regulatory

decision making and thereb y 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 A genc y 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 test ing methods are unlikely to be of interest to EPA, because the degree to which those results correspond to EPA’s regulatory criteria is unknown
. 2 Through its evaluation process, the A gency 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 A gency

has determined how to interpret the data with respect to EPA’s regulat ory 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 A genc y issues criteria for interpreting data from individual methods with respect to E PA’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, l ike 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 “ 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 is required irrespective of whether the study i s 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
2 Even in the absence of a reasonably reliable correlation between the O ECD methods and EPA’s methods , it is possible

– though unlikely

– that testing under the OECD methods could produce information reportable under FIFRA section 6(a)(2). For example, if a product or class of products that routinely show low levels of toxici ty

in [some EPA method] were to consistently show unexpectedly high levels of toxicity under an alternative method, a reasonable person might vie w the divergence in results as raising questions about which method adequately reflects the true risk of the pr oduct(s). It would be im portant 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.Page **6** of **6**

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 “ Proces s f or Evaluating & Imple menting Alternative Approaches t o Traditional In Vivo Acute Toxicity Studies f or F IFRA 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 sy s tematic review processes to enhance the transparency of scientific literature reviews that support chemical
- specific risk assessments to inform regulatory decision making 3

. According to the National Research Council, s ys tematic reviews “have several commo n 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 co nsistent summative language. ” EPA’s Office of Chemical Safety and Pollution Prevention is currentl y developing sy stematic review policies and procedures . W eight of evidence anal ys is is the A genc y’ s process for evaluating the strength of the scientific evidence along with integrating such evi dence as a component of sy stematic 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 b e 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 pesticide s.” ( § 159.195(a) ). However, EPA emphasizes that i nformation 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 previousl y su bmitted 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 clarificatio n on this footnote.**  F ootnote 5 has been removed.

3 NRC 2011. “Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde” ; NRC 2014. “Review of EPA's Integrated Risk Information System (IRIS) Process”