Response to Public Comments on the Notice of Receipt of application for registration of pethoxamid, submitted by FMC Corporation, and on EPA's "Proposed Registration Decision for the New Active Ingredient Pethoxamid" (Docket ID: EPA-HQ-OPP-2017-0510)
This document summarizes the U.S. Environmental Protection Agency (referred hereafter as EPA or the Agency) responses to public comments received through the public notification of the receipt of application for registration of the new active ingredient pethoxamid, and the announcement of the proposed decision to unconditionally register pethoxamid under 3(c)(5) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).
The Agency, as required by FIFRA section 3(c)(4), published in the Federal Register on February 27, 2018 a Notice of Receipt (NOR) of application for registration of pethoxamid, submitted by FMC Corporation, and announced a public comment period of 30 days.  During the public comment period, one comment was received from the Center for Biological Diversity (CBD).  The Agency's review and response is summarized in this document.
EPA then announced the proposed decision of the unconditional registration of pethoxamid on May 18, 2020 and held another public comment period for 30 days. Three comments were received during that period, from CBD, the United States Department of Agriculture (USDA), and from an anonymous commenter.  The Agency's review and responses are summarized in this document.  
 Comment Received on NOR of Pethoxamid
CBD Comment #1 (presented in summary form): Comply with duties under Section 7 of the Endangered Species Act (ESA), including completion of consultation on all synergistic and cumulative uses.
EPA Response: OPP's ecological risk assessment process is based on EPA's Guidelines for Ecological Risk Assessment (https://www.epa.gov/risk/guidelines-ecological-risk-assessment) and consists of a comprehensive, robust, and peer-reviewed process that considers extensive environmental fate and ecological effects data used to evaluate the potential ecological exposure and impacts of a pesticide in the environment. This risk assessment is conducted to support the overall decision-making for the proposed pesticidal use.
In November 2013, the EPA, along with the U.S. Fish & Wildlife Service (USFWS), the National Marine Fisheries Service (NMFS) (collectively, the Services), and the U.S. Department of Agriculture (USDA) released a summary of their joint Interim Approaches for assessing risks to Federally listed threatened and endangered species (collectively, listed species) from pesticides. The Interim Approaches were developed jointly by the agencies in response to the National Academy of Sciences' (NAS) recommendations and reflect a common approach to risk assessment shared by the agencies as a way of addressing scientific differences between the EPA and the Services. The NAS report outlines recommendations on specific scientific and technical issues related to the development of pesticide risk assessments that EPA and the Services must conduct in connection with their obligations under the Endangered Species Act (ESA) and FIFRA.
The details of the joint Interim Approaches are contained in the white paper "Interim Approaches for National-Level Pesticide Endangered Species Act Assessments Based on the Recommendations of the National Academy of Sciences April 2013 Report," dated November 1, 2013.
Since that time, EPA has conducted biological evaluations (BEs) on three pilot chemicals representing the first nationwide pesticide consultations (final pilot BEs for chlorpyrifos, malathion, and diazinon were completed in January 2017). These initial pilot consultations were envisioned to be the start of an iterative process. The agencies are continuing to work to improve the consultation process. For example, after receiving input from the Services and USDA on proposed revisions to the pilot interim method and after consideration of public comments received, EPA released an updated Revised Method for National Level Listed Species Biological Evaluations of Conventional Pesticides (i.e., Revised Method)  in March 2020. During the same timeframe, EPA also released draft BEs for carbaryl and methomyl, which were the first to be conducted using the Revised Method. 
Also, a provision in the December 2018 Farm Bill included the establishment of a FIFRA Interagency Working Group to provide recommendations for improving the consultation process required under section 7 of the Endangered Species Act for pesticide registration and Registration Review and to increase opportunities for stakeholder input. This group includes representation from EPA, NMFS, FWS, USDA, and the Council on Environmental Quality (CEQ). Given this new law and that the first nationwide pesticide consultations were envisioned as pilots, the agencies are continuing to work collaboratively as consistent with the congressional intent of this new statutory provision. EPA has been tasked with a lead role in this group, and EPA hosted the first Principals Working Group meeting on June 6, 2019.  
Given that the agencies are continuing to develop and work toward implementation of the Interim Approaches to assess the potential risks of pesticides to listed species and their designated critical habitat, the risk assessment for pethoxamid does not include a complete ESA analysis and effects determinations for specific listed species or their designated critical habitat.
With respect to the evaluation of pethoxamid and as explained in the proposed decision, current data indicate that the ecological risks presented by uses of pethoxamid are generally low. To the extent that the EPA receives new information indicating that pethoxamid may pose a greater risk to listed species than indicated by the existing scientific database for this pesticide, the EPA will reevaluate the terms of registration and determine whether use restrictions to protect listed species are necessary.
CBD Comment #2: Require that the registrant provide all necessary data and studies.
EPA Response: The registrant (FMC Corporation) for pethoxamid has satisfied all guideline requirements in their submission in support of registration of pethoxamid. The current database is complete and supports the human health and ecological assessments. No data gaps were identified for pethoxamid.
CBD Comment #3: Incorporate necessary factors (effects on ESA listed species, effects on pollinators and other beneficial insects, endocrine disruption, and cumulative or synergistic effects) into evaluation and any proposed decision.
EPA Response: Effects on ESA listed species is addressed above (see EPA response to CBD comment #1).
Furthermore, the ecological risk assessment conducted in support of the registration of pethoxamid, evaluated potential risks to pollinators. In estimating risk to bees associated with the proposed uses of pethoxamid, the Agency followed OPP's published guidance entitled "Guidance for Assessing Pesticide Risks to Bees." This guidance presents an iterative, tiered process for assessing risks that considers multiple lines of evidence related to exposure and effects of pesticides to bees. 
There is no evidence in the available data of endocrine disruption for pethoxamid (all available toxicity data is summarized in the toxicity profile table of the human health risk assessment). Furthermore, EPA prioritizes chemicals undergoing registration review for screening under the Endocrine Disruptor Screening Program. 

Cumulative effects were considered in the human health risk assessment. EPA has not made a common mechanism of toxicity finding as to pethoxamid and any other substances and pethoxamid does not appear to produce a toxic metabolite produced by other substances. 
For EPA's response to comments on synergistic effects, see response to CBD Comment #7 under this section.
CBD Comment #4: Place appropriate restrictions on uses to avoid and minimize adverse effects.
EPA Response: Based on all available data, the Agency has determined that use of this pesticide according to the label directions on the final stamped label will not result in unreasonable adverse effects to human health or the environment. Resistance management language has been incorporated into the precautionary label language to not only help maximize the effectiveness of tools available for growers but to reduce pesticide loading in the environment and non-target exposure to pesticides and to minimize adverse effects. Any restrictions necessary to protect human health and the environment from unreasonable adverse effects are included on the final labels.
CBD Comment #5: The EPA must support any assertion that products with new active ingredients are "safer" or that they will actually replace older pesticide use.
EPA Response: The Agency does not permit use of the word "safe" on labels or in labelling. EPA's regulation, in 40 CFR 156.10(a)(5) provides examples of statements that are considered to be misbranded, which includes "claims as to the pesticide, or its ingredients, including statements such as "safe" ... without such a qualifying phrase as "when used as directed." It is the Agency's position that, though some pesticides hold more or less risk than others, none are completely without risk. The word "safe" has potential to lull users into a sense of complacency about taking the appropriate measures to protect themselves and the environment. 
The EPA identified registered alternative herbicides and completed a comparison of the toxicity (i.e., hazard) of pethoxamid. These alternative herbicides include glyphosate, atrazine, acetochlor, S-metolachlor, mesotrione, dimethenamid-P, tembotrione, mepiquat, trifluralin, dicamba, glufosinate, fomesafen, 2,4-D, chlorimuron, and sulfentrazone. Toxicity data for fish, aquatic invertebrates, aquatic plants, birds, mammals, honey bees, and terrestrial plants were compiled for each of the compounds, when available, from their most recent ecological risk assessments. This chemical-by-chemical toxicity comparison revealed that based on the most sensitive toxicity endpoints, pethoxamid is generally less toxic than atrazine, acetochlor, S-metolachlor, trifluralin, and chlorimuron and more toxic than glyphosate.  For the chemicals mesotrione, dimethenamid-P, tembotrione, mepiquat, dicamba, glufosinate, fomesafen, 2,4-D, chlorimuron, and sulfentrazone toxicity was higher than pethoxamid for some taxa and lower for others. Pethoxamid is generally as and in some cases more or less toxic to non-target organisms than the identified alternatives, thus pethoxamid represents a similar hazard and in some case more or less of a hazard to non-target organisms relative to many of the identified alternatives.  The Agency's benefits assessment has not determined pethoxamid to be a replacement to older pesticides but we have identified this chemical as an additional weed control and resistance management tool.

CBD Comment #6: The EPA must take into account real-world scenarios.
EPA Response: The Agency accounts for real-world scenarios from both ecological and human health perspective. Estimated environmental concentrations are generally conservative where aquatic exposure estimates are based on a reasonably conservative conceptual model of a standard ecological water body that was reviewed by a Scientific Advisory Panel. Monitoring data sometimes detect or report values that are above estimated exposure modeling values used in risk assessment, supporting the environmental relevance of the modeling results. Terrestrial exposure estimates are based on measured pesticide residue data and, therefore, represent real-world exposure values. They also represent high-end values from the distribution such that higher exposure values are expected to be rare. However, misuse or accidental exposures resulting from not following pesticide labels are not specifically assessed.
Additionally, as a part of every human health risk assessment, the Agency considers a large variety of consumer subgroups according to well-established procedures. In line with the Agency policy, risks to population subgroups from pesticide exposures are estimated based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by USDA's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Moreover, the Agency is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.
CBD Comment #7: The EPA must assess the enhanced toxicity of pesticide mixtures.
EPA Response: The EPA has developed an interim process to evaluate effects of mixtures of active ingredients based on patents granted by the U.S. Patent and Trademark Office (U.S. PTO) on the basis of the applicant showing the combined effects of the mixture are synergistic (i.e., the effect of a mixture of pesticides is greater than the sum of the individual effects). To ensure that effects data on the mixture that may be relevant to ecological risk assessments are considered, the EPA requests that registrants of new chemicals submit toxicity data for mixtures that were provided to the U.S. PTO to support patents. The EPA has provided guidance to assist registrants in identifying relevant data for such submissions. In response to the request and guidance, FMC Corporation completed a search of U.S. patent data to identify any claims of synergy (or greater than additive (GTA) effects) with other currently registered pesticides and these data were submitted to EPA.  EPA's review of these patents did not identify any that met all of the established criteria as described by the Agency's approaches for GTA review. Therefore, the EPA does not have any risk concerns about environmental effects relating to GTA effects of pesticides with pethoxamid at this time.  

 Comments Received on the Agency's Proposed Decision to Register Pethoxamid
USDA Comment:
The USDA Office of Pest Management Policy (OPMP) commented in favor of the registration of pethoxamid. Some benefits of pethoxamid mentioned by OPMP include flexibility with regards to tank mix partners, application timing, and crop rotations due to the rapid degradation of pethoxamid in the environment, in addition to offering effective control of a broad spectrum of annual broadleaf and grass weeds.  OPMP stated that registration of new active ingredients like pethoxamid will provide growers an additional tool to assist in the management of herbicide resistance in integrated weed management programs.
EPA Response: The Agency thanks USDA for their comment and support. 
Anonymous Comment: No Environmental Chemistry Method (ECM) is reported for pethoxamid in the EPA index (https://www.epa.gov/pesticide-analytical-methods/environmental-chemistry-methods-ecm-index-p). The Enforcement Methods listed in the Pethoxamid Human Health Risk Assessment only included livestock and plants (pp. 8-9).
EPA Response: The environmental chemistry method (ECM) has been submitted and reviewed.  The analytical methods in soil and water will be included in the index soon after the final decision on the registration of pethoxamid is posted.
CBD comment #1: Pethoxamid is a likely Carcinogen and EPA must analyze cancer risk associated with exposure.
EPA Response: In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005), the Cancer Assessment Review Committee (CARC) classified pethoxamid as "Suggestive Evidence of Carcinogenic Potential" based on male rat thyroid follicular cell adenomas. There is no concern for mutagenicity in vivo.  The chronic Reference Dose (RfD) will adequately account for all chronic toxicity, including carcinogenicity, which could result from exposure to pethoxamid.
CBD comment #2: EPA must protect infants and children by applying a 10x Food Quality Protection Act (FQPA) uncertainty factor.
EPA Response: EPA has evaluated the toxicity database of pethoxamid and concludes that there is low concern for pre- and postnatal susceptibility for infants and children. The FQPA safety factor has been reduced to 1X because: (1) the toxicity database is adequate to characterize potential pre- and postnatal risk for infants and children; (2) no reproductive effects were observed in rats; (3) although there were slight developmental/offspring effects in the reproductive and developmental studies, these were seen in the presence of comparable maternal/parental toxicity; (4) the endpoints selected are protective of any potential neurotoxic effects; and, (5) the points of departure (POD) selected for risk assessment purposes are protective of the developmental effects seen in the database.
CBD Comment #3: The Agency has not identified any clear benefits of pethoxamid, making the potential harms unjustifiable
EPA Response: Pethoxamid provides control of economically important grasses and some broadleaf weeds, with enhanced crop rotation or cover crop flexibility compared to similar active ingredients. Pethoxamid is an additional element of resistance management programs showing efficacy on weed biotypes exhibiting resistance to active ingredients with the same Weed Science Society of America Mode of Action grouping. Pethoxamid's selectivity among grass species makes it a useful tool in the mangement of grass weeds in crops closely related to those same weed species. The intent of the risk assessments is to inform the risk management decision of the potential adverse effects that may occur from exposure to a specific compound. The risk management decision balances the risks identified in the risk assessments with the benefits provided by the compound and determines whether those risks are unreasonable.  The potential risks are not unreasonable when considered in conjunction with the use pattern and the benefits of pethoxamid.  
CBD Comment #4: Comply with duties under Section 7 of the Endangered Species Act (ESA), including completion of consultation.
EPA Response: See EPA's response to CBD Comment #1 under Comment Received on NOR of Pethoxamid.
CBD Comment #5: Require that that the registrant provide all necessary data and studies.
EPA Response: See EPA's response to CBD Comment #2 under Comment Received on NOR of Pethoxamid.
CBD Comment #6: Incorporate necessary factors into evaluation and any proposed decision.
EPA Response: See EPA's response to CBD Comment #3 under Comment Received on NOR of Pethoxamid.
CBD Comment #7: Place appropriate restrictions on uses to avoid and minimize adverse effects.
EPA Response: See EPA's response to CBD Comment #4 under Comment Received on NOR of Pethoxamid.
CBD Comment #8: The EPA must support any assertion that products with new active ingredients are "safer" or that they will actually replace older pesticide use.
EPA Response: See EPA's response to CBD Comment #5 under Comment Received on NOR of Pethoxamid.
CBD Comment #9: The EPA must take into account real-world scenarios.
EPA Response: See EPA's response to CBD Comment #6 under Comment Received on NOR of Pethoxamid.

