Docket Number EPA-HQ-OPP-2015-0749 www.regulations.gov



# Diphenylamine Preliminary Work Plan Registration Review: Initial Docket Case Number 2210

Approved by:

Date: 

# December 2015**O-LCLP ,:-0>**  Richard P. Keigwin, Jr. Director Pesticide Re-evaluation Division 

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### Diphenylamine Preliminary Work Plan - Table of Contents

OVERVIEW
............. .. ...... .... .... ........... ... . .. . ... .... ... .. ......................................... . ... ........ ... ..... . .. ........ 4 ANTICIPATED DATA NEEDS
.... .. ... .. .. .. . ... ............................................. . ...... ...... .... .. ................. 4 STATUTORY AND REGULATORY AUTHORITY
.... .. ... .. ... .. ..... .. .. .. ................... . ... ...... ........ ... 4 CHEMICAL FACTS
.. .. ... .. . ...................... . .... . .. . ........ . .. . .. ... ................. .......... .... . ... . ...... ... .. ... . .. ....... 5 USE AND USAGE INFORMATION
....... . .... . ........... . .................. . ......... . ...... .. .. ... .. .. .. ... ............. . .. 6 RECENT ACTIONS
.. .... . ...... . .................. . ........... . ................................. . .. . .. ..... . .. ... . ...................... . 7 ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW
............. . .. . .. .. .... . ... ... 7 TIMELINE
... . ... .. . ........ . .............................. . .. ................................. . .. . ... ......... ... ........ . ...... . ... .. .. ....... 9 NEXT STEPS
............................................................. . .............. . .. ... ..... .. ............ . ..... . .. .. .. . .. .. .. ... ..... 9 Appendix -Additional Areas Considered in the Diphenylamine Registration Review
... .. ...... 10

References: This Preliminary Work Plan summarizes the Environmental Protection Agency's current position based on the following documents : 1. Registration Review: Combined Problem Formulation and Environmental Fate, Ecological Preliminar y RiskAssessment and Endangered Species Assessment for Diphen ylamine. Andrew Sayer 12/09/2015. 

### 2. Diphenylamine. Human Health Assessment Scoping Document in Support of Registration Review. Karlyn Middleton. 12/ 10/2015
. 3. Diphenylamine : Tier I (Scoping) Review of Human Incidents andEpidemiology
. Elizabeth Evans. 10/22/2015. 4. BEAD Chemical Profile ( BCP)for Registr ation Review: Diphenylamine (038501). Carl Chen. 06111 /2015
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2These and other supporting documents for the diphenylamine registration review case may be found in the docket EPA-HQ-OPP-2015-0749 at http: //www.regulations.gov
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3OVERVIEW The docket for diphenylamine is now open, initiating the first public comment period for this registration review (docket number EPA-HQ-OPP-2015-0749). Diphenylamine is registered as a post-harvest treatment to prevent scald in stored apples
. Diphenylamine is also registered for use on pears, although the registrant has committed to request cancellation ofthat use. This Preliminary Work Plan (PWP) document explains what EPA's Office ofPesticide Programs knows about diphenylamine, highlighting anticipated data and assessment needs , identifying the types ofinformation that would be especially useful to the Agency in conducting the review, and providing an anticipated timeline for completing the registration review for diphenylamine. The registration review process was designed to include a public participation component to solicit input from interested stakeholders. The Agency intends , by sharing this information in the docket, to inform the public ofwhat it knows about diphenylamine and what types ofnew data or other information would be helpful for the Agency to receive as it moves toward a decision on diphenylamine. The Agency encourages all interested stakeholders to review the PWP and Appendix and to provide comments and additional information that will help the Agency ' s decision-making process for this diphenylamine. In addition to general areas on which persons may wish to comment, there are some areas identified in the PWP and Appendix about which the Agency specifically seeks comments and information. Interested stakeholders could include: environmental non-profit or interest groups ; pesticide manufacturers; agricultural labor or commodity groups ; commercial, institutional, residential , and other users ofpesticides; or the public at large. The Preliminary Work Plan begins by listing the anticipated data needs for diphenylamine. Next, it discusses the statutory and regulatory authority for registration review. Then the document provides chemical facts , use and usage information, recent actions , the anticipated risk assessments , and a projected registration review timeline for diphenylamine. Finally, the Appendix to this document includes identification and discussion of some areas that are considered generally in registration review along with some additional chemical case-specific information
. ANTICIPATED DATA NEEDS There are no additional data needed at this time given the limited use ofthe compound as a postharvest treatment. STATUTORY AND REGULATORY AUTHORITY The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distributed or sold in the United States (U.S.) generally must be registered by the Environmental Protection Agency (EPA or the Agency) , based on scientific data showing that they will not cause unreasonable risks to human health or the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard ofno unreasonable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time
. 4Through the registration review program, the Agency periodically reevaluates pesticides to make sure that as change occurs , products in the marketplace can be used safely. Information on this program is provided on EPA's website. 1 The Agency is implementing the registration review program pursuant to Section 3(g) ofthe Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration. The regulations governing registration review begin at 40 CFR 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the Agency's opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. After reviewing and responding to comments and data received in the docket during this initial comment period, the Agency will develop a Final Work Plan (FWP) and anticipated schedule for the registration review ofdiphenylamine. CHEMICAL FACTS Table 2 provides a summary ofthe chemical facts for diphenylamine. Table 2: Chemical Facts for Diphenylamine PC code 038501 Case Number 2210 CAS Number 122-39-4 Year first registered 19472 Pesticide Type Anti-scald Agent Chemical class Bridged Diphenyl Reregistration Eligibility March 1, 1997 Decision (RED) Tolerance Reassessment No TRED was issued; the exemption from a tolerance was reEligibility Decision (TRED) assessed for the RED. Cumulative group Not applicable. Diphenylamine has not been identified as a member ofa cumulative group that shares a common mechanism oftoxicity. 40 CFR Citation Tolerances for diphenylamine are established at 40 CFR 180.190. Dual-use Diphenylamine is registered for conventional pesticidal uses only and has no registered antimicrobial or biopesticidal uses. Non-pesticidal uses There are no identified non-pesticidal uses ofdiphenylamine. Pesticide Re-evaluation Roy Johnson Division, Chemical Review johnson.roy@ epa.gov Manager 703-347-0492

1 http :// www2.epa.gov/ pesticide-reevaluation 2 Sources cite different dates for first registration
. It seems likely that diphenylamine was registered as a pesticide prior to the establishment ofthe U
.S. Environmental Protection Agency
. 5Table 2: Chemical Facts for Diphenylamine Registration Division, Tony Kish Product Manager kish
. tony @ epa.gov 703-308-9443 USE AND USAGE INFORMATION Table 3 summarizes the use and usage information for diphenylamine. Please see the BEAD Chemical Profile (BCP)far Registration Review: Diphenylamine (038501 ) in the registration review docket for more details. Table 3: Diphenylamine Use and Usage Information Summary ofUse Diphenylamine an anti-scald agent registered for use as a postharvest treatment on apples to prevent fruit scald. Scald is a condition ofthe fruit in which the skin and eventually the interior ofthe fruit become discolored and soft; it is thought to be caused by biochemical changes in the fruit related to chilling and storage (it does not appear in fruit on the tree)
. The chemical is classified as an indoor /food use pesticide. Use Sites Apples. The registrant has committed to requesting cancellation ofthe use on pears . Summary ofUsage Data are limited and do not necessarily originate from the areas where diphenylamine is used the most. Based on the California Department ofPesticide Regulation Use Report, approximately 250 pounds ofactive ingredient were used on average annually between 2009 and 2013 in California. Formulation Type(s) Emulsifiable concentrate, soluble concentrate, pressurized gas. Application Method(s) Drenching, spraying, and thermal fogging. Technical Registrant(s) Pace International LLC and Decco US Post-Harvest Inc. No. ofRegistrations Two technical and five end-use products Restricted Use No Guidance for Commenters: Additional areas of use and usage related information requested for this registration review, and ofparticular interest to EPA, are described below.

• Some product labels allow for a second application under certain circumstances; others do not specify a number ofapplications/year. The Agency seeks confirmation ofnumber oftreatments for all product labels
. • The Agency seeks confirmation ofthe maximum application rate per storage lot, and will work with the registrant to revise labels to provide a maximum rate ofthe active ingredient to be applied to a single storage lot. • Minimum and typical application rates , and conditions under which less than the maximum rate would be used, if any.



### 6RECENT ACTIONS There are no recent actions for diphenylamine. ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW The most recent comprehensive human health risk assessment for diphenylamine was completed in August 2005. The most recent ecological and environmental fate risk assessment was completed December 9, 2015 for registration review
. Findings and conclusions from these risk assessments are summarized in the Combined Problem Formulationfor the Environmental Fate, Ecological Risk , Endangered Species, and Drinking Water Assessments for Diphenylamine and Human Health Assessment Scoping Document in Support of Registration Review
. For this registration review, the Agency has conducted a comprehensive ecological risk assessment, including an endangered species assessment, for the use ofdiphenylamine. For human health, the need for an acute dietary assessment should be re-evaluated during registration review since an appropriate endpoint/POD could be selected from a previously reviewed and acceptable in vivo mouse micronucleus study. EPA also anticipates the need to conduct revised occupational handler and post-application risk assessments during registration review. Table 4 below summarizes the anticipated registration review risk assessments based on the EFED Combined Problem Formulation/Risk Assessment and HED Scoping Document.

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### Table 4: Anticipated Risk Assessments for the Diphenylamine Registration Review Type of Risk Assessment Conduct? Notes Ecoloi!ical and Environmental Fate Comprehensive ecological The Agency has conducted a comprehensive (species to be assessed include 

### y ecological risk assessment including an endangered terrestrial and aquatic organisms) , species risk assessment. The Agency has concluded including endangered species that the diphenylamine use pattern is not likely to result in relevant environmental exposures given existing and proposed label language on the disposal ofused treatment solution
. Incidents There were no reported ecological incidents for Will check diphenylamine ; see page 22 ofthe combined Problem for updates Formulation/Preliminary Risk Assessment for additional information. Human Health Dietary Food The acute dietary risk assessment will be revisited ifa 

### y new endpoint/POD is selected. A cancer risk assessment for the impurity nitrosamine will be considered. Drinking water A drinking water assessment (DWA) has not been N conducted for diphenylamine, as the compound is categorized as an indoor /food use, for which a DWA is not needed. Occupational Handlers (mixers , loaders, A dermal occupational handler and an inhalation applicators) occupational post-application risk assessment will be Post-application 

### y revised to reflect updated policies and chemical

- specific use data. Cancer risk assessments for the impurity nitrosamine will be considered. Residential Handlers N There are no residential uses ofdiphenylamine
. Post-application Other Aggregate Because there are no residential uses of 

### y diphenylamine, an aggregate assessment is not needed
. Cumulative Diphenylamine has not been identified as a member N ofa cumulative group that shares a common mechanism oftoxicity.



### 8Tolerances Pursuant to cancellation ofthe pear use, the Agency will consider changing the current pear tolerance to account for inadvertent residues only, as there is 

### y evidence suggesting that the storage ofpears in bins previously used for apples to which diphenylamine has been applied will result in contamination ofthe pears with diphenylamine. Incidents There are no incident cases reported for Will check diphenylamine ; see page 10 ofthe Scoping Document and Diphenylamine : Tier I ( Scoping) Review of for updates Human Incidents and Epidemiology for additional ' information. TIMELINE EPA has created the following estimated timeline for the completion ofthe diphenylamine registration review in Table 5 below. Table 5: Projected Diphenylamine Registration Review Timeline Activities Estimated Date Opening the Docket Open Docket and 60-day Public Comment Period 2015 December Close Public Comment 2016 February Case Development Final Work Plan 2016 May 60-day Public Comment Period for Draft Risk 2018 January

- March Assessments 3 Registration Review Decision 60-day Public Comment Period for Proposed 2018 October

- December Registration Review Decision Registration Review Decision and Begin Post-Decision 2019 Follow-up Total (years) 4 NEXT STEPS After the 60-day public comment period closes , the Agency will review and respond to any comments received in a timely manner and then issue a Final Work Plan for the registration review ofdiphenylamine.

3 The regulations governing Registration Review generally require the Agency to provide a public comment period

of at least 30 calendar days for draft risk assessments ; see 40 CFR Part 155 .5 3(c). For conventional pesticides , the Agency plans to provide a 60 calendar day public comment period generally for draft risk assessments. 9

### Appendix - Additional Areas Considered in the Diphenylamine Registration Review Environmental Justice : EPA seeks to achieve environmentaljustice, the fair treatment and meaningful involvement of all people, regardless ofrace, color, national origin, or income, in the development, implementation, and enforcement of environmental laws , regulations , and policies. To help address potential environmentaljustice issues , the Agency seeks information on any groups or segments ofthe population who , as a result oftheir location, cultural practices, or other factors, may have atypical, unusually high exposure to diphenylamine compared to the general population
. Please comment ifyou are aware of any sub-populations that may have atypical, unusually high exposure compared to the general population. ENDANGERED SPECIES: EFED has concluded that the post-harvest use ofdiphenylamine on apples will have 'No Effect' on federally listed endangered or threatened terrestrial or aquatic species, or their designated critical habitats , as identified by the U.S. Fish and Wildlife Service and the National Marine Fisheries Service. This determination is based in large part on the low likelihood of environmental exposure from the product use patterns, the registrants ' commitment to expand to all diphenylamine product labels language concerning the disposal ofused treatment solution and NPDES permitting. EPA anticipates conducting no further analysis ofpotential risks to endangered or threatened species from diphenylamine for this use unless the Agency obtains data or information that would otherwise inform the Agency's determination. ENDOCRINE DISRUPTOR SCREENING PROGRAM: As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments ofcarcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights , estrus cyclicity, sexual maturation, fertility , pregnancy rates , reproductive loss, and sex ratios in offspring
. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part ofthe reregistration decision for diphenylamine, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), diphenylamine is subject to the endocrine screening part ofthe Endocrine Disruptor Screening Program (EDSP). EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate ." The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists ofa battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 10systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage ofthe EDSP where EPA will determine which, ifany, ofthe Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients4• A second list ofchemicals identified for EDSP screening was published on June 14, 2013 5 and includes some pesticides scheduled for registration review and chemicals found in water. Neither ofthese lists should be construed as a list ofknown or likely endocrine disruptors. Diphenylamine is not included in either list. For further information on the status ofthe EDSP, the policies and procedures , the lists of chemicals, future lists , the test guidelines and the Tier 1 screening battery, please visit our website. 6 HUMAN STUDIES: Past diphenylamine risk assessments may rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi-pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct ofany ofthem was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements ofEPA ' s Rule for the Protection ofHuman Subjects ofResearch (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies
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4 http: //www .regulations
.gov/# !documentDetail;D=EPA-HO-OPPT-2004-0 I09

-0080 5 http: //www .regulations
.gov/# !documentDetail;D=EPA-HO-OPPT-2009-0477

-0074 6 http ://www .epa.gov/endo/
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