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 

I 01.) ~ 4-/ ~ 0 Is-
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 

Preliminary Risk Assessment and Endangered Species Assessment for Diphenylamine. 

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 and Epidemiology. Elizabeth 

Evans. 10/22/2015. 

4. BEAD Chemical Profile (BCP) for Registration Review: Diphenylamine (038501). Carl 

Chen. 06111/2015. 

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These 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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OVERVIEW 

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 of that use. This 

Preliminary Work Plan (PWP) document explains what EPA's Office of Pesticide Programs 

knows about diphenylamine, highlighting anticipated data and assessment needs, identifying the 

types of information 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 of what it knows about diphenylamine and what types of new 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 of pesticides; 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 of the 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 of no unreasonable adverse effects to human health or the 

environment. Changes in science, public policy, and pesticide use practices will occur over time. 

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Through 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) of the 

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 15 5 .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 of diphenylamine. 

CHEMICAL FACTS 

Table 2 provides a summary of the 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 of a cumulative group that shares a common 

mechanism of toxicity. 

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 of diphenylamine. 

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 of the U.S. Environmental Protection Agency. 

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Table 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 of Use Diphenylamine an anti-scald agent registered for use as a postharvest treatment on apples to prevent fruit scald. Scald is a 

condition of the fruit in which the skin and eventually the interior 

of the 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 

of the use on pears. 

Summary of Usage Data are limited and do not necessarily originate from the areas 

where diphenylamine is used the most. Based on the California 

Department of Pesticide Regulation Use Report, approximately 

250 pounds of active 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. of Registrations 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 of particular interest to EPA, are described below. 

• Some product labels allow for a second application under certain circumstances; others 

do not specify a number of applications/year. The Agency seeks confirmation of number 

of treatments for all product labels. 

• The Agency seeks confirmation of the maximum application rate per storage lot, and will 

work with the registrant to revise labels to provide a maximum rate of the 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. 

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RECENT 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 Formulation for 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 of diphenylamine. 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 

of used treatment solution. 

Incidents There were no reported ecological incidents for 

Will check diphenylamine; see page 22 of the combined Problem 

for updates Formulation/Preliminary Risk Assessment for 

additional information. 

Human Health 

Dietary 

Food The acute dietary risk assessment will be revisited if a 

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 of diphenylamine. 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 of a cumulative group that shares a common 

mechanism of toxicity. 

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Tolerances Pursuant to cancellation of the 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 of pears in bins 

previously used for apples to which diphenylamine 

has been applied will result in contamination of the 

pears with diphenylamine. 

Incidents There are no incident cases reported for 

Will check diphenylamine; see page 10 of the Scoping Document 

and Diphenylamine: Tier I (Scoping) Review of for updates Human Incidents and Epidemiology for additional 

' information. 

TIME LINE 

EPA has created the following estimated timeline for the completion of the 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 

Assessments3 

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 of diphenylamine. 

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 .53( c ). For conventional pesticides, the 

Agency plans to provide a 60 calendar day public comment period generally for draft risk assessments. 

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Appendix - Additional Areas Considered in the Diphenylamine Registration 

Review 

Environmental Justice : 

EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all 

people, regardless of race, color, national origin, or income, in the development, implementation, 

and enforcement of environmental laws, regulations, and policies. To help address potential 

environmental justice issues, the Agency seeks information on any groups or segments of the 

population who, as a result of their location, cultural practices, or other factors, may have 

atypical, unusually high exposure to diphenylamine compared to the general population. Please 

comment if you 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 of diphenylamine 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 of used treatment solution and 

NPDES permitting. EPA anticipates conducting no further analysis of potential 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 of carcinogenicity, 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 of the 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 of the 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 of a 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 

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systems. 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 of the EDSP where EPA 

will determine which, if any, of the 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 

of chemicals identified for EDSP screening was published on June 14, 20135 and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors. Diphenylamine is not 

included in either list. 

For further information on the status of the 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 of any of them 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 of Human Subjects of Research (40 

CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on 

these studies. 

4 http://www.regulations.gov/#!documentDetail;D=EPA-HO-OPPT-2004-0 I 09-0080 5 http://www.regulations.gov/#!documentDetail;D=EP A-HO-OPPT-2009-04 77-0074 6 http://www.epa.gov/endo/ 

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