Docket Number EPA-HQ-OPP-2010-0498

www.regulations.gov

Piperonyl Butoxide Final Work Plan 

Registration Review

May 2011

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Introduction

This is the Environmental Protection Agency’s (EPA’s) Final Work Plan for the registration review 

of piperonyl butoxide. This work plan includes the expected registration review timeline. The work 

plan also addresses public comments received concerning the Preliminary Work Plan in the 

Summary Document, which was posted in the piperonyl butoxide registration review docket (EPAHQ-OPP-2010-0498), and any other comments concerning the initial docket postings. The 

Summary Document provided information on what EPA knows about the pesticide and what 

additional risk analyses and data or information the Agency believes are needed to make a 

registration review decision.

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. 

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

of registration review begins when the initial docket is opened for each case. Information on this 

program is provided at: http://www.epa.gov/oppsrrd1/registration_review/.

Piperonyl butoxide (PBO) is a pesticide active ingredient that acts as a synergist, enhancing the 

pesticidal properties of other chemicals. It is registered for use in combination with insecticide and 

acaricide active ingredients, such as pyrethrins, synthetic pyrethroids and organophosphates, in a 

variety of agricultural and non-agricultural sites. Registered residential uses include insect control 

inside and outside of the home, as well as direct applications to pets. Formulations and application 

methods are diverse. PBO was first registered in the United States in the 1950s. The Reregistration 

Eligibility Decision (RED) for PBO was issued in 2006.

Comments Received on Preliminary Work Plan

Multiple comments were received during the 60-day public comment period on the planned 

ecological assessment and human health scoping document discussed in the Preliminary Work Plan. 

However, these comments do not alter the Agency’s Preliminary Work Plan for the registration 

review of PBO. For further discussion on these comments please see the Summary of Comments 

and Agency Responses section of this document. In the Preliminary Work Plan, EPA also solicited 

comments on three specific topics: environmental justice, water body impairment, and trade 

irritants. No comments or information were received during the comment period concerning 

environmental justice or trade irritants, however, the Agency did receive comments on potential 

impaired water bodies in California (CA) attributed to PBO’s synergistic effect on other pesticides. 

Anticipated Risk Assessment and Data Needs

The Agency anticipates requiring data considered necessary to conduct a comprehensive ecological 

risk assessment, including an endangered species risk assessment, and to update and revise the 
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human health risk assessment for all uses of PBO. Below is a summary of the issues relevant to the 

registration review of PBO and the data the Agency anticipates requiring. 

Ecological Risk:

Exposure to PBO from agricultural use will take place mainly in soil, sediment, and surface 

water, and from consumption of plants and other food items onto which it is sprayed. It may 

also reach the aquatic environment and may pass through wastewater treatment plants where 

it may be included in wastewater discharge.

The Agency has not conducted an ecological risk assessment that supports a complete 

endangered species determination for PBO. The ecological risk assessment planned during 

registration review will allow the Agency to determine whether PBO’s use has “no effect” or 

“may affect” federally listed threatened or endangered species (listed species) or their 

designated critical habitats. When an assessment concludes that a pesticide’s use “may 

affect” a listed species or its designated critical habitat, the Agency will consult with the U.S. 

Fish and Wildlife Service (FWS) and/or National Marine Fisheries Service (NMFS) (the 

Services), as appropriate.

A 2009 PBO Data Call-in required a number of studies that will be considered in the PBO 

registration review ecological risk assessment.

Synergism studies examining the toxicity of typical end-use products containing PBO were 

required in the RED data call-in (DCI). Additional synergism data is anticipated in 

registration review to examine the effects of PBO when co-applied with other pesticide 

active ingredients.

The Agency anticipates needing the following data in order to conduct a complete ecological 

risk assessment, including an endangered species assessment for PBO:

Environmental fate data gaps

o Guideline No. 835.1230 – Adsorption/Desorption (batch equilibrium)

o Guideline No. 835.4100 – Aerobic soil metabolism

o Guideline No. 835.4300 – Aerobic aquatic metabolism

o Guideline No. 835.4400 – Anaerobic aquatic metabolism

o Guideline No. 835.6100 – Analytical method for residues in soil and sediment

o Guideline No. 835.6200 – Analytical method for residues in water

o Guideline No. 875.2100 – Dislodgeable foliar residue (modified, total foliar dissipation 

data are required) 
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Ecological toxicity data gaps

Data Gaps for Studies Testing Typical End Use Product (TEP)

o Guideline No. 850.3020 – Honey bee acute contact toxicity

o Guideline No. 850.4100 - Terrestrial plant toxicity, Tier II (seeding emergence)1

o Guideline No. 850.4150 - Terrestrial plant toxicity, Tier II (vegetative vigor)1

Studies Triggered by PBO’s Use as a Synergist

o Guideline No. 850.1010 – Acute Freshwater Invertebrate Study

o Guideline No. 850.1075 – Acute Freshwater Fish Study

Data Gaps for Studies Testing Technical Grade Active Ingredient (TGAI)

o Guideline No. 850.1400 – Fish early life stage (estuarine/marine)

o Guideline No. 850.2100 – Avian acute oral toxicity (passerine species)

o Guideline No. 850.4400 – Aquatic vascular plant growth – Lemna spp. Tier II2

o Guideline No. 850.5400 – Aquatic non-vascular plant growth Tier II2

The Agency anticipates requiring the following data to use as an input to the Exposure and Fate 

Assessment Screening Tool’s (E-FAST) down-the-drain module to assess the amount of PBO that 

would degrade during treatment, remain in biosolids, or remain in waste water. 

o Non-Guideline – Publicly-owned Treatment Works (POTWs) Effluent Monitoring and 

POTW Treatability Study

Please refer to the December 13, 2010 “EFED Registration Review Problem Formulation for 

Piperonyl Butoxide,” for a more detailed discussion of the anticipated ecological risk 

assessment and data needs.

Human Health Risk:

The dietary exposure assessment (including food and water) may be updated to reflect 

current methodologies. 

A 2009 PBO Data Call-in required a number of studies that will be considered in the PBO 

registration review human health risk assessment.

The residential and occupational exposure assessments are adequate, but may be updated to 

reflect current standard operating procedures.

 

1 Tier II data requirements depend on the results of the Tier I study, which were included in the 2009 Data Call-in.

2 Registrants may opt to conduct a Tier I study, with the understanding that any adverse effects (even if <25%) will 

necessitate a Tier II study.
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The aggregate risk assessment is adequate, but may be updated to incorporate any changes to 

the dietary and/or residential exposure assessments. 

Acute and subchronic neurotoxicity and immunotoxicity studies are required under 40 CFR 

Part 158 as a part of the new data requirements for registration of a conventional pesticide. 

In the absence of required studies, EPA may use a database uncertainty factor of up to 10X. 

Once all of the newly required toxicity data have been received and subsequently reviewed,

points of departure and safety factors may be reexamined and a new risk assessment may be 

conducted. 

The Agency will re-evaluate the tolerance expression for PBO during registration review to 

ensure it appropriately covers the metabolites and degradates of PBO and that it specifies 

the residues to be measured for each commodity.

The Agency anticipates requiring the following data in order to conduct a complete human 

health risk assessment for PBO:

o Guideline No. 870.6200 – Acute and subchronic neurotoxicity

o Guideline No. 870.7800 – Immunotoxicity study

o Guideline No. 860.1900 – Field accumulation study in rotational crops

Please refer to the September 15, 2010 “Piperonyl Butoxide Human Health Risk Scoping Document in 

Support of Registration Review” available in the docket, for a detailed discussion of the anticipated

human health risk assessment and data needs.

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 its most recent registration decision, 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), piperonyl butoxide 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.” 
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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 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 ingredients. Piperonyl butoxide is

included on that list and have been issued an order to conduct the Tier 1 testing. Once all required 

Tier 1 and Tier 2 data have been received and reviewed, the endpoints and safety factors used for 

risk assessment purposes will be examined and a new risk assessment performed if necessary. For 

further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, 

future lists, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/. 

Timeline

 

The Agency has created the following estimated timeline for the completion of the piperonyl 

butoxide registration review. One year has been added to the projected timeline included the 

Preliminary Work Plan. In the Preliminary Work Plan, the time frame between issuing the DCI 

and data submission was projected to be two years. However, one of the anticipated data 

requirements, field accumulation study in rotational crops (Guideline No. 860.1900), is actually a 

three year study.

Registration Review for Piperonyl Butoxide – Projected Registration Review Timeline

Activities Estimated Date

Opening the docket

Open Docket and Public Comment Period 2010 – December

Close Public Comment 2011 – February

Case Development

Final Work Plan 2011 – May

Issue DCI 2012 – Jan. – March

Data Submission 2015 – Jan. - March

Open Public Comment Period for Preliminary Risk Assessments 2016 – July – Sept.

Close Public Comment Period 2016 – Oct. – Dec.

Registration Review Decision
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Open Public Comment Period for Proposed Registration Review 

Decision

2017 – Jan. – March

Close Public Comment Period 2017 – Apr.- June

Registration Review Decision and Begin Post-Decision Follow-up 2017

Total (years) 7

Summary of Comments and Agency Responses

The piperonyl butoxide registration review docket was open for a 60-day comment period beginning 

on December 22, 2010. The comments received did not result in a change to the Agency’s 

Preliminary Work Plan for PBO. 

The Piperonyl Butoxide Task Force II, a group composed of the PBO technical registrants, 

commented on the human health risk assessment work plan. They requested a description of 

changes made within the last 5 years to EPA’s risk assessment methodologies, and asked the Agency 

to provide a list of the data requirements specified in the RED DCI which remain outstanding. The 

Task Force submitted multiple comments on the ecological data requirements and requested 

information on the ecological risk assessment approach for other active ingredients co-applied with 

PBO. Clarification has been provided in the response to comments documents.

The California Regional Water Quality Control Board and the California Stormwater Quality 

Association provided comments in support of the additional data the Agency is seeking to assess the 

risks from the synergism of PBO. They cited a study that suggests PBO spray drift contributed to 

the synergism of pyrethroids already present in California waterways. The Agency made note of the 

comments.

The Physicians Committee for Responsible Medicine commented on potential alternative methods 

for conducting some of the anticipated toxicity studies. The Agency responded that the studies 

proposed would be considered during registration review.

The public comments and the two Agency response documents, “Piperonyl Butoxide: Response to 

Comments on the Human Health Assessment Scoping Document in Support of Registration Review,” 

dated April 14, 2011, and “EFED Response to Public Comments on Registration Review Problem 

Formulation for Piperonyl Butoxide,” dated May 5, 2011, are available in docket EPA-HQ-OPP2010-0684.

Next Steps

The Agency plans to issue a Data Call-in for PBO in 2011. The information received in response to 

this DCI will be used to conduct the planned human health, ecological risk, and endangered species 

assessments for PBO.
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Summary of Data Needs for the registration review of PBO

Guideline 

Number Data Requirement

Test 

Material

Estimated 

Timeframe

(Months)

835.1230 Adsorption/Desorption (batch equilibrium) TGAI 12

835.4100 Aerobic soil metabolism TGAI 24

835.4300 Aerobic aquatic metabolism TGAI 24

835.4400 Anaerobic aquatic metabolism TGAI 24

835.6100 Analytical method and Independent Laboratory 

Validation for residues in soil and sediment TGAI 24

835.6200 Analytical method and Independent Laboratory 

Validation for residues in water TGAI 24

850.1010 Acute Freshwater Invertebrate Study TEP 24

850.1075 Acute Freshwater Fish Study TEP 24

850.1400 Fish early life stage (estuarine/marine) TGAI 12

850.2100 Avian acute oral toxicity (passerine species) TGAI 12

850.3020 Honey bee acute contact toxicity TEP 12

850.4100 Terrestrial plant toxicity, Tier II (seeding 

emergence)1 TEP 12

850.4150 Terrestrial plant toxicity, Tier II (vegetative vigor)1 TEP 12

850.4400 Aquatic vascular plant growth – Lemna spp. Tier II2 TGAI 12

850.5400 Aquatic non-vascular plant growth Tier II2 TGAI 12

860.1900 Field accumulation study in rotational crops3 TGAI 36

870.6200 Acute and subchronic neurotoxicity TGAI 12

870.7800 Immunotoxicity TGAI 12

875.2100 Dislodgeable foliar residue (modified, total foliar 

dissipation data are required) TGAI 12

Non-GDLN POTW Effluent Monitoring TGAI 12

Non-GDLN POTW Treatability Study TGAI 12

 

1 Tier II data requirements depend on the results of the Tier I study, which were included in the 2009 Data Call-in.

2 Registrants may opt to conduct a Tier I study, with the understanding that any adverse effects (even if <25%) will 

necessitate a Tier II study.

3 This study may be waived depending on the results of the confined accumulation in rotational crops study (Guideline 

860.1850), which was included in RED Data Call-in.