1 Docket Number EPA-HQ-OPP-2011-0885 www.regulations.gov



## Pyrethrins Summary Document Registration Review: Initial Docket
December 20113 TABLE OF CONTENTS

I. Preliminary Work Plan (PWP) 4

II. Fact Sheet 14

III. Summary of Data Gaps 23

This Preliminary Work Plan and Fact Sheet su mmarize the Environmental Protection Agency’s current position based on the following documents:

1. EFED Registration Review Preliminary Problem Form ulation for Pyrethrins . November 30, 2011.

2. Pyrethrins. Human Health Risk Scoping Document in Support of Registration Review . December 1, 2011.

3. Pyrethrins: Review of Human Incidents . August 11, 2011.

4. BEAD Chemical Profile for Registrati on Review: Pyrethrins (PC Code 069001). September 22, 2011.

5. Pyrethrin (069001) Screening Level Usage Analysis (SLUA) . January 21, 2011.

6. Appendix A: Uses of Pyrethrins Eligible for Reregistration

. 1 March 22, 2010.

Supporting documents for the registration review of pyrethrins are lo cated in docket EPA-HQOPP-2011-0885 at www.regulations.gov.

1 Appendix A is based on uses eligible after reregistration in 2006.4 I. PRELIMINARY WORK PLAN

Introduction

The Food Quality Protection Act (F QPA) of 1996 mandated a regist ration review program. All pesticides distributed or sold in the United Stat es (U.S.) generally must be registered by the Environmental Protection Agency (EPA or the Ag ency), based on scientific data showing that they will not cause unreasonable ri sks 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 unreasonabl e adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review prog ram, the Agency periodically r eevaluates pesticides to make sure that as change occur, products in the marketplace can be used safely. Information on this program is provided at: http://www.epa.gov/oppsrrd1/registration_review/

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The Agency is implementing the registration revi ew 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 th e FIFRA standard for registration. 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 belie ves 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 de velop and commit to a final work plan and schedule for the registration review of pyrethrins.

Products containing the active ingred ient pyrethrins are registered for use against a wide range of insects in many agricultural crop systems, such as lepidopterous caterpillars, leafhoppers, aphids, beetles, and thrips. They are also registered for use against a vari ety of urban insect pests, such as cockroaches and ants. Pyrethrins are registered for use on most fruit, nut, and vegetable crops, which includes crops such as corn, soybean, and wheat. Some of th e non-agricultural uses include wood products (e.g., beams, decks, and pilings), residential ar eas, woodland areas, wood surfaces, residential and commercial buildings, food handling establishments, and mosquito
abatement.

The term “pyrethrins” refers to all six isomers (pyrethrin I, pyrethrin II, cinerin I, cinerin II, jasmolin I, and jasmolin II) found in pyrethrum extracts which are obtained from the dried and ground flowers of the pyrethrum plant, Chrysanthemum cinerariaefolium

. Pyrethrins are most toxic to the target pest on contact, and have a quick “knockdown” effect. The majority of manufacturers formulate pyrethrins with a synerg ist compound to increase their toxic effect on target insects, such as with the pesticides piperonyl butoxide (PBO) or MGK-264, as well as with pyrethroids. Products formulated with pyrethrins alone are re gistered for use in organic5 agriculture production. Pyrethrins were first re gistered as an insecticide in the 1950s. The Reregistration Eligibility Decision fo r Pyrethrins was competed in 2006.

Anticipated Risk Assessment and Data Needs

The Agency anticipates requiring data for us e in updating and refini ng the ecological risk assessment (including an endangered species ri sk assessment) and the human health risk assessment for all uses of pyrethrins. Below is a summary of the issues relevant to the registration review of pyret hrins and the data the Agen cy anticipates requiring.

Ecological Risk:

• The most recent ecological risk assessment for pyrethrins is reflected in the “Revised Pyrethrins RED Chapter After Additional 60- Day Comment Period, Phase 5” dated April 4, 2007.

• The Agency has not conducted a risk asse ssment that supports a complete endangered species determination for pyrethrins. Th e ecological risk assessment planned during registration review will allow the Agency to determine whether pyrethrins’ use has “no effect” or “may affect” federally listed threat ened or endangered sp ecies (listed species) or their designated critical ha bitats. When an assessment c oncludes that a pesticide’s use “may affect” a listed species or its designate d critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service (USFWS) and/or Nationa l Marine Fisheries Service (NMFS) (the Servic es), as appropriate.

• On January 19, 2011, the Center for Biologi cal Diversity and the Pesticide Action
Network North America filed a lawsuit in th e United States District Court for the Northern District of California, against th e Environmental Protection Agency (EPA) for allegedly failing to undergo consultation with the United States Fish and Wildlife Service
and the National Marine Fisheries Service re garding the effects of over 350 pesticides, including pyrethrins, on ove r 200 endangered and threaten ed species throughout the United States (Center for Biological Dive rsity, et al. v. EPA, et al., No. C 11-00293 (N.D.Cal.).

• Data gaps exist in the environmental fate and ecological toxicity database for pyrethrins. The Agency anticipates needing the following data, in addition to the data already required in GDCI-069001-27992, for use in co nducting a complete ecological risk assessment, including an endangered species assessment, for pyrethrins:6 Environmental Fate Data Gaps

o GLN 835.4100 Aerobic Soil Metabolism 2

o GLN 835.4200 Anaerobic Soil Metabolism 3

o GLN 835.4300 Aerobic Aquatic Metabolism 4

o GLN 835.4400 Anaerobic Aquatic Metabolism 5

o GLN 835.6100 Analytical method and a ssociated independent laboratory
validations in soil

o GLN 835.6200 Analytical method and a ssociated independent laboratory
validations in water and sediment

Ecological Toxicity Data Gaps

o GLN 850.1020 Acute Freshwater Invertebrate Toxicity ( Hyalella azteca ) – water
column

o GLN 850.2100 Avian Acute Oral Toxicity, Passerine

o GLN 850.2300 Avian Reproduc tion Test, Quail/Duck 6

o GLN 850.4100 Seedling Emergence, Tier II

o GLN 850.4250 Vegetative Vigor, Tier II

• Please refer to the EFED Registration Review Prelim inary Problem Formulation for Pyrethrins dated November 30, 2011, located in docket EPA-HQ-OPP-2011-0885 at www.regulations.gov, for a more detailed discu ssion of the anticipat ed ecological risk assessment and data needs for pyrethrins.

Human Health Risk:

• The most recent comprehensive human health risk assessment was conducted in support of the 2006 Reregistration Eligibility D ecision (RED) and is dated March 16, 2006. Since the RED, additional human health assessments for pyrethrins occurred regarding a revision of the assessment for directly treating pets (01/24/08) and it s use to treat in-home bedbug infestations (3/28/11).

• The Food Quality Protection Act (FQPA) require s the Agency to consider the cumulative risks of chemicals sharing a co mmon mechanism of toxicity. Pyrethrins are a member of the pyrethroid/pyrethrins common mechanism group ( http://www.regulations.gov ; EPAHQ-OPP-2008-0489-0006). The members of this group share the ability to interact with

2 Conduct studies in three different soil types; fo r metabolism studies, domestic soils are preferred.

3 Conduct studies in four different soils; for me tabolism studies, domestic soils are preferred.

4 Conduct studies in two different sediment systems, one of which is of marine origin.

5 Conduct studies with two water/sedime nt systems, with one of the sediment systems from estuarine/marine origin.

6 Tests are recommended for the technical product with waterfowl and an upland game bird species.7 voltage-gated sodium channels ultimately lead ing to neurotoxicity. The cumulative risk assessment for the pyrethroids/pyrethrins was published on Nov. 9, 2011 and is available

at http://www.regulations.gov ; EPA-HQ-OPP-2011-0746. No cumulative risks of concern were identified, allowing the Agency to consider new uses for pyrethroid actives. For information regarding EPA’s efforts to evaluate the risk of exposure to pyrethroids,
refer to http://www.epa.gov/oppsrrd1/reevaluati on/pyrethroids- pyrethrins.html

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• During registration review, the endpoints, doses, and safety factors used in the most recent human health risk assessments may be revisited based on current policy as well as to incorporate any new data received and determined to be adequate. The re-evaluation of the FQPA safety factor may be conducte d following a final determination of the potential for increased susceptibility of infa nts and children to pyrethroid pesticides based
on the review of all available data.

• The uncertainty factor for Pyrethrins is currently 300X for acute dietary and short-term incidental oral (3X FQPA safety factor ( SF) due to lack of a DNT and concerns for neurotoxicity, 10X for inter-sp ecies variation, 10X for intr a-species variation). An uncertainty factor of 100X was applied to e ndpoints selected for oral exposure (10X for interspecies extrapolation, 10X for intraspecies variation). An uncertainty factor of 1000 was applied to intermediate- and long-term inha lation endpoints due to both the lack of a
DNT and the lack of a NOAEL for the identifi ed endpoint, respirator y tract lesions.

• Under FQPA, the Agency is required to appl y a 10X SF to be protective of infants and
children unless there is data to support a reduction or removal. The Agency’s current position is that there is sufficient evidence to reduce the FQPA SF to 1X for adults and 3X for children <6 years of age. The 3X is based on age-dependent-pharmacokinetics and is further supported by physiological ly-based pharmacokinetic (PK) model predictions of a 3-fold increase of pyrethroi d concentration in j uvenile target tissue compared to adults. A more complete descri ption of the Agency’s reasoning behind a 3X FQPA SF for children can be found at www.regulations.gov ; EPA-HQ-OPP-2011-0746- 0011. These UFs are subject to review and possible revision dur ing the registration
review.

• The Agency anticipates conducting updated dietary (food and wa ter), aggregate, residential, and occupational exposure risk assessments to include any changes in toxicological endpoints, doses, and procedures for risk assessment.

• The residential and occupational exposure asse ssments may need to be updated to reflect current standard operating procedures a nd to incorporate new unit exposures, new transfer coefficients, and any new chemical-s pecific data submitted by the registrants, as well as reflecting current endpoi nts and points of departure.8 • The Agency also anticipat es conducting an updated dr inking water exposure risk assessment during registration review.

• The tolerance expression for pyrethrin s in 40 CFR §180.128 and §180.905(a)(6) will be reviewed during registration review to ensure that it appropriately covers the metabolites and degradates of pyrethrins and that it specif ies the residues to be measured in each commodity.

• The Agency will modify tolerance levels as needed, and work to harmonize tolerances/maximum residue limits (MRLs) , where possible, in key export markets during registration review.

• A Generic Data Call-in (GDCI-069001-27992) was issued for pyrethrins in 2009 following the RED. Most of the data require ment studies remain outstanding. This is
discussed further in th e Fact Sheet section of this document.

• The Agency anticipates requiring the followi ng toxicity data for use in conducting a complete human health risk assessment for pyrethrins:

o GLN 870.7800 – Immunotoxicity

• Pyrethrins are among several agricultural chem icals included in the Agricultural Health Study (AHS). The AHS began in 1993 and is a collabora tion of the National Institute of Environmental Health Sciences (NIEHS), the National Cancer In stitute (NCI), the EPA, and the National Institute for Occupational Safety and Health (NIOSH). Designed as a large long- term epidemiological study, the AHS collects and analyzes data on th e health and work practices of nearly 90,000 farmers and their families in Iowa and North Carolina who enrolled in the study before any disease developed. The study focuses part icularly on farmers' exposure to 50 chemicals including many of the most widely used pesticides. As data are collected over a period of years, scientists can compare overall health outcomes for people who differ in whether they have had exposure to various chemicals. While these comparisons cannot conclusively de monstrate how exposure affects health, they can show some statistical as sociations. More information on the AHS can be
found at: http://aghealth.nci.nih.gov . EPA is monitoring the results of the AHS and will consider this study in the registration review of Pyrethrins as appropriate.

• Please refer to Pyrethrins. Human Health Risk Scopi ng Document in Support of Registration
Review dated December 1, 2011, available in docket EPA-HQ-OPP-2011-0885 at www.regulations.gov, for a detailed discussion of th e anticipated human he alth risk assessment
and data needs.9 Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of its most recent reregistration decisi on for pyrethrins, EPA
reviewed these data and select ed the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), pyrethrins are subject to the endocrine screeni ng part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whet her 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 ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required
determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects 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 pest icide active ingredients and 9 inert ingredients. Pyrethrins are not among the group of 58 pesticide active ingredient s on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issu e future EDSP orders/data callins, requiring the submission of EDSP screening assays for pyreth rins. For further information on the status of the EDSP, the policies and procedur es, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screen ing battery, please visit our website: http://www.epa.gov/endo/

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Timeline

The projected timeline for the completion of the pyrethrins registration review is presented
below in Table 1.10 Table 1. Projected Pyrethrins Registration Review Timeline 7 Activity Estimated Date Opening the Docket Open Docket and Open Public Comment Period 2011 – December
Close Public Comment Period 2012 – February Case Development Develop Final Work Plan (FWP) 2012 – May Issue Data Call-In (DCI) 2013 – Jan. - March
Data Submission 2015 – Jan. - March Open Public Comment Period for Draft Risk Assessments 2016 – July – Sept.
Close Public Comment Period 2016 – Oct. – Dec. Registration Review Decision Open Public Comment Period for Proposed Re gistration Review Decision 2017 – Jan. - March
Close Public Comment Period 2017 – April - June Issue Registration Review Decision a nd Begin Post-Decision Follow-up 2017 Total (years) 6

Guidance for Commenters

The public is invited to comment on EPA’s preliminary work plan and rationale. The Agency will carefully consider all commen ts, as well as any additional information or data provided in a timely manner, prior to issuing a fina l work plan for the pyrethrins case.

Trade Irritants

Through the registration review process, the Ag ency intends to solicit information on trade irritants and, to the extent feas ible, take steps toward facilitating irritant resolution. Growers and other stakeholders are asked to comment on any tr ade irritant issues resulting from lack of Maximum Residue Limits (MRLs) or disparitie s between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the na ture of the concern.

Environmental Justice

EPA seeks to achieve environmenta l justice, the fair tr eatment and meaningful involvement of all people, regardless of race, color, national origi n, or income, in the deve lopment, implementation, and enforcement of environmental laws, regulati ons, 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 thei r location, cultural practices, or other factors, may have atypical, unusually high exposure to pyrethrin s compared to the general population. Please

7 Any changes in the cumulative risk from the pyrethroid class of insecticides may impact this time estimate.11 comment if you are aware of any sub-populatio ns that may have atypical, unusually high exposure, compared to the general population.

Water Quality

On October 11, 2011, EPA issued its final deci sion regarding the waters EPA added to California's 2008-2010 list of impaired water bodi es that require total maximum daily loads (TMDLs) pursuant to Clean Water Act, secti on 303(d), and 40 CFR 130.7( d)(2). This list includes 11 water body impairments due to pyrethr oid chemicals (including pyrethrins), and 3 water body impairments which list the pyrethr oids bifenthrin, lambda cyhalothrin, esfenvalerate/fenvalerate, and permethrin as pollutants. More information on California’s additional impaired water body listings can be found at: http://www.epa.gov/region9/wa ter/tmdl/california.html

On October 28, 2011, the California Department of Pesticide Regulation (DPR) announced proposed restrictions to 17 pyrethroid pesticides used by pest control applicators and maintenance gardeners in urban areas to protect water quality in urban areas. Restrictions would include reduced application rate s around structures; and to prohi bit applications during rain, when puddles are present, and over drains or natura l drainage areas. More information about the proposed regulations are avai lable on DPR’s website at: http://www.cdpr.ca.gov/docs/le gbills/rulepkgs/11-004/11-004.htm

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On October 31, 2011, EPA issued a final NPDES Pesticide General Permit (PGP) for point source discharges from the application of pesticides to waters of the United States. This action was in response to a 2009 decision by th e U.S. Sixth Circuit Court of Appeals ( National Cotton Council, et al. v. EPA ) in which the court vacated EPA's 200 6 Final Rule on Aquatic Pesticides and found that point source discharges of biological pesticides, and chem ical pesticides that leave a residue, into waters of the U.S. were pollutants under the Clean Water Act (CWA). The Agency’s final permit covers operators that apply pesticides that result in discharges from the following use patterns: (1) mosquito and other flyi ng insect pest control; (2) aquatic weed and algae control; (3) aquatic organism pest cont rol; and (4) forest canopy pest control.

The final pesticide general permit requires permittees to minimize pesticide discharges through the use of pest management measures, and monito r for and report any adverse incidents. While the permit’s requirements must be met as of October 31 st , 2011, operators are not required to submit Notices of Intent (NOIs) until January 12, 2012. No permit will be required for discharges from agricultural runoff or irrigati on return flows, both of which are exempt from permitting under the CWA. EPA’s pesticide general permit will cover pesticide applications in the areas where EPA is the permitting authority, which include Massachusetts, New Hampshire, New Mexico, Idaho, Oklahoma, Alaska, Washingt on, D.C., most U.S. territories and Indian country lands, and many federal facilities. For more information, please visit: http://www.epa.gov/npdes/pesticides

.12 Other Information

Stakeholders are also specifically asked to prov ide information and data that will assist the Agency in refining risk assessments, includ ing any species-specific ecological effects determinations for pyrethrins. The Agency is in terested in receiving the following information:

1

. Usage data such as pounds active ingredient (a .i.) applied, area trea ted, typical use rates, and typical number of applica tions on the following sites: indus trial sites, livestock, milk,
and meat
2. Importance to users in organic farming (e .g., frequency of use per season, application rates and methods in specific organic crops)
3. Usage data for the agricultural crops that ar e not covered in the us age section of this
document
4. Usage data (pounds a.i. applied and area treate d) for indoor/outdoor consumer use, use in food handling establishments /food processing establishments, and use in and around
commercial and institutional facilities
5. Confirmation on the following label information

a. sites of application
b. formulations

c. application methods and equipment
d. maximum application rates

e. frequency of application, applicati on intervals, and maximum number of applications per season and per year
f. geographic limitations on use
6. Use or potential use distribution ( e.g ., acreage and geographical distribution of relevant uses/use sites)
7. Use history
8. Median and 90 th percentile reported use rates (lbs ac tive ingredient(a.i.) /acre, lbs a.i./1000 sq. ft.) from usage data – national, state and county
9. Application timing (date of firs t application and application intervals) by use – national, state, and county
10

. Sub-county use site location data
11. Directly acquired county-level usage data (not derived from state level data)

a. m aximum reported use rate (lbs a.i./acre) from usage data – county
b. median and 90 th percentile number of applications – county

c. total pounds per year – county
d. the year the pesticide was last us ed in the county/sub-county area

e. the years in which the pesticide was applied in the county/sub-county area
12

. Typical application interval (days)
13. State or local use restrictions13 14. Ecological incidents (non-target plant dama ge and avian, fish, reptilian, amphibian, mammalian mortalities, and bee or beneficial insect mortalit ies) not already reported to the Agency
15. Monitoring data

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 i ssue a Final Work Plan for the registration review of pyrethrins.14 II. FACT SHEET

Background Information

• Re gistration Review Case Number: 2580

• Pesticide Chemical (PC) Code: 069001

• Chemical Abstracts Servi ce (CAS) Number: 8003-34-7

• Pyrethrins were first registered in the U.S. in the 1950s.

• The Reregistration Eligibility Decision for pyrethrins was completed in June 2006. The RED and its supporting risk assessments are available in docket EPA-HQ-OPP-2005-
0043 at www.regulations.gov

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• Technical registrants: Botanical Resour ces Australia Pty Ltd., Horizon Sopyrwa, McLaughlin Gormley King Co., Prentiss Inc., Pyranha Inc., Pyrethrum Board of Kenya, Pyrethrum Company of Tanzania Ltd., S.C. Johnson & Son Inc., Valent Biosciences Corp., Whitmire Micro-Gen Re search Laboratories Inc.

• Active registrations as of October 2011:

o 601 Section 3 registrations

o 1 Section 24(c) registration (Special Lo cal Need) for use on lake margins in
California

• U.S. tolerances for pyrethrins range from 0.05 ppm to 3.0 ppm [40 CFR §180.128]. There is currently an exemption from a to lerance for raw agricultural commodities [40 CFR §180.905(a)(6)].

• Pesticide Re-evaluation Divisi on (PRD) Contact: Joel Wolf ( wolf.joel @epa.gov )

• Registration Division (RD) Contact: Richard Gebken ( gebken.richard@epa.gov )

Use and Usage Information

For additional details, please refer to BEAD Chemical Profile for Registration Review: Pyrethrins (069001) , dated August 24, 2011; Pyrethrins (069001) Screening Level Usage Analysis (SLUA) , dated January 21, 2011; and PRD Appendix A: Food/Feed & Non-Food/NonFeed Uses Considered in Re gistration Review Work Planning

. Pyrethrins (069001) , dated March 22, 2010; located in docket EP A-HQ-OPP-2011-0885 at www.regulations.gov.15 • Pyrethrins are registered for hundreds of agri cultural uses, including most fruit, nut, and vegetable crops, as well as most major acr eage crops such as corn, soybean, and wheat

. There are also indoor (greenhouse) uses listed for a variety of crops ( e.g. , tomatoes, ornamental plants, etc. ).

• Non-agricultural uses for pyrethrins incl ude, but are not limite d to, wood products ( e.g. , beams, decks, and pilings), woodland areas , wood surfaces, and zoos (enclosures and outdoor perimeter areas). Other non-agricultu ral use sites where pyrethrins are used
include residential and commer cial buildings, food handling establishments, institutional turf, nursery/greenhouse, and mosquito abatement areas.

• Pyrethrins are formulated as granules, emulsi fiable concentrates, re ady-to-use solutions, and as pressurized gas and liquid.

• Pyrethrins are commonly used in formulations with the pesticidal synergists PBO and MGK-264. These compounds enhance the in secticidal activity of pyrethrins.

• Application methods in agri cultural and non-agricultural us es are diverse and include: aerosol can, mist blower, metered release devices, total release aerosol, fixed wing aircraft, helicopter, truck-mounted ultra lo w volume (ULV) equipment, cold aerosol generator, hand held sprayers (high or low pressure handwands), thermal/cold/ULV fogging equipment, conven tional dusting equipment ( e.g ., power duster, bulb duster, shaker can), outdoor misting system s, and irrigation systems.

• The annual total agricultural usage av eraged approximately 2,000 pounds active ingredient for the period 1998-2010, while the no n-agricultural annual usage total for the period 2002-2008 is about 32,000 lbs. a.i. The la rgest markets in term s of total pounds of a.i. applied are lettuce (17%), winter wheat (16%), oranges (9%), and strawberries (8%). The highest total area treated (TAT) are wi nter wheat (20%), a nd soybeans and lettuce (9% each).

Recent and Pending Actions

• Product mitigation identified in the 2006 RED is still being implemented, as such, not all pyrethins labels reflect the most up-to-date label language

• On May 5, 2011, the Agency accepted a label language amendment for pyrethrins use on mattresses and box springs for bed bug infestations. This is not considered a “new use”
because indoor residential uses are already registered for the product.16 Ecological Risk Assessment Status

The following are key findings from the most rece nt ecological risk assessments regarding the environmental fate, ecological effects, and risks of pyrethrins. Please refer to the EFED Registration Review Preliminary Problem Formulation for Pyrethrins , November 30, 2011, located in docket EPA-HQ-OPP-2011-0885 at www. regulations.gov, for a detailed discussion.

• The most recent ecological risk assessment for pyrethrins is contained in the “ Revised Pyrethrins RED Chapter After Addi tional 60-Day Comment Period, Phase 5 ” dated April 4, 2007.

Ecological Effects:

• Based upon toxicity data and ot her information, acute risks fro m the use of pyrethrins to mammals, birds, terrestrial amphibians, and reptiles is below the Agency’s level of concern (LOC).

• The review indicated risk concerns for freshwater and estuarine/ marine organisms, including benthic organisms. Chronic risk estimates exceeded the LOC triggers for estuarine/ marine invertebrates, while fi sh (freshwater and estuarine/ marine) and
freshwater invertebrates were found not to be at chronic risk from exposure to pyrethrins
in the water column.

• On an acute basis, pyrethrins ar e highly toxic to honey bees.

• The Agency also evaluated the pharmacological uses of pyrethrin using the “Down-theDrain” module of the Exposure and Fate A ssessment Screening Tool (E-FAST) model and found that aquatic LOCs were not exceed ed for freshwater or estuarine/marine organisms.

Human Health Risk Assessment Status

The following are key findings from the most re cent human health risk assessments conducted for pyrethrins registered uses. Please refer to Pyrethrins. Human Health Risk Scoping Document in Support of Registration Review, December 1, 2011, located in docket EPA-HQ-OPP-2011-0885 at www.regulations.gov, for a detailed discussion of the human health
risk assessment status.

• The most recent human health risk asse ssment was conducted in support of the 2006 Reregistration Eligibility Decision (RED) a nd is dated March 16, 2006. Since the RED, additional human health assessments for pyrethr ins occurred regarding its use to treat in-17 home bedbug infestations (3/28/11) and a revision of the assessment for directly treating pets (1/24/08).

Human Studies:

• Past pyrethrins risk assessments 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, invo lving exposure to many different pesticides, comprise generic pesticide exposure database s such as the Pestic ide Handlers Exposure Database (PHED), the Agricultural Reentry Task Force (ARTF) Database, the Agricultural Handlers Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF) Database.

• EPA has reviewed all the studies suppor ting these multi-pesticide generic exposure databases, and has found no clear and convinc ing evidence that the conduct of any of them was either fundamentally unethical or si gnificantly deficient relative to the ethical standards prevailing at the time the research was conducted. All appl icable requirements
of EPA’s Rule for the Protection of Human S ubjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to conti nued reliance on these studies.

Hazard Characterization:

• The major target organs for pyrethrins-induced toxicity are the ner vous system, liver, and thyroid. Neurobehavioral effects were observed in rats and mice following acute, subchronic, and chronic exposur e, and neuropathological lesions were ob served in rats following acute exposure. Following inhalati on exposure, neurobehavioral effects were observed initially, and histopathological lesi ons of the lungs/respiratory tract were
observed at all dose levels. Pyrethrins show no significant developmental or reproductive
effects in rats.

• Pyrethrins were classified as “Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential” be cause there was suggestive evidence that pyrethrins are carcinogenic based on wei ght-of-the-evidence considerations.

• Toxicity points of departure (PODs) were selected for oral and inhalation exposure pathways for the risk assessment conducted in the 2006 RED. No endpoints were selected for dermal exposure since no system ic effects were observed at the limit dose in the 21-day dermal toxicity study in rabbits.

• Since there were adequate deve lopmental toxicity studies in rats and rabbits, an adequate two-generation reproduction study in rats, and no residual uncer tainties that indicate the need for retaining an additional factor, the FQPA factor was reduced to 1X. An18 uncertainty factor of 100X was applied to e ndpoints selected for oral exposure (10X for interspecies extrapolation, 10X for intraspecies variation). An uncertainty factor of 300 was applied to acute dietary and short-term incidental oral en dpoints (conventional uncertainty factor of 100X plus an additional 3X for the lack of a DNT and concerns for neurotoxicity). An uncertainty factor of 1000 was applied to interm ediate- and long-term inhalation endpoints due to both the lack of a DNT and the lack of a NOAEL for the identified endpoint, resp iratory tract lesions.

Summary of Risks:

Dietary

• The dietary assessment (food and water) did not indicate risk estimates of concern.

Residential

• Residential scenarios assessed include short-term and intermediate-term exposures for handlers (i.e., mixers, loaders, applicators) that occur during application of pyrethrins and short-term, post-application exposure from activities in treated areas.

• In the assessments for the pyrethrins RED there was no residential risk estimates of concern identified when pyrethrins were mixed, loaded, applied, or handled by
homeowners. There were several residentia l post-application scenarios where risk estimates of concern were identified: 1) indoor broadcast dust applications to carpets, 2) indoor metered release systems, and 3) outdoor residential misting systems. In order to mitigate these risks, the RED specified ame nded label language, including the prohibition
of metered release devices in residential i ndoor areas. In addition, the Agency required data to confirm the assumptions used in its risk assessment.

Aggregate

• The most recent risk assessment included aggr egate assessments that considered exposure from food, drinking water, and residential uses. Acute aggr egate exposures assessments for pyrethrins showed no risk estimates of concern.

• The short-term aggregate exposure assessment for pyrethrins showed no risk estimates of concern for adults and children using the A ggregate Risk Index (ARI) method since the dietary contribution included high-end field trial data a nd assumed 100% percent crop treated for all but a few crops.19 Occupational

• A number of occupational exposure scenarios were assessed for agricultural, forestry, professional pest control operator, and mosquito control applications of pyrethrins. The
scenarios assessed that indicat ed potential risk concerns fo r occupational handlers were those using wettable powder formulations ov er the intermediate-term exposure duration. Mitigation measures, such as the use of wa ter soluble packaging for all wettable powder formulations were specified in the RED. These mitigation measures addressed the
identified risk concerns.

Cumulative

• The Food Quality Protection Act (FQPA) require s the Agency to consider the cumulative risks of chemicals sharing a co mmon mechanism of toxicity. Pyrethrins are a member of the pyrethroid/pyrethrins common mechanism group ( http://www.regulations.gov ; EPAHQ-OPP-2008-0489-0006). The members of this group share the ability to interact with voltage-gated sodium channels ultimately lead ing to neurotoxicity. The cumulative risk assessment for the pyrethroids/pyrethrins was published on Nov. 9, 2011 and is available

at http://www.regulations.gov ; EPA-HQ-OPP-2011-0746. No cumulative risks of concern were identified, allowing the Agency to consider new uses for pyrethroid actives. For information regarding EPA’s efforts to evaluate the risk of exposure to pyrethroids,
refer to http://www.epa.gov/oppsrrd1/reevaluati on/pyrethroids- pyrethrins.html

.

Incidents

Ecological Incidents:

• The Agency reviewed the Ecological Incide nt Information System (EIIS), which is maintained by the EPA Office of Pesticide Programs (OPP), and the Avian Monitoring System (AIMS), which is maintained by the American Bird Conservancy, for ecological incident reports associated with th e use of pyrethrins in the U.S.

• The EIIS database contained 7 major incident s involving pyrethrins. The reports included 2 fish incidents and 5 plant incidents. With respect to the lik elihood that pyrethrins caused the reported incidents, th e certainty ranged from possible to probable. Four of the incidents resulted from registered uses, two were misuses and one use pattern is
unknown. The AIMS database contains no avian incidents involving pyrethrins.

• For pyrethrins, the registrants have repor ted 231 minor plant incidents. All reported
incidents occurred between 1995 and 2010 and involved currently registered products.20 Human Health Incidents:

• The Agency reviewed the OPP Incident Data System (IDS) for human health pesticide
incident data associated with the active i ngredient pyrethrins in the U.S. to identify potential patterns on the freque ncy and severity of health e ffects attributed to pyrethrins exposure. The IDS aggregate summaries fr om January 1, 2006 to June 6, 2011 include 4,375 minor, unknown, or no effects outcomes re ported for pyrethrins (664 of the exposures are classified as an unknown/no effects outcome, 3,711 of the exposures are classified as resulting in a minor outcome). For the Main IDS, from January 1, 2006 to June 6, 2011, there were 13 exposures reported for single chemical only in the database, and 803 additional exposures that involved more than one chemical.

• In general, a relatively high frequency of inci dents were reported i nvolving pyrethrins. Although most of these incidents were of low severity, it appears exposures to pyrethrins have the potential to result in high severi ty outcomes. Consequently, based on the frequency of exposures and the potential fo r exposures to resu lt in high severity outcomes, these incident data warrant further analysis in the preliminary risk assessment phase of Registration Review.

• The Agency has considered/discussed the pot ential relationship between pyrethrum, pyrethrins and pyrethroids and allergic/asthmatic effects in a variety of analyses (e.g., EPA's OPP "Recognition and Management of Pesticide Poisonings" manual, the EPA
Office of Radiation and Indoor Air commissi oned a review by the National Academy of
Sciences’ Institute of Medicine about the re lationship between asthma and exposure to various substances, including pesticides; a nd OPP staff have conducted pyrethrins and various pyrethroid incident re views). Most recently, a report by the Center for Public Integrity prompted EPA to conduct its latest review of pyrethrins a nd pyrethroid incidents to identify any trends in the data. Agency scientists have concluded that there does not appear to be a clear re lationship between pyrethrins/pyrethroid exposure and asthma/allergies 8 . However, the pyrethrins registrants committed to a product stewardship program that invol ves outreach to physicians and Poison Control Centers with better guidance and diagnostic standards, as well as prospec tive in-depth follow-up of reported cases in order to better understa nd the cause of the inci dents with pyrethrins. 9

Tolerances and International Harmonization

• U.S. tolerances for pyrethrins are located at 40 CFR §180.548 and §180.905(a)(6).

8 http://www.epa.gov/oppsrrd1/reevaluation/pyrethr ins-pyrethroids-asthma-allergy-9-18-09.pdf

9 This is a 5-year program requiring annual reports. To date, one annual report has been submitted.21 • A table listing the differences between U. S. tolerances and Canadian, Mexican, and CODEX Maximum Residue Limits (MRLs) for pyrethrins is included in the Pyrethrins. Human Health Risk Scoping Document in Support of Registration Review  ̧ dated December 1, 2011, available in docket EPA-HQ-OPP-2011-0885 at www.regulations.gov.

• Currently, there are no harmonization issues with Canada, CODEX, or Mexico. During registration review, if any C odex MRLs have been establis hed, the Agency anticipates harmonizing the U.S. tolerances with the Codex MRLs when the data warrant
harmonization.

Data Call-Ins

• A DCI was issued to pyrethrin s technical registrants in Ma y 2009 to address data gaps identified in the 2006 RED. These data, al ong with the anticipated registration review data requirements that are required, submitted, and determined to be adequate will be used in conducting the forthcoming human hea lth and ecological risk assessments for the registration review of pyrethrins. Th e following data for GDCI-069001-27992 have been required:

Data that have been submitted

o GLN 860.1850 Confined accumula tion in rotational crops

Data still outstanding

o GLN 830.7050 UV/Visible absorption

o GLN 850.1075 Freshwater and mari ne fish acute toxicity

o GLN 850.1350 Mysid chronic toxicity

o GLN 850.1400 Fish early-life stage toxicity test

o GLN 850.1500 Fish full life cycle toxicity

o GLN 850.4100 Terrestrial pl ant toxicity, Tier I (seedling emergence)

o GLN 850.4150 Terrestrial pl ant toxicity, Tier I (vegetative vigor)

o GLN 850.4400 Aquatic plant toxicity te st using Lemna spp. Tiers 1 and II

o GLN 850.5400 Algal toxicity, Tiers I and II

o GLN 860.1380 Storage stability data

o GLN 860.1500 Crop field trials (for various commodities) 10

o GLN 860.1520 Processed food/feed (for various commodities)

o GLN 870.6300 Developmental neurotoxicity study

o GLN 875.1400 Inhalation exposure—indoor (metered release devices)

o GLN 875.1400 Inhalation expos ure - indoor - ULV fogger

10 See Appendix D: Required Crop Field Trial Data in Pyrethrins. Human Health Risk Scoping Document in Support of Registration Review, December 1, 2011 for a complete list of the required crop field trials.22 o GLN 875.1700 Product use information (outdoor residential misting systems)

o GLN 875.2500 Inhalation exposure – residential misting systems

o Non-GLN Chronic freshwater sediment toxicity ( Chironomus spp. and Hyalella azteca ) 11

o Non-GLN Chronic estuarine sediment toxicity 12

o Non-GLN Pyrethrins stewardship program 13

o Non-GLN Developmental thyroid assay

Data compensation

o GLN 840.1100 Spray droplet size spectrum

o GLN 840.1200 Spray drift field deposition

o GLN 875.1300 Inhalation exposure—outdoor (ORETF)

o GLN 875.2300 Indoor surface residue dissipation

o GLN 875.2400 Dermal exposure (loadi ng and application of dust)

o GLN 875.2500 Inhalation exposure – post application (fogging)

o GLN 875.2500 Inhalation exposure - po st application (trigger pump sprayer)

o GLN 875.2500 Inhalation exposure – po st application (loading and application of dust)

Labels

• Active Section 3 labels for pyrethrins can be obtained from the Pesticide Product Label System (PPLS) website: http://oaspub.epa.gov/pestlabl/ppls.home

.

11 In more recent DCIs this data requirement is indicated as Non-GLN/Test # 100.4 Whole Sediment: chronic invertebrates freshwater and marine (Hyalella azteca) and Non-GLN/Test # 100.5 Whole Sediment: chronic invertebrates freshwater and marine (Chironomus dilutes).

12 In more recent DCIs this data requirement is indicated as Non-GLN Whole Sediment: chronic invertebrates freshwater and marine (Leptocheirus plumulosus).

13 This is a 5-year program requiring annual reports. To date, one annual report has been submitted.23 III. SUMMARY OF DATA GAPS

A summary of the anticipated data needs for pyret hrins registration review is presented in Table
2.

Table 2. Summary of Anticipated Data Needs for Pyrethrins

Guideline Number Anticipated Data Requirement Test
Material Estimated
Timeframe
(Measured
in Months
from DCI Receipt)

835.4100 Aerobic Soil Metabolism TGAI 24

835.4200 Anaerobic Soil Metabolism TGAI 24

835.4300 Aerobic Aquatic Metabolism TGAI 24

835.4400 Anaerobic Aquatic Metabolism TGAI 24

835.6100 Analytical method and associated independent laboratory
validations in soil TGAI 24

835.6200 Analytical method and associated independent laboratory
validations in water and sediment TGAI 24

850.1020 Acute Freshwater Inve rtebrate Toxicity ( Hyalella azteca ) –
water column TGAI 12

850.2100 Acute Avian Oral, Passerine TGAI 12

850.2300 Avian Reproduction Quail/Duck TGAI 24

850.4100 Seedling Emergence, Tier II TGAI 12

850.4250 Vegetative Vigor, Tier II TGAI 12

870.7800 Immunotoxicity TGAI 12