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



## Pyrethrins
Final Work Plan Registration Review

May 2012

## Pyrethrins

Final Work Plan Registration Review

Case # 

## 2580

Approved By:

### ~-?~~4J Richard P. Keigwin, Jr.

Director

Pesticide Re-evaluation Division



# 5J \ 8' 

### 1..:1.0 1;:L


### Date

23 Introduction

This is the Environmental Protection Agency’s (EPA’s) Final Work Plan for the registration review of pyrethrins. 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 pyrethrin s registration review docket (EPAHQ-OPP-2011-0885), and any othe r comments concerning the in itial docket postings. The Summary Document provided information on what EPA knows about the pesticide and what additional risk analyses and da ta or information the Agency believes are needed to make a registration review decision.

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. Changes in science, public policy, and pesticide use practi ces will occur over time. The registration review program is intended to ma ke sure that, as the ability to assess risk evolves and as policies and practi ces change, all registered pes ticides continue to meet the statutory standard. The public pha se of registration review begins when the initial docket is opened for each case. Information on this program is provided at: http://www.epa.gov/oppsrr d1/registration_review/

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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), re sidential areas, woodland areas, wood surfaces, residential and commercial buildings, food handling establishments, and mosquito

abatement.

The term “pyrethrins” refers to all six compounds (pyrethrin 1, pyrethrin 2, cinerin 1, cinerin 2, jasmolin 1, and jasmolin 2) 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 pi peronyl butoxide (PBO) or MGK-264, as well as with pyrethroids. Products formulated with pyrethrins alone are re gistered for use in organic agriculture production. Pyrethrins were first re gistered as an insecticide in the 1950s. The Reregistration Eligibility Decision fo r Pyrethrins was competed in 2006.4 Comments Received on Preliminary Work Plan

McLaughlin Gormley King Co. (MGK), registrant of technical grade pyrethrins, and Physicians Committee for Responsible Medicine (PCRM) provi ded the only two submi ssions to the docket during the 60-day public comment period on the pl anned human health and environmental fate and ecological risk assessment s discussed in the pyrethrins Preliminary Work Plan (PWP). The comments do not alter the Agency’s PWP for the re gistration review of pyr ethrins. While the data gaps identified in the PWP remain uncha nged, because guideline number 850.1020 is still in draft, the study is now listed as guideline number 850.1010. This change does not alter the data being required. For further discussion on these comments, please see the Summary of Comments and Agency Responses section of this document as well as the supporting response to

comment documents included in the docket, EPA-HQ-OPP-2011-0885.

Summary of Comments and Agency Responses

Comments related to the Environmental Fa te and Ecological Problem Formulation
MGK Comment: With respect to pyrethrins in the e nvironment, they are one of the shortestlived active ingredients, with ha lf lives on the order of hours rather than days. Further, with respect to the CBD 1 lawsuit, we believe that ecological risk assessments on pyrethrins will not trigger levels of concern in the environment.

EPA Response: EPA acknowledges pyrethrins appear to be labile to certain routes of degradation/ metabolism. Under anaerobi c conditions, it seems to persist longer (t 1/2 = 86 days). In the last risk as sessment performed on the pyrethrin s, there were exceedances of
acute and chronic levels of concern for bot h freshwater and estuarine/marine aquatic animals, as well as benthic organisms. The acute and chronic levels of concern (LOCs)

were not exceeded for listed or non-listed ma mmals or birds. For environmental fate and ecological risk assessment supporting the forthcoming registration review, all the available environmental fate and ecologi cal effects data will be evaluated.

MGK Comment: Ecological Toxicity Data Gaps, the Pyrethrins Joint Venture and Piperonyl Butoxide Task Force II, of which MGK is a member, has provided EPA with a special study design under the GLN 850.1020, to inves tigate the acute aquatic toxi city of combinations of concentrations of pyrethrins and piperonyl butox ide (PBO). Studies ar e underway determining

the LD 50 of Hyalella azteca to these different combinations of concentrations. We will be able to

determine both the critical concentr ations of PBO and pyrethrins as well as what ratio of PBO to pyrethrins result in the greatest LD 50 . This will be extremely useful information from which data with other pyrethroids can inform any synerg istic effect of PBO a nd pyrethroids in the

environment.

EPA Response: EPA acknowledges the comment a nd supports the data submission.

1 CBD refers to Center for Biological Diversity.5 MGK Comment : With respect to Water Quality, pyrethrin s have a very short half life in the environment, degrading rapidly in sunlight. Therefore we are ve ry surprised to read of 11 bodyof-water impairments listing pyrethrins. We will respond further during Registration Review.

EPA Response : It was noted that the summary doc ument says that there are several bodies of water impaired due to the presence of pyrethroids (not pyr ethrins). However, pyrethroids are related synthetic chemicals with a similar structure. EPA will be investigating whether pyrethrins were dir ectly or indirectly implicated in these impairments.

MGK Comment : With respect to CDPRs recent proposed restrictions to 17 pyrethroids used by pest control applicators, we woul d like to point out to EPA that pyrethrins is NOT one of the 17.

EPA Response : Acknowledged. The proposed DPR Regulation No. 11-004, which contains the full list of 17 pyrethroid active ingr edients affected by the rule, is located at http://www.cdpr.ca.gov/docs/le gbills/rulepkgs/11-004/notice.pdf

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MGK Comment : By direct contact pyrethrins is highl y acutely toxic to bees, but we would like to point out because of the s hort half-life in the environment pyrethrins would not have longterm toxicity to bees exposed to treated foliage over time.

EPA Response : EPA will characterize the environmental fate of pyrethrins using appropriate models and field re sidue data. Regarding the pote ntial for pyrethrins to cause adverse effects on bees as a result of exposure due to existing uses of the chemicals, EPA will utilize available information to qualitative ly characterize potential risks to bees and the need for appropriate label language. EPA further notes that procedures for quantifying risks to honeybees a nd other insect pollinators and the data needed to inform that process will be evaluated at a FIFRA Scientific Advisory Panel (SAP) currently anticipated in fall, 2012. Based on the outcome of this SAP, the need for any additional data for evaluating risks to pollinators and/or appropriate label language will be

determined.

PCRM Comment : The Summary Document indicates that the Agency may request testing for avian acute oral toxicity, however , available data already exists for six pyrethroids (allethrin, cypermethrin, metofluthrin, resmet hrin, tefluthrin, and tetramethrin ), with the Agency requesting testing for an additional 10 through the Registrati on Review process. While it is understood that the common mechanism group designation applie s to mammalian toxicity, the Agency should

consider whether this is also the case for avian acute toxicity. It is si mply unacceptable to test every single member of thes e two groups of substances in lethal bird tests.6 EPA Response : As of July 1, 2008, the CFR 40 Part 158 pesticide data requirements now include avian acute oral data for one passe rine species and either a waterfowl or an upland game species for outdoor end-use pestic ides for all new federal actions (72 FR 60957, dated October 26, 2007). Additional avian acu te oral toxicity data for passerine species are intended to provide informa tion to assess differential sensitivity on a chemical-specific basis, determine whether a ssumptions of allometric relationships can be confidently applied to chemical classes th at have not been tested, and to include a taxonomic group of avian wildlife that is highl y represented in most pesticide use areas and may potentially exhibit differences in metabolic rate, physiol ogy, and toxicokinetics from the currently tested waterfowl and upland game test species.

Only a small pesticide toxicity data set is available for passerine species of birds. Currently, no acceptable avian acute oral da ta with a passerine species have been submitted to the Agency for pyrethrins or any pyrethroid, including the six pyrethroids mentioned in the public comment (allethri n, cypermethrin, metofluthrin, resmethrin, tefluthrin and tetramethrin). Furthermore, a recent study by Addy- Orduna et al. (2011) 2
indicated that some passerine species may be up to 13X more sens itive than some nonpasserine species to formulated beta-cyfluthri n . As additional information on the toxicity

of this class of insecticides to passerine species becomes available, options for bridging toxicity data for additional passerine species could be considered.

MGK Comment : In addition, as a member of the Re sidential Exposure Joint Venture (REJV), the original survey database, and the new one ju st getting underway, will provide highly refined use and usage information for consumer products containing pyrethrins. We strongly urge the Agency to use the surveys not only for Human Hea lth risk assessments, but also the surveys can

be mined for detailed information that can re fine ecological risk assessments for outdoor products.

EPA Response: EPA looks forward to reviewing revised REJV survey to inform both human health and ecological risk assessments when that survey data is submitted to the Agency.

Comments Related to the Human Health Risk Scoping Document
MGK Comment: With respect to the uncertainty f actor of 1000 for the short-term and intermediate-term inhalation endpoin ts related to respiratory tract lesions, we disagree with the Agency’s position on metaplasia. A number of re search studies on the re spiratory tract provide evidence that a wide variety of factors (including chemical exposure) can bring about the histopathological transformation of squamous metaplasia of th e larynx. Other factors that suggest squamous metaplasia in the larynx of rats should not be viewed as a toxicological

2 Addy-Orduna, LM, Zaccagnini, M, Canavelli, SB, Mineau, P. 2011. Fo rmulated Beta-Cyfluthrin ShowsWide Divergence in Toxicity among Bird Species. J. Toxicol. vol. 2011, Article ID 803451, 10 pp.7 response, but rather an adap tive one. We provided more detail information during the Reregistration process and plan to revisit this issue during th e Registration Review process.

EPA Response: With respect to the short-term inha lation endpoint, EPA points out that it is based on tremors, labored breathing, hype ractivity, secretory signs, matted coat, and decreased body weight/body weight gain, wh ich were observed during the first few weeks of the subchronic inhalation study. The intermediate-term inhalation endpoint is not based solely on metaplasia. The LOAEL in the subchronic inhalation study is based on hypertrophy/hyperplasia in the mucosal seromucous glands of the larynx, pseudostratified ciliated/nonciliated column ar epithelial hyperkeratosis of the larynx (both sexes), goblet cell hyperpla sia in the nasopharynx and na soturbinates (males), and epithelial intracytoplasmic eosinophilic materi al in the nasoturbinates, which were

observed at all dose levels at the end of the study.

MGK Comment: EPA has made a gross error in the haza rd characterization section and quoted

the incorrect cancer classification for pyrethrins. After review of the mechanism of action data of the PJV, in the EPA report “PYRETHRINS: F ourth Report of the Cancer Assessment Review Committee”, TXR No.: 0054822, dated February 14, 2008, EPA reclassified pyrethrins as “Not Likely to be Carcinogenic to Humans” at doses that do not cause a mitogenic response in the liver/cell proliferation.

EPA Response: The Agency acknowledges this error. MGK Company is correct in pointing out that the cancer cl assification for pyrethrins is “ Not Likely to be Carcinogenic to Human s” at doses that do not cause a mit ogenic response in the liver/cell proliferation.

MGK Comment: The large number of incidents reported in the time period of 2006 to 2011, is misleading with respect to produc ts containing pyrethrins. Many of the products with pyrethrins also contain more toxic residual pyr ethroids which are more likely to have caused effects, if they were attributable to the pesticide exposure (m any reportable incidents are deemed unrelated to exposure to the product.) The PJV is mid wa y through a 5 year product stewardship program with the Agency providing information to clarif y any role pyrethrins may have in adverse effects, particularly possible allergic reactions. So far, the results indicate many fewer effects directly related to pyrethrins exposure. This pr ogram is further describe d in bullet three in the

EPA document.

EPA Response: EPA acknowledges that when an incident involves more than one pesticide, it is difficult to determine which e ffects are attributed to the pesticide being considered. However, because pyrethrins ar e usually co-formulated with other active ingredients, and because there is about a 50-fold difference between the frequency of incidents involving pyrethrins al one versus pyrethrins and othe r chemicals, it is important to attend to the incidents involving multiple chemicals. Consequently, based on the8 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. EPA agrees it will be importa nt to consider Pyrethrins Joint Venture (PJV) product st ewardship program during the preliminary risk assessment phase of Registration Review.

MGK Comment: With respect to the Immunotoxicity study requirement, MGK points EPA to the ongoing effort between CropLife America and EP A OPP’s Health Effects Division review of all of the existing immunotoxicity data submitted to date. This effort brings out the fact that no toxicological endpoints have change d or been further informed by this data requirement. We look forward to EPA’s review and further dialog in hopes that clear criteria for waiving out of the data requirement can be identified to pr event the unnecessa ry sacrifice of animals from unnecessary studies.

EPA Response: OPP is conducting an independent retr ospective analysis of more than 150 immunotoxicity studies submitted to Ag ency. Preliminary findings of OPP’s retrospective analysis suggest that immunotoxicity studies have not yet provided lower PoDs than are selected from other guideline experimental toxicology studies and thus, so far, immunotoxicity studies w ould not have impacted the Agency’s risk assessments. The OPP retrospective analysis is anticipated to be completed in the summer of 2012. In the interim, EPA recommends that the imm unotoxicity continue to be required for registration and registra tion review chemicals.

PCRM Comment: The Physician’s Committee for Responsible Medicine raised two studies that may be relevant for bridging pyrethroid (and in this case, pyrethrins) data in regard to immunotoxicology. The two citations fo r the two studies are as follows:

• Zhang Y et al. 2010. Immunotoxicity of pyrethr oid metabolites in an in vitro model. Environ Toxicol Chem. Nov;29(11):2505-10.

• Agency for Toxic Substances and Disease Registry, Public Hea lth Service, U.S. Department of Health. and Human Services. EPA Toxicological Profile for Pyrethrins and Pyrethroids. Pg. 77. September 2003.

EPA Response: EPA will investigate these studies as part of the toxicological evaluation of pyrethrins conduc ted for Registration Review.

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.9 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 fo r Biological Diversity, 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:

Environmental Fate Data Gaps

o GLN 835.4100 Aerobic Soil Metabolism 3

o GLN 835.4200 Anaerobic Soil Metabolism 4

o GLN 835.4300 Aerobic Aquatic Metabolism 5

o GLN 835.4400 Anaerobic Aquatic Metabolism 6

o GLN 835.6100 Analytical method and a ssociated independent laboratory

validations in soil

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

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

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

6 Conduct studies with two water/sedime nt systems, with one of the sediment systems from estuarine/marine origin.10 o GLN 835.6200 Analytical method and a ssociated independent laboratory

validations in water and sediment

Ecological Toxicity Data Gaps

o GLN 850.1010 Aquatic toxicity fr eshwater invertebrates ( Hyalella azteca ) –
water column 7

o GLN 850.2100 Avian Oral Toxicity, Passerine

o GLN 850.2300 Avian Reproduction, Quail/Duck 8

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 discussion of the anticipated 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 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

7 Refer to 850.1020 Gammarid Acute Toxicity Test as a basis for study development for Aquatic Toxicity Freshwater Invertebrates ( Hyalella azteca ) – water column.

8 Tests are recommended for the technical product with waterfowl and an upland game bird species.11 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.

• 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.12 • 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 requi rement studies remain outstanding and are

summarized in the DAT Call-Ins se ction 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 ch emicals included in the Agricultural Health Study (AHS). The AHS began in 1993 and is a collaboration of the National Institute of Environmental Health Sciences (NIEHS), the National Cancer Institute (NCI), the EPA, and the National Institute for Occupational Sa fety and Health (NIOSH). Designed as a large long-term epidemiologica l study, the AHS collects and analyzes data on the health and work practices of nearly 90,000 farmer s and their families in Iowa and North Carolina who enrolled in the study before any disease developed. The study focuses particularly on farmers' exposure to 50 chem icals including many of the most widely used pesticides. As data are collected ove r a period of years, sc ientists can compare overall health outcomes for people who diffe r in whether they have had exposure to various chemicals. While these comparis ons cannot conclusively demonstrate how exposure affects health, they can show some statistical associations. 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 th e registration review of Pyrethrins as appropriate.

• Please refer to 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, for a detailed disc ussion of the anticipated human health

risk assessment and data needs.

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,13 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 chemi cals, future lists, the test guidelines and the Tier 1 screen ing battery, please visit our website: http://www.epa.gov/endo/

.14 Timeline

The projected timeline for the completion of the pyrethrins registration review is presented

below in Table 1.

Table 1. Projected Pyrethrins Registration Review Timeline 9
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

Next Steps

The Agency plans to issue a Data Call-in (DC I) for pyrethrins in 2013. Th e information received in response to this DCI will be used to conduc t the planned human health, ecological risk, and endangered species assessments for pyrethrins.

Summary of Data Needs for the Registration Review of Pyrethrins

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

9 Any changes in the cumulative risk from the pyrethroid class of insecticides may impact this time estimate.15 o GLN 860.1850 Confined accumula tion in rotational crops

o GLN 875.2500 Inhalation exposure – residential misting systems

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

o GLN 875.1700 Product use information (outdoor 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)

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.

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 dilutus ).

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.16 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)

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

850.1010 Aquatic toxicity freshwater invertebrates 14 TGAI 12

850.2100 Avian Oral Toxicity, Passerine TGAI 12

850.2300 Avian Reproduction - Quail/Duck TGAI 24

850.4100 Seedling Emergence, Tier II TEP 12

850.4250 Vegetative Vigor, Tier II TEP 12

870.7800 Immunotoxicity TGAI 12

14 Refer to 850.1020 Gammarid Acute Toxicity Test as a basis for study development for Aquatic Toxicity Freshwater Invertebrates ( Hyalella azteca ) – water column.