settings. Based on the current use profile, exposures to pyrethrins can be expected to occur via the dietary (food and drinking wate r), residential (handler and pos tapplication), and occupational (handler and postapplication) routes.

The 2006 risk assessment, conducted for the Rere gistration Eligibility Decision (C. Olinger, D326648, 3/16/06) addressed exposures and risks asso ciated with the dietary, drinking water, occupational, and residential uses of pyrethrins . Based on this, acute and chronic dietary and drinking water aggregate exposures for pyrethrins di d not present risk estimates of concern. The residential exposure assessment conducted for th e Reregistration Eligibility Decision (RED) determined that residential handler exposure scen arios showed no risk estimates of concern. All of the short-term occupational handler exposure scenarios assessed showed no risk estimates of concern; several intermediate-term occupationa l handler scenarios i nvolving wettable powders

showed risk estimates of concern. Several resi dential post-application exposure scenarios and occupational exposure scenarios assessed pres ented risk estimates of concern. PRD implemented mitigation measures in the form of use pattern limitations and confirmatory exposure and efficacy data to address these reside ntial and occupational risks. Since the RED, HED has completed assessments for pyrethrins used to treat in-home bedbug infestations and to directly treat pets. These non-occ upational assessments did not identif y risk estimates of concern.

HED’s scoping document conclusions are as follows: 1) 1) A number of residue chemistry requirem ents identified in the RED have not been submitted. The outstanding data must be submitted for registration review. 2) For hazard assessment, an immunotoxicity st udy is required under 40 CFR Part 158 as a part of the new data requirements for regist ration of a pes ticide (food and non-food uses). This study has not been submitted and is re quired to support registration review. A developmental thyroid assay, which was requi red in the 2006 risk assessment, has not been submitted and is required to support re gistration review. In lieu of conducting a DNT study for pyrethrins, which was required in the 2006 risk assessment, the Registrant may instead choose to cite the six previously submitted DNT studies for pyrethroids to fulfill this data gap. 3) Several residential/occupational exposure st udies requested in the RED have not been submitted and are necessary to address outstanding risk concerns identified in the RED. 4) Upon receipt of outstanding chemistry data, HED will determine if a new dietary risk assessment is required. Updates to dietar y risk assessment methodologies (updated consumption data, and utilization of the ne west version of Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID) may also impact the dietary risk assessment. 5) The residential exposure assessment was ad equate but should be updated to reflect updates to the standard operating procedures that will be implemented in the near future. 6) The occupational exposure assessment was ad equate but should be updated to reflect current standard operating procedures. The outstanding inhalation fogger data must be submitted for registration review. 7) The aggregate risk assessment was adequate but may need to be updated to incorporate any changes to dietary and/or re sidential exposure assessments.

Page 2 of 25Introduction HED has evaluated the existing human health ri sk assessments for the insecticides known collectively as the pyrethrins to determine whet her sufficient data are available and whether a

new human health risk assessment is needed to support Registration Review. HED has considered the most recent risk assessments for py rethrins, updates to its toxicity, exposure and usage databases, and current Agency science po licies and risk assessment methods. The risk assessment used to support the 2006 Reregistra tion Eligibility Decision (RED) and several addendum memoranda (e.g., pet collar rate corr ections, new use actions for bedbug treatments) were the primary sources for this evaluation.

Throughout this document the individual pyrethrin compounds are referred to by the common names of the acid (in lower case e.g. pyrethrin, cinerin, and jasmolin) followed by a number in Arabic (1 or 2). If common names are plural, but not followed by a numeric al designation, then it refers to both I and II forms. If the term Pyrethrins is used, and followed by a numerical designation, then the term refers to all of the isomers of that number in the pyrethrum extract (e.g. Pyrethrins I includes pyrethrin I, cinerin I, and jasmolin I). Both “pyrethrins” and “pyrethrum” are used as a term for insecticidal extract of the Chrysanthemum cinerarieaefolium plant, and are used in this document as a term to denote all six active i ngredients collectively.

Use Profile Pyrethrins have numerous and varied commercial a nd residential applicati ons, are available in a broad range of formulations, and are applied by a wide variety of application methods. Pyrethrins formulations include a variety of formulated intermedia tes, emulsifiable concentrates, and soluble concentrates. Formulated products generally contain 0.25 - 0. 5 % active ingredients.

pproximately 200,000 pounds are sold every year, w ith ~90% being used in non-agricultural

ites. A

s

Pyrethrins have a wide use pattern including (i) pre-harves t and post-harvest uses on many agricultural crops; (ii) direct and indirect trea tments of livestock animals and premises; (iii)

treatments of commercial and industrial facili ties and storage areas wh ere raw and processed food/feed commodities are stored or processed; (i v) mosquito abatement areas including aquatic areas; (v) structural treatments; and (vi) treatment of domestic animals. Pyrethrins are used with a variety of other insecticides and they are typically formulated with the synergist piperonyl butoxide or synthetic pyrethroid s. Pyrethrins currently have 70 tolerances (40 CFR 180.128 & 180.905) in/on various crop and livestock food commod ities. Pyrethrins are used residentially to

control insects both inside the home and outside on gardens, lawns and ornamentals, patios, and

other outdoor structures , and can be directly applied to pets.

The main active ingredients in pyrethrins extracts are pyrethrin I and pyrethrin II plus smaller amounts of the related cinerin I and II and jasmolin I and II. The chemical names and structures of these ingredients may be found in the chemical identity table in Appendix A.

Page 3 of 25Hazard Identification/Toxicology Pyrethrins cause neurotoxicity in insects and mammals by the modulation of nerve axon sodium channels. Pyrethrins interfere with the ability of the nervous syst em to relay nerve transmissions, potentially resulting in tremors, convulsions, salivation, and other clinical effects at high doses.

The toxicity database for pyrethr ins is incomplete at the present time; data gaps include an immunotoxicity study, a developmental thyroid assa y, and fulfillment of the data requirement for a DNT. The immunotoxicity study in rats, which is required in accordance with new data requirements for conventional pesticide registra tion (40 CFR Part 158), has not been submitted and is considered to be a data gap. Although av ailable hematology, lymphoid organ weights, and histopathology data on pyrethrins do not suggest any immunotoxic effects, these endpoints alone are insufficient to predict immunotoxicity. As part of the 2006 risk assessment (D326648), a developmental thyroid study ( "Guidance for Thyroid Assays in Pregnant Animals, Fetuses and Postnatal Animals, and Adult Animals" ) was required due to thyr oid effects observed following chronic exposure. This request stems from concerns regarding the possible impact of perturbations of thyroid func tion on the development of the young. A developmental thyroid assay has not been submitted to the Agency to date and is considered a data gap. Also in the 2006 risk assessment (D326648), the Agency requested that a DNT study be conducted on rats with pyrethrins. This request was based on ev idence of neuropathology in rats following acute exposure in the acute neurotoxicity study. Increased incidence of ne urobehavioral effects in rats and mice following short-term and chronic expos ure further supported this request. However, based on the Agency’s review of existing pyret hrins/pyrethroid data, EPA has come to the conclusion that the DNT is not a particularly sensitive study for comparing the sensitivity of young and adult animals to pyrethrins/pyrethroi ds. In lieu of conducting a DNT study for pyrethrins, the Agency has determ ined that the registrants may instead choose to cite the six previously submitted DNT studies for pyrethroids (Kei gwin, Sept 4, 2009) to fulfill this data gap. The science supporting this conclu sion can be found in “Pyrethroids: Evaluation of Data from DNTs & Consideration of Comparative Sensitivity 1 ” (E. Scollon, 1/20/10, D371723). Regarding the new data requirement for a s ubchronic neurotoxicity study for conventional pesticide registration, pyrethrins are acutely neurotoxic in mammals and data demonstrate that rapid clearance from the body prevents bioaccumula tion and, therefore, repe ated dose studies are actually a series of acute doses . Since there was an acute ne urotoxicity study on pyrethrins, which identifies a clear NOAEL and LOAEL, a subchronic neurotoxic ity study on pyrethrins would not be expected to identify a different endpoi nt or effect level than is already available. Therefore, a subchronic neurot oxicity study is not required for pyrethrins at this time.

In the acute lethality studies that assess primar ily mortality, pyrethrins are not acutely toxic by the oral, dermal, or inhalation rout es of exposure. Pyrethrins are m oderately irritating to the eyes, minimally irritating to the skin, and are not a skin sensitizer.

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 exposure, and neur opathological lesions were observed in rats following acute

1 http://www.epa.gov/oppsrr d1/reevaluation/pyrethroids-pyrethrins.html

Page 4 of 25exposure. Following inhalation exposure, neurobehavioral effects were ob served initially, and histopathological lesions of th e lungs/respiratory tract were observed at all dose levels. Pyrethrins show no significant developmen tal or reproductive effects in rats.

There is suggestive evidence that pyrethrins are carcinogenic based on weight-of-the-evidence considerations. The finding of t hyroid tumors in rats of both sexes was not of concern for humans based on the mode of carcinogenic action da ta. There was an increase in the occurrence of benign liver tumors only in female rats. No treatment-related increase in other tumors was observed in male rats, and no treatment-related increase in tumors in mice of either sex was observed. There was no concern for mutagenicity. Pyrethrins are classified as “Suggestive Evidence of Carcinogenicity, but Not Sufficien t to Assess Human Carc inogenic Potential”; therefore a quantitative cancer risk assessment was not conducted.

Toxicity points of departure (P ODs) 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 systemic effects were observed at the limit dose in the 21-day dermal toxicity study in rabbits. In further evaluating the potential for dermal exposure, no findings were identified in the developmental or reproduction studies that would indicate the need for a dermal risk assessment for pyrethrins. Since there are ad equate developmental toxicity st udies in rats and rabbits, an adequate two-generation reproduction study in rats, and no residual uncertaintie s that indicate the need for retaining an additional factor, the FQ PA factor was reduced to 1X. Although there was evidence of increased quantitative susceptibility in the 2-generation repr oduction study in rats, the reproductive/ offspring toxi city NOAELs and LOAELs are we ll characterized. Additionally, the relevance of the findings in the rabbit develo pmental toxicity study (one abortion and one full litter resorption) in ascribing ev idence of developmental toxicity is equivocal since it is not

uncommon for rabbits to abort/re sorb their litters, and the NOA EL and LOAEL for these effects are well characterized. Further, since these studies (i.e., two-genera tion reproduction and rabbit developmental studies) serve as the basis for the endpoints used for risk assessment for the appropriate population subgroups, re duction of the FQPA factor to 1X was determined to be appropriate.

Subsequent to the RED, a special Functi onal Observational Battery (FOB) study, which measured behavioral changes that are associated with the central and peripheral nervous system following acute oral exposure to pyrethins and pyre throids, was published in the open literature. Additionally, there was evidence of age-dependent toxicity in the open literature. Juveniles appear to be more susceptible based on decreased metabolic capacity to detoxify pyrethroids/pyrethrins. The Agency recently presen ted this topic to a Scie ntific Advisory Panel (SAP) (July 23, 2010). Based on comments from the SAP, a conglomeration of pyrethroid registrants and product formulators (Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA)) are conducting a series of studies to further examine the relationship between age and pyrethroid toxi city. Studies will include in vitro examination of pyrethroid

interaction with rat a nd human voltage-gated sodium cha nnels, development of human PBPK models, and in vivo behavioral testing using auditory st artle in rats. The FQPA factor for pyrethrins will be re-evaluated during registration review following a final determination of the potential for increased susceptibility of infants and children to pyrethrins pesticides based on the

results of all available data.

Page 5 of 25An uncertainty factor of 100X was applied to endpoints selected for or al exposure (10X for interspecies extrapolation, 10X fo r intraspecies variation). An uncertainty factor of 300 was applied to acute dietary and shor t-term incidental oral endpoints (conventional uncertainty factor of 100X plus an additional 3X for the lack of a developmental neurotoxicity (DNT) study and the concern for neurotoxicity resulting from exposur e to pyrethrins. An un certainty factor of 1000 was applied to intermediate- and long-term inhala tion endpoints due to both the lack of a DNT and the lack of a NOAEL for the identified endp oint, respiratory tract lesions. Upon receipt of the outstanding toxicology data a nd consideration of all availabl e data, the endpoints for risk assessment and all uncertainty factors will be re-evaluated during registration review to reflect updated data and uncertain ty factor policies.

Data Requirements The hazard database for the pyrethrins rema ins incomplete. A Pyrethrins DCI (GDCI-069001- 27992) was issued in 2009 and EPA has not yet receive d all of the studies to satisfy the toxicity data requirements. The outstandi ng data requirements for pyrethri ns are listed in the final

section of this document.

Conclusions The HED Registration Review probl em formulation team has re-evaluated the toxicity analysis conducted for the 2006 pyrethrins risk assessments based on current Agency policies. Based on this evaluation, the toxic ity database is incomplete. Once all of the required toxicity data have

been received and reviewed and all available data considered, the Pyrethrins Registration Review Team recommends that the points of departure and safety factors be reexamined and a new risk assessment be completed, if necessary.

Dietary and Drinking Water Exposures Dietary Exposures

Pyrethrins are registered for use on most agricu ltural crops. Residues of the pyrethrins tend to stay on the plant surfaces, with litt le translocation to the root and other parts of the plant. Surface residues are vulnerable to photolysis . Pyrethrins are used in many types of indoor settings where food may be present, such as warehouses, grain storage areas, restaurants, and food manufacturing plants. Generally, the pyrethrin s break down more slowly indoors than outdoors where the residues are prone to photolysis.

When applied to livestock, or when livestock cons ume feed bearing residues of pyrethrins, little breakdown of the parent compound was observed in fa tty matrices, such as fat, milk fat, egg yolk, and poultry skin. In plants , livestock, and the environment, the breakdown products of the pyrethrins are of less toxicological concern th an the parent compound, so only the six active ingredients of pyrethrin s are considered in the dietary assessment.

Many residue studies were required in the RE D to support tolerance reassessment and dietary risk assessment, including storage stability, rotational crop, crop field trial, and processing studies (Olinger and Deluzio, 2005). Some of th ese studies have been submitted, but numerous studies remain outstanding. HED has modified th e data requirements (C. Olinger, 2009/2010, D. Soderberg, 2011) in response to wa iver requests. Residues have b een quantifiable in most field

Page 6 of 25trials submitted to date, with the exception of th e root and tuber vegetables . This residue profile

was consistent with the metabolism data that indicate that residues do not translocate.

Due to the lack of residue data in a number of commodities, HED made several conservative assumptions (with respect to residue levels) for some crops, but refi ned the dietary risk assessment conducted to support the RED using pe rcent crop treated information (Deluzio, 2004). The dietary assessment (food and water) did not indicate ri sk estimates of concern. In the period 2005-2009, the USDA Pesticide Data Program (PDP) analyzed over 64,000 fruit, vegetable, poultry, and pork samples for resi dues of pyrethrins. Only two poultry samples showed quantifiable residues, at 0.1 ppm; residu es were below the limit of quantitation in all other samples. These PDP data further confirm th e health protective nature of HED’s previous dietary risk assessment in that it overes timates dietary exposure to pyrethrins.

Drinking Water Exposures

The Environmental Fate and Effects Division perfo rmed a Tier I drinking water assessment for pyrethrins in surface water and groundwater. EF ED used the FIRST model for estimating the upper bound on the concentrations th at could occur in surface-wate r-source drinking water, and

the SCI-GROW model to estimate the concentrations in ground water used for drinking water.

Parent pyrethrin I is not very pe rsistent. When applied to soil, it is likely to remain near the surface and degrade relatively rapidly via phot olysis and more slowly via aerobic soil metabolism. Parent pyrethrin is considered im mobile and there is an extremely small likelihood of its leaching to groundwater. Pyrethrins may be applied by air and surface water could become contaminated through spray drift or runoff even ts accompanied by erosion that occur shortly after application. In aquatic environments, pyr ethrins are moderately persistent under aerobic aquatic metabolism and more persiste nt under anaerobic aquatic metabolism.

Since new environmental fate data was required for pyrethrins, EFED has indicated that a new drinking water assessment should be completed.

Data Requirements

The database for the dietary exposure assessment remains incomplete in numerous commodities. A Pyrethrins DCI (GDCI-069001-27992) was issued in 2009 and EPA has not yet

received all of the studies to satisy the residue chemistry da ta requirements. The outstanding data requirements for pyrethrins are listed in the final section of this document.

Conclusions

A new dietary risk assessment may be necessary on ce all of the residue data have been received

and reviewed. This assessment will use PDP data along with the new crop field trials for those commodities not analyzed by PDP. In addition, HED will reassess all tolerances using the new crop field trial and processing studies. HED will re-evaluate the need fo r poultry tolerances once all of the magnitude of residue data on poultry feed items have been received and reviewed.

Page 7 of 25Also, an updated drinking water assessment from EFED may dictate further changes to the existing dietary or aggregate risk assessments.

Residential Exposure

Residential scenarios assessed in clude short-term and intermedia te term exposures of handlers (mixers, loaders, applicators, etc.) that occur during application oi f pyr ethrins and short-term post-application exposure from activ ities in treated areas. As pr eviously noted, dermal exposure was not assessed because no systemic effects were observed at the limit dose in a 21-day dermal toxicity study in rabbits and no findings were identified in th e developmental or reproduction

studies that would indicate a dermal hazard for pyrethrins.

Pyrethrins are registered for residential uses as a pest control agent in homes and outdoor domestic structures, on gardens, lawns, and orna mentals, and direct application to household pets. Pyrethrin formulations include aerosol ; combustible coil; dilutable concentrate; dust; emulsifiable concentrate; gel; impregnated p ackaging mat; microemulsion; microencapsulated (ready-to-use spray and liquid c oncentrate), ready-to-use liqui d, pour-on (spot-on), pressurized dust, pressurized liquid, pressurized spray, sham poo, water-based concentrate, wettable powder, and towelette. They are applie d by commercial and resi dential applicators by a wide spectrum of application equipment methods. These uses have b een previously assessed in the Health Effects Division (HED) human health ri sk assessment for the registration eligibility decision (RED) (D326648). Residential scenarios as sessed include mosquito abatement, turf treatment, indoor fogger use, pet treatment, space sprays, crack and crevice sprays, and metered release.

In the assessments for the pyrethrins RED, there were no residential risk estimates of concern identified when pyrethrins are mixed, loaded, applied, or handled by homeowners. There are a number of residential postapplication scenarios where risk estimates of concern were identified and risk mitigation measures were impleme nted by PRD including 1) indoor broadcast applications, 2) indoor metered release systems, and 3) outdoor residential misting systems.

The pyrethrins RED identified risk estimates of concern for indoor applications with metered release devices and outdoor residential misting sy stems. The Agency required data submissions for residential indoor metered release system s and outdoor residential misting systems for pyrethrins and piperonyl butoxide. That data ha s been submitted to the Agency and is under review by HED for use in future risk assessments.

Since the RED, HED has completed assessments for pyrethrins used to treat in home bedbug infestations and to directly treat pets. Thes e assessments did not id entify residential risk

estimates of concern.

Data Requirements The 2006 RED requested data on indoor and outdoor metered release systems, as well as some specific product use information. A Pyreth rins DCI (GDCI-069001-27992) was issued in 2009 and EPA has not yet received all of the studi es to satisy the reside ntial exposure data requirements. The majority of the required data has already been submitted to the Agency. The outstanding data requirements for py rethrins are listed in the fi nal section of this document.

Page 8 of 25Conclusions It should also be noted that policy revisions su ch as anticipated modifications in the Agency standard operating procedures for completing re sidential exposure assessments could require revision of elements of the current exposure assessments. The residential exposure assessment may also be updated to incorporate any new data submitted by registrants or other stakeholders.

Aggregate Risk Assessment The most recent risk assessment included aggregat e assessments that considered exposure from food, drinking water, and residential uses. Acute aggregate exposures asse ssments for pyrethrins

showed no risk estimates of concern. The short-term aggregate exposure assessment for pyrethrins showed no risk estimat es of concern for adults and the children’s Aggregate Risk Index (ARI) was calculated to be 0.96 and charact erized as not of concern because the dietary contribution included high-end fiel d trial data and assumed 100% percent crop treated for all but a few crops.

Conclusions A new aggregate assessment may be needed that considers the required ne w toxicity and residue data as well as any changes in the residential use pattern.

Occupational Exposure A number of occupational exposure scenarios were assessed for agricultural, forestry, professional pest control operator, and mosquito control applications of pyrethrins. Current labels require the use of normal work clothing fo r handlers with gloves and dust/mist respirators added for handheld fogging applications. The curren t Restricted-Entry Interval is 12 hours. A number of occupational handler scenarios were assessed. The s cenarios assessed that indicated potential risk concerns for occupational handlers were those using wettable powder formulations over the intermediate-term exposure duration. The RED mitigation measures included water soluble packaging for all wettable powder formulations. The addition of this mitigation

addresses the identified risk concerns.

Handlers applying with handheld foggers were not assessed for the pyrethrins RED due to lack of use and application information; the RED require d data on air concentra tions and residues as a result of handheld fogging applications. The Non-Dietary Exposure Task Force is currently working on a data submission to the Agency to a ddress these exposure scenarios in future risk

assessments.

A revised occupational risk assessment may be required if endpoints or points of departure change and/or because updated monitoring data are being developed for pertinent occupational handler exposures and additional handler exposure s cenarios also need to be addressed that were not included in previous assessments. Additionally, a revised risk assessment will be needed to address possible exposure to workers doing activ ities in previously tr eated areas (i.e., postapplication exposure). The existing policy on fa rmworker activities was recently revised and includes either updated values fo r quantitatively evaluating thes e exposures or it will provide a more definitive qualitative rationale for not conducting a quantitative assessment.

Page 9 of 25After the Non-Dietary Exposure Task Force (NDETF) submits the required studies on occupational fogger applications, adequate data w ill be available to asse ss all the occupational exposure scenarios for the registered uses of pyrethr ins. Policy revisions, such as updates to the Occupational Pesticide Handler Exposure Data 2 ( OPHED), could cause elements of the current exposure assessments to be revised (e.g., changes in transfer coefficients for field workers and unit exposures for handlers). Also, additional changes in other risk assessment policies related to spray-drift, worker protection a nd volatilization of pes ticides may dictate further changes to the existing risk assessment.

Data Requirements The 2006 RED requested data on indoor and outdoor-metered release systems and handheld fogging applications. A Pyrethrins DCI ( GDCI-069001-27992) was issued in 2009 and EPA has not yet received all of the studi es to satisy the applicator ex posure data requirements. The majority of the required data has already been submitted to the Agency. The outstanding data requirements for pyrethrins are listed in the final section of this document.

Conclusions The occupational exposure assessment may need to be updated to reflect current standard operating procedures and to incorporate new unit exposures, new transfer coefficients, and any new chemical-specific data submitted by the regist rants, as well as reflecting current endpoints and PODs for the pyrethrins.

Public Health and Pesticide Epidemiology Data An updated incident report was recently conducted. The OPP Incident Data System (IDS) was utilized for pesticide incident data on the active ingredient pyrethrins (PC Code 069001). Additionally, if there are Agricultural Health Study (AHS) findings rele vant to a particular pesticide, they are considered in the problem formulation/scoping document. Pyrethrins are not

included in the AHS.

For the main IDS, from January 1, 2006 to J une 6, 2011, there are 13 e xposures reported for single chemical only in the database, and 803 add itional exposures that involved more than one chemical. During the scoping phase of Registrati on Review, the higher severity exposures (those resulting in fatal or major outcomes) are considered in more detail. Additionally, as described above, incidents involving one pesticide are typica lly focused on because they are considered to provide more certain information about the potentia l effects of the particul ar pesticide. However, because pyrethrins are usually co-formulated wi th other active ingredients, and because there was a ~50-fold difference between the frequency of incidents involving pyrethrins alone versus pyrethrins and other chemicals, it is important to attend to the incidents involving multiple

chemicals in this case.

The Agency has considered/discussed the potenti al relationship between pyrethrum, pyrethrins and pyrethroids and allergic/asthmatic effect s in a variety of analyses (e.g., EPA's OPP "Recognition and Management of Pesticide Po isonings" manual, the EPA Office of Radiation and Indoor Air commissioned a review by the Na tional Academy of Scie nces’ Institute of Medicine about the relationship between asthma and exposure to various substances, including

2 http://www.epa.gov/opp00001/science/handler-exposure-data.html

Page 10 of 25pesticides; and OPP staff have conducted pyrethrins and various pyrethroid incident reviews). Most recently, a report by the Center for Public Integrity prompted EPA to conduct its latest review of pyrethrins and pyrethroid incidents to identify any trends in the data. Agency scientists have concluded that there does not app ear to be a clear relationship between pyrethrins/pyrethroid exposure and asthma/allergies 3

.

During the Reregistration of pyrethrins, EPA requi red the Pyrethrins Joint Venture (PJV), an industry task force, to institute a product stewardship program that involves outreach to physicians and Poison Control Centers with better guidance and diagnostic standards, as well as prospective in-depth follow-up of reported cases to better understand the cause of the incidents with pyrethrins. 4

In general, a relatively high frequency of incide nts has been reported involving pyrethrins. Most of these incidents were of low severity. Add itional human incident data may warrant further analysis for the risk assessment and/or risk management of pyrethrins. The Agency will

continue to monitor the incident information a nd if a concern is triggered, additional analysis

will be included in the risk assessment. Du ring the preliminary risk assessment phase of Registration Review, the HED risk assessment team will revisit pyrethrins incident data (including an analysis of the PJV) and if a c oncern is triggered, additional analysis will be

included in the risk assessment.

Tolerance Assessment and International Harmonization

Tolerances are established for residues of pyrethrins in or on numerous food and feed commodities and are listed in 40 CFR 180.128 and 180.905(a)(6). A summary of the existing tolerances may be found in Appendix B, as well as international tolerances . Many tolerances are harmonized with Canada Maximum Residue Limits (M RLs) with respect to residue level. There are many differences between the US and Codex MRLs with respect to residue definition and residue level. Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

Some field trial data required in the RED re main outstanding. Once these data have been

received modifications to tolera nce levels will be needed. In addition, the residue definition should be modified in accordance with the gu idance issued in 2009 (S. Knizner, 5/27/09) and

with other international standards. The registrants are encouraged to work with the Agency and international regulatory authoritie s to develop a consistent appr oach for the residue definition.

In registration review, HED will r econsider the U.S. tolerances and will harmonize them with

Codex MRLs when the data warrant harmonization.

Environmental Justice Potential areas of environmental ju stice concerns, to the extent po ssible, were considered in the human-health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions

to Address Environmental Just ice in Minority Populations an d Low-Income Populations,” ( http://www.hss.energy.gov/nuclearsafe ty/env/guidance/ju stice/eo12898.pdf). The OPP typically considers the highest potential exposures from the le gal use of a pesticide when

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

4 This is a 5-year program requiring annual reports. To date, one annual report has been submitted.

Page 11 of 25conducting human-health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diet s within the U.S., and people who might be exposed when harvesting crops. Should these highest exposures indicate potential risk estimates of concern, OPP further re fines the risk assessments to ensure that the

risk estimates are based on the best available information.

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 e ndpoints that 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 reregistration 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 s ection 408(p), pyrethrins are subject to the endocrine screening part of the Endocrine Disruptor Screenin g Program (EDSP).

As required under FFDCA section 408(p), EPA ha s developed the EDSP to determine whether certain substances (including pesticide active an d 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 Admi nistrator may designate.” The EDSP employs a two-tiered approach to making the statutoril y 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 dete rmine 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 substanc e, and establish a dos e-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 screening battery, please vi sit the Agency’s website: http://www.epa.gov/endo/

.

Cumulative Risk Assessments The Food Quality Protection Act (F QPA) requires the Agency to c onsider the cumulative risks of chemicals sharing a common mechanism of toxi city. Pyrethrins are a member of the

Page 12 of 25pyrethroid/pyrethrin co mmon mechanism group ( http://www.regulations.gov ; EPA-HQ-OPP2008-0489-0006). The members of this group share th e ability to interact with voltage-gated sodium channels ultimately leading to neurotox icity. 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 ne w uses for pyrethroid actives. For information regarding EPA’s efforts to evaluate the ri sk of exposure to py rethroids, refer to http://www.epa.gov/oppsrrd1/reevalua tion/pyrethroids-pyrethrins.html

.

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 de termine their dermal and inhalation exposure. Many such studies, involving exposur e to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handl ers Exposure Database (PHED), the Agricultural Reentry Task Force (ARTF) Database, the Agricultural Handlers Exposure Task Force (AHETF), and the Outdoor Residential Exposur e Task Force (ORETF) Database. EPA has reviewed all the studies supporting these multi-pe sticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or signifi cantly deficient relativ e to the ethical sta ndards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subject s of Research (40 CFR Part 26) ha ve been satisfied, and there is no regulatory barrier to conti nued reliance on these studies.

Conclusions/Future Actions Needed The actions needed in the future Registrati on Review for pyrethrins are listed below.

Hazard Identification an d Endpoint Selection Pyrethrins are axonic toxicants, and there was evidence of neurotoxicity following exposure to pyrethrins, based on clinical signs (tremors, convulsions, decreased motor activity, excessive salivation, head arched backwa rd) and neuropathology in acute , developmental, reproductive studies submitted to the Agency. To date, EPA ha s not received these hazard-related studies to satisfy the 2009 Pyreth rins DCI (GDCI-069001-27992):

• Although the data gap of a developmental neurotoxicity study (DNT) (GLN 870.6300) has not been satisfied, as disc ussed above, the pyrethrins regi strants plan to satisfy the data requirement by citing the six previously submitted DNT studies for pyrethroids to fulfill this data gap/requirement.

• Additionally, the previously required devel opmental thyroid assay has not been submitted to the Agency. In future human health risk assessments, the Agency may use a database uncertainty factor to account for any missing data.

The following data gaps/study requirements are new and have not been previously required by the Agency:

• U nder the revised 40 CFR Part 158 Toxicology Data Requirements, an immunotoxicity study is required for all pesticides. The re quired study rationale is included in Appendix C. However, since the results of the availa ble toxicity studies provide no evidence for immunotoxicity following pyrethrins exposure, the Agency may consider a waiver for

Page 13 of 25this data requirement provided the necessary information to perform an immunotoxicity evaluation is submitted as part of the waiver request.

Dietary Exposure and Risk The dietary risk assessment should be updated to reflect current policies and SOPs and to incorporate outstanding data requirements. To da te, EPA has not received these dietary-related studies to satisfy the 2009 Pyrethrins DCI (GDCI-069001-27992):

• Storage Stability Data (GLN 860.1380) on o ilseeds, non-oily grai ns, and root crops

• Crop Field Trials (GLN 860.1500) See Appendix D for the outstanding required field

trial data 5

.

• Processed Food/Feed data (GLN 860.1520); Proce ssing studies were required in the DCI for the following commodities: apple, barley, cacao, coconut, coffee, corn, cotton, fig, flax, oat, peanut, pineapple, plum, rice, ry e, safflower, sorghum, soybean, sugarcane, sunflower, tea, and wheat.

• Confined Accumulation in Rotational Crops (GLN 860.1850)

Residential Exposure and Risk The residential risk assessment may need to be updated to reflect any ch anges in endpoints or points of departure, changes in current policie s and the upcoming revisions to the residential SOPs as well as incorporating any new data submissions. The data requirements, originally identif ied in the 2009 Pyrethrins DCI (GDCI-069001-27992), are intended to inform post-application e xposure assessment and remain outstanding:

• Product Use Information (GLN 875. 1700) on metered release devices

Aggregate Exposure and Risk The existing aggregate exposure assessment need to be updated to reflect current policies and SOPs and to incorporate any changes to the dietary and/or residential exposu re assessments.

Occupational Exposure and Risk The occupational risk assessment should be updat ed to reflect current policies and SOPs (e.g., new unit exposure data) and to incorporat e the outstanding da ta requirements: These data requirements (relati ng to handheld foggers), origin ally identified in the 2009 Pyrethrins DCI (GDCI-069001-27992), remain outstanding:

• Inhalation Indoor Exposure (GLN 875.1400)

Incident Report The Agency will continue to monitor the incident information related to pyrethrins and if a concern is triggered, additional analysis wi ll be included in the risk assessment.

5 Additional detail is available in the memos “Pyrethrins. Response to Comments on Residue Data Requirements”; C. Olinger (D366246, 10/27/09) & “Pyrethrins. Response to a “Proposal to Further Reduce Pre-Harvest Residue Data Requirements Due to Low Usage of Pyrethrins” and a Request for Extension on Time to Submit DCI Studies by 2-3 Years”; D. Soderberg (D392195, 08/31/11).

Page 14 of 25References Pyrethrins: DNT DCI Letter for Pyrethrins. Keigwin, 9/04/09

Pyrethrins: Revised Human Health Risk Assessme nt for the Reregistration Eligibility Decision, C. Olinger (D326648, 03/16/06)

Pyrethrins: Revised Human Health Risk Assessme nt for the Reregistration Eligibility Decision, C. Olinger (D321641, 09/14/05)

Pyrethrins Review of Human Incidents. Sarah Winfield (D392811, 8/11/11)

Tier I Estimated Drinking Water Concentrations of Pyrethrin and Derivatives for use in Human Health Risk Assessment, S. Dutta, 8/19/04, DP Barcode D295750

Pyrethrins. Request for Waiver of Pr ocessing Studies, C. Olinger (D375958, 5/11/10)

Pyrethrins. Response to Comments on Re sidue Data Requirement s, C. Olinger (D366246, 10/27/09)

Pyrethrins. Response to a “Proposal to Further Redu ce Pre-Harvest Residue Data Requirements Due to Low Usage of Pyrethrins” and a Re quest for Extension on Time to Submit DCI Studies by 2-3 Years. (D. Soderberg, D392195, 08/31/11)

Pyrethrins. Revised Residue Ch emistry Considerations for Rere gistration Eligibility Decision, C. Olinger/J. Deluzio (D318633, 9/8/05).

Pyrethrins. Acute and Chroni c Dietary Exposure Assessment for Reregistration Eligibility Decision Document, J. Deluzio (D295748, 12/20/04)

Pyrethrins: Human Health Aggregate Risk Asse ssment to Account for Pet Spray Use Rate Correction, T. Dole, (01/24/08)

Pyrethrin. Occupational and Resi dential Exposure Assessment for the Use of a Pyrethrin Product for Bed Bug Treatment. A. LaMay (03/28/11)

Draft Science Policy Paper for the Proposed Common Mechanism Grouping for the Pyrethrins and Synthetic Pyrethroids, A. Lowit, E. Scollan (D381210, 06/30/11)

Re-evaluation of the FQPA Safety Factor for Pyrethroid Pesticides, A. Lowit, E. Scollan (D381210, 06/30/11)

Pyrethroid Cumulative Risk Assessment , D. Davis, et. al (D394576, 10/05/11)

Page 15 of 25Appendix A: Chemical Identity

Pyrethrins is the collective name of the inse cticidal active ingredients present in pyrethrum

extracts which are obtained from the drie d and ground flowers of the pyrethrum plant, Chrysanthemum cinerariaefolium . The CAS Registry No. for the mixture is 8003-34-7. Currently, food/feed uses are onl y registered for products under PC code 069001, mixed esters of (+)-trans-chrysanthemic acid a nd (+)-pyrethroic acid. The nomenclature of the individual pyrethrins active ingredients is presented below in Table 1. The physicochemical properties of the refined pyrethrins extracts (TGAI) are listed in Table 2.

TABLE 1. Pyrethrins Nomenclature

.

Chemical Structure

Common name Pyrethrin I or Pyrethrin 1

Molecular Formula C 21 H 28 O 3
Molecular Weight 328.4

IUPAC name (Z)-(S)-2-methyl-4-oxo-3-(penta-2,4-dienyl)cyclopent-2-enyl (1R,3R)-2,2- dimethyl-3-(2-methyl prop-1-enyl)cyclopropanecarboxylate

CAS name (1S)-2-methyl-4-oxo-3-(2Z)-2,4-pentadienylcyclopenten-1-yl (1R,3R)-2,2- dimethyl-3-(2-methyl -1-propenyl)cyclopropanecarboxylate

CAS # 121-21-1

Common name Pyrethrin II or Pyrethrin 2

Molecular Formula C 22 H 28 O 5
Molecular Weight 372.4

IUPAC name (Z)-(S)-2-methyl-4-oxo-3-(penta-2,4-dienyl)cyclopent-2-enyl (E)-(1R,3R)-3-(2- methoxycarbonylprop-1-enyl)-2,2-dimethylcyclopropane-carboxylate

CAS name (1S)-2-methyl-4-oxo-3-(2Z)-2,4-pentadienyl-2-cyclopenten-1-yl (1R,3R)-3-[(1E)- 3-methoxy-2-methyl-3-oxo-1-propenyl]-2,2-dimethylcyclo-propanecarboxylate

CAS # 121-29-9

Common name Cinerin I or Cinerin 1

Molecular Formula C 20 H 28 O 3
Molecular Weight 316.4 O

R2

O O

R1 CH 3

CH

3 CH

3 CH 3 Pyrethrin I: R1 = CH 3 ; R2 = CH 2 CH=CHCH=CH 2 Pyrethrin II: R1 = COOCH 3 ; R2 = CH 2 CH=CHCH=CH 2 Cinerin I: R1 = CH 3 ; R2 = CH 2 CH=CH 3 Cinerin II: R1 = COOCH 3 ; R2 = CH 2 CH=CH 3 Jasmolin I: R1 = CH 3 ; R2 = CH 2 CH=CHCHCH 3 Jasmolin II: R1 = COOCH 3 ; R2 = CH 2 CH=CHCHCH 3

Page 16 of 25TABLE 1. Pyrethrins Nomenclature

.

IUPAC name (Z)-(S)-3-(but-2-enyl)-2-methyl-4-oxocyclopent-2-enyl (1R,3R)-2,2-dimethyl-3- (2-methylprop-1-enyl)cyclopropanecarboxylate

CAS name (1S)-3-(2Z)-2-butenyl-2-methyl-4-oxo-2-cyclopenten-1-yl (1R,3R)-2,2-dimethyl3-(2-methyl-1-propenyl)cyclopropanecarboxylate

CAS # 25402-06-6

Common name Cinerin II or Cinerin 2

Molecular Formula C 21 H 28 O 5
Molecular Weight 360.4

IUPAC name (Z)-(S)-3-(but-2-enyl)-2-methyl-4-oxocyclopent-2-enyl (E)-(1R,3R)-3-(2- methoxycarbonylprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate

CAS name (1S)-3-(2Z)-2-butenyl-2-methyl-4-oxo-2-cyclopenten-1-yl (1R,3R)-3-[(1E)-3- methoxy-2-methyl-3-oxo-1-propenyl]-2,2-dimethylcyclopropanecarboxylate

CAS # 121-20-0

Common name Jasmolin I or Jasmolin 1

Molecular Formula C 21 H 30 O 3
Molecular Weight 328.4

IUPAC name (Z)-(S)-2-methyl-4-oxo-3-(pent-2-enyl)cyclopent-2-enyl (1R,3R)-2,2-dimethyl-3- (2-methylprop-1-enyl)cyclopropanecarboxylate

CAS name (1S)-2-methyl-4-oxo-3-(2Z)-2-pentenyl-2-cyclopenten-1-yl (1R,3R)-2,2- dimethyl-3-(2-methyl -1-propenyl)cyclopropanecarboxylate

CAS # 4466-14-2

Common name Jasmolin II or Jasmolin 2

Molecular Formula C 22 H 30 O 5
Molecular Weight 374.4

IUPAC name (Z)-(S)-2-methyl-4-oxo-3-(pent-2-enyl)cyclopent-2-enyl (E)-(1R,3R)-3-(2- methoxycarbonylprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate

CAS name (1S)-2-methyl-4-oxo-3-(2Z)-2-pentenyl-2-cyclopenten-1-yl (1R,3R)-3-[(1E)-3- methoxy-2-methyl-3-oxo-1-propenyl]-2,2-dimethylcyclopropanecarboxylate

CAS # 1172-63-0

TABLE 2. Physicochemical Properti es of Refined Pyrethrins (TGAI)

.

Parameter Value Reference

Boiling point Pyrethrin 1 = 146-148 C at 2 x 10 -3 Torr Pyrethrin 2 = 196-198 C at 7 x 10 -3 Torr
Cinerin 1 = 136-138 C at 8 x 10 -3 Torr
Cinerin 2 = 182-184 C at 1 x 10 -3 Torr RD, 10/9/90, A. Smith

pH Not applicable b ecause the TGAI is practically insoluble in water.

Page 17 of 25TABLE 2. Physicochemical Properti es of Refined Pyrethrins (TGAI)

.

Parameter Value Reference

Density, bulk density, or specific gravity 0.982 g/mL at 20 C

Pyrethrin 1 = 1.5242 g/mL Pyrethrin 2 = 1.5355 g/mL D172245, 1/5/93, C. Olinger

RD, 10/9/90, A. Smith

Water solubility <10 ppm

Pyrethrin 1 = 0.00002 g/100 mL at 20 C Pyrethrin 2 = 0.00090 g/100 mL at 20 C DEB No. 4525, 12/9/88, M. Flood

RD, 10/9/90, A. Smith

Solvent solubility Completely soluble in nonpolar organic solvents; <0.1% in ethylene glycol

Soluble in alcohol, petroleum ether, and methylene chloride DEB No. 4525, 12/9/88, M. Flood

RD, 10/9/90, A. Smith

Vapor pressure Pyrethrin 1 = 2 x 10 -5 mm Hg at 25 C Pyrethrin 2 = 4 x 10 -7 mm Hg at 25 C RD, 10/9/90, A. Smith

Dissociation constant, pK

a Not applicable because pyrethrins do not

dissociate

Octanol/water partition

coefficient Pyrethrin 1 = 5.90 K OW at 25 C Pyrethrin 2 = 4.30 K O W at 25 C RD, 10/9/90, A. Smith

UV/visible absorption spectrum Not available

Page 18 of 25Appendix B: Summary of US and Internationa l Tolerances and Maximum Residue Limits 

### Pyrethrins (PC Code 069001; 7/22/11)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US – See footnote 1 Canada Mexico 2 Codex 3

40 CFR 180.128:

Plant/Livestock: See footnote 1

below 4-hydroxy-3-methyl-2- (2,4-pentadienyl)-2- cyclopenten-1-one 2,2- dimethyl-3-(2- methylpropenyl)cyclop ropanecarboxylate and 4-hydroxy-3-methyl-2- (2,4-pentadienyl)-2- cyclopenten-1-one 1-methyl 3-carboxyα ,2,2- trimethylcyclopropanea crylate ester total pyrethrins,

calculated as the sum of pyrethrins 1 and 2, cinerins 1 and 2, and jasmolins 1 and 2, determined after

calibration with the

World Standard pyrethum extract.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3
Almond, postharvest 1.0 1.0 0.5 (*) tree nuts (Po) Apple, postharvest 1.0 1.0 0.2 dried fruits (Po) Barley, grain, postharvest 3.0 3.0 raw cereals 0.3 cereal grains (Po) Bean, succulent, postharvest 1.0 1.0 beans Birdseed, mixtures, postharvest 3.0 Blackberry, postharvest 1.0 1.0 Blueberry, postharvest 1.0 1.0 Boysenberry, postharvest 1.0 1.0 Buckwheat, grain, postharvest 3.0 3.0 raw cereals 0.3 cereal grains (Po) Cacao bean, roasted bean, postharvest 1.0 1.0 cocoa beans

Cattle, fat 1.0 Cattle, meat 0.05 0.05 Cattle, meat byproducts 0.05 0.05 Cherry, sweet, postharvest 1.0 1.0 cherries Cherry, tart, postharvest 1.0 1.0 cherries Coconut, copra, postharvest 1.0 1.0 copra Corn, field, grain, postharvest 3.0 3.0 raw cereals 0.3 cereal grains (Po) Corn, pop, grain, postharvest 3.0 3.0 raw cereals 0.3 cereal grains (Po) Cotton, undelinted seed, postharvest 1.0

Crabapple, postharvest 1.0 1.0 Currant, postharvest 1.0 1.0 Dewberry, postharvest 1.0 1.0 Fig, postharvest 1.0 1.0 0.2 dried fruits (Po) Flax, seed, postharvest 1.0 Goat, fat 1.0 Goat, meat 0.05 0.05

Page 19 of 25Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US – See footnote 1 Canada Mexico 2 Codex 3
Goat, meat byproducts 0.05 0.05 Gooseberry, postharvest 1.0 1.0 Grape, postharvest 1.0 1.0 0.2 dried fruits (Po) Guava, postharvest 1.0 1.0 Hog, fat 1.0 Hog, meat 0.05 0.05 Hog, meat byproducts 0.05 0.05 Horse, fat 1.0
Horse, meat 0.05 0.05 Horse, meat byproducts 0.05 0.05 Loganberry, postharvest 1.0 1.0 Mango, postharvest 1.0 1.0 Milk, fat (reflecting negligible residues in milk) 0.05 0.05

Muskmelon, postharvest 1.0 1.0 Oat, grain, postharvest 1.0 0.3 cereal grains (Po) Orange, postharvest 1.0 1.0 0.05 citrus fruits Pea, dry, seed, postharvest 1.0 1.0 peas 0.1 Pulses (Po); 1 pea hay or pea fodder (dry) Peach, postharvest 1.0 1.0 Peanut, postharvest 1.0 1.0 0.5 (Po) Pear, postharvest 1.0 1.0 Pineapple, postharvest 1.0 1.0 Plum, prune, fresh, postharvest 1.0 1.0 Potato, postharvest 0.05 0.05 root and tuber vegetables (*) Raspberry, postharvest 1.0 1.0 Rice, grain, postharvest 3.0 3.0 raw cereals 0.3 cereal grains (Po) Rye, grain, postharvest 3.0 3.0 raw cereals 0.3 cereal grains (Po) Sheep, fat 1.0 Sheep, meat 0.05 0.05 Sheep, meat byproducts 0.05 0.05 Sorghum, grain, grain, postharvest 1.0 3.0 raw cereals 0.3 cereal grains (Po)

Sweet potato, postharvest 0.05 0.05 root and tuber vegetables (*) Tomato, postharvest 1.0 1.0 0.05 (*) Walnut, postharvest 1.0 1.0 Wheat, grain, postharvest 3.0 3.0 raw cereals 0.3 cereal grains (Po)

MRLs with NO US equivalent Fruiting vegetables, cucurbits 0.05 (*)

Huckleberries 1.0 Peppers 0.05 (*)

Page 20 of 25Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US – See footnote 1 Canada Mexico 2 Codex 3
Peppers chili, dried 0.5

Pulses 0.1 Po

Completed: M. Negussie; 07/25/2011

1 Tolerances for residues of the in secticide pyrethrins ((1S)-2-methyl-4-oxo -3-(2Z)-2,4-pentadien ylcyclopenten-1-yl (1R,3R)-2,2-dimethyl-3- (2-methyl-1-propenyl)cyclopropa necarboxylate (pyrethr in 1), (1S)-2-met hyl-4-oxo-3-(2Z)- 2,4-pentadienyl-2-cyclopenten-1-yl (1R,3R)-3-[(1E)-3-methoxy-2-methyl-3-oxo-1-propenyl]-2,2- dimethylcyclopropane-carboxylate (pyrethrin 2), (1S)-3-(2Z)-2-butenyl-2-methyl-4-oxo-2-cyclopenten-1-yl (1R,3R)-2,2-dimethyl-3- (2-methyl-1-propenyl)cyclopr opanecarboxylate (cinerin 1) , (1S)-3-(2Z)- 2-butenyl-2- methyl-4-oxo-2-cyclopenten-1-yl (1R,3R)-3-[(1E)-3-methoxy-2-methyl-3-oxo-1-propenyl]-2,2- dimethylcyclopropanecarboxylate (cinerin 2), (1S)-2-methyl-4-oxo-3-(2Z)-2-pentenyl-2-cyclopenten-1-yl (1R, 3R)- 2,2-dimethyl-3-(2-methyl-1 -propenyl)cyclopropa necarboxylate (jasmolin 1), an d (1S)-2-methy l-4-oxo-3-(2Z)- pentenyl-2-cyclopenten-1-yl (1R,3R)-3-[(1E)-3-methoxy-2-methyl-3-oxo-1-propenyl]-2,2- dimethylcyclopropanecarboxylate (jasmolin 2)), the insecticidally active principles of Chrysanthemum cinerariaefolium, which are measured as cumulative residues of pyrethrin 1, cinerin 1, and jasmolin 1 are not to exceed the following

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated co mmodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

In addition, the following tolerances are established for pyrethrins:

(2) A tolerance of 1.0 ppm is established for residues of the insecticide pyrethrins in or on milled fractions derived from grain, cereal when present as a result of its use in ce real grain mills and in storage areas for milled cereal grain products.

(3) A tolerance of 1.0 ppm is established for residues of th e insecticide pyrethrins in or on all food items in food handling establishments where food and food products are held, processed, prepared and/or served. Food must be removed or covered prior to use.

(4) Where tolerances are established on both the raw agricultural commodities and processed foods made therefrom, the total residues of pyrethrins in or on the processed food shall not be greater than that permitted by the larger

of the two tolerances.

Page 21 of 25Appendix C: Required Study Rationale

Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticid e (food and non-food uses).

The Immunotoxicity Test Guideline (OPPTS 870 .7800) prescribes functional immunotoxicity testing and is designed to evaluate the potenti al of a repeated chemical exposure to produce adverse effects (i.e., suppression ) on the immune system. Immunos uppression is a deficit in the ability of the immune system to respond to a chal lenge of bacterial or vi ral infections such as tuberculosis (TB), Severe Acqui red Respiratory Syndrome (SARS) , or neoplasia. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to charact erize a pesticide’s potential im munotoxicity. While data from hematology, lymphoid organ weights, and hist opathology in routine ch ronic or subchronic toxicity studies may offer useful information on potential immunotoxic e ffects, these endpoints

alone are insufficient to predict immunotoxicity. Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provi de critical scientific informati on needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk as sessment. These animal studies can be used to select endpoints and doses for use in risk assessm ent of all exposure scenar ios and are considered a primary data source for reliable reference dos e calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachlorodibenz o-p-dioxin) among developm ental, reproductive, and endocrinologic toxicities. Additionally, the EPA ha s established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making?

If the immunotoxicity study shows that pyrethrins pos e either a greater or a diminished risk than that identified in the RED, the risk assessments for pyrethrins may need to be revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have these data, a 10X da tabase uncertainty factor may be applied for conducting a risk assessment from the available studies.

Page 22 of 25Appendix D: Required Crop Field Trial Data EPA has previously required many crop field trial studies to support the c ontinued registration of pyrethrins. A summary of the field trials need ed is provided in Table D-1 below. Additional detail is available in the memo “Pyrethr ins. Response to Comments on Residue Data Requirements”, C. Olinger (D366246, 10/27/09).

Table D-1. Summary of Field Trials Needed to Support the Registration Review of Pyrethrins Commodity – Number of Field Trials Typically Required Number of Field Trials Required for Pyrethrins Number

Submitted Number of Field Trials

Still Needed CG1: Vegetable, root and tuber, group 1 No further field trials are required for root and tuber vegetables CG2: Vegetable, leaves of root and tuber, group 2 Radish Tops 0 1 0 Turnip Tops - 5 4 0 4 Sugar or Garden Beet Tops - 9 6 2 4 CG3: Vegetable, bulb, group 3-07

Green Onion – 3 3 0 3

Bulb Onion - 6 3 0 3 CG4: Vegetable, leafy, except brassica, group 4

Head Lettuce – 6 4 2 2

Leaf Lettuce – 6 5 5 0 Celery – 6 4 2 2 Spinach - 6 5 2 3 CG5: Vegetable, brassica, leafy, group 5

Broccoli - 6 4 3 1 Cabbage – 6 5 3 2

Mustard Greens - 5 4 2 2 CG6: Vegetable, legume, group 6

Succulent Bean – 12 6 2 4

Dried Bean – 9 5 2 3

Succulent Pea – 9 5 2 3

Dried Pea – 5 2 2 0 Soybean - 15 8 0 8 CG7: Vegetable, foliage of legume, group 7

Bean – 3 2 2 0

Field Pea - 3 3 4 0 Soybean - 15 8 0 8 CG8: Vegetable, fruiting, group 8-10 No further field trials are required for fruiting vegetables. CG9: Vegetable, cucurbit, group 9 No further field trials are required for cucurbit vegetables. CG10: Fruit, citrus, group 10-10 No further field trials are required for citrus fruits. CG11: Fruit, pome, group 11-10 Apples – 12 9 0 9

Pears - 6 4 0 4 CG12: Fruit, stone, group 12-11 Sweet or Tart Cherry – 6 4 0 4

Peach - 9 6 3 3

Plum - 6 4 0 4 CG13: Fruit, berry and small fruit, group 13-07 Blackberry or raspberry – 3 2 1 1 Blueberry - 6 5 5 0

Page 23 of 25Table D-1. Summary of Field Trials Needed to Support the Registration Review of Pyrethrins Commodity – Number of Field Trials Typically Required Number of Field Trials Required for Pyrethrins Number Number of Field Trials

Submitted Still Needed Grape – 9 7 1 6

Kiwifruit – 3 2 0 2 Strawberry - 6 4 2 2 CG14: Nut, tree, group 14-11

Almond – 5 3 0 3

Pecan – 5 2 0 2 CG15: Grain, cereal, group 15

Fresh sweet corn – 9 5 0 5

Dried field corn – 15 8 0 8

Rice - 12 6 0 6 Sorghum – 9 4 0 4

Wheat - 15 8 0 8 CG16: Grain, cereal, forage, fodder and straw, group 16

Corn – 15 8 0 8

Wheat – 15 8 0 8

Other Cereal Grain - 12 6 0 6 CG17: Grass, forage, fodder and hay, group 17 Bermuda grass – 4 3 0 3 Bluegrass – 4 3 0 3 Bromegrass or Fescue - 4 3 0 3 CG18: Animal feed, nongrass, group 18

Alfalfa – 9 6 6

Clover - 9 6 6 CG19: Herbs and spices group 19 Basil (fresh and dried) - 3 2 0 2

Chive – 3 2 0 2 Dill Seed or Celery Seed – 3 2 1 A 1 Black Pepper – 3 2 0 2

Other Commodities Cotton Forage - 9 6 0 6 CG20: Oilseed group 20 Rapeseed (canola varieties only) -

9 6 0 6

Sunflower – 9 6 0 6 Cotton, undelinted seed - 9 6 0 6 Cotton gin-byproducts - 9 6 0 6 CG21: Fungi, edible, group 21

White Button Mushroom - 2 2 0 2 Oyster Mushroom/Shitake - 1 1 0 1

Miscellaneous Commodities Asparagus – 8 6 0 6 Atemoya - 3 3 0 3

Avocado – 5 5 0 5

Banana – 5 5 0 5

Coffee – 5 3 0 3

Guava – 3 A 3 0 3

Peanut – 12 6 0 6 Pineapple - 8 5 0 5 Sugarcane - 8 5 0 5

Tea - 3 2 0 2

Tobacco - 3 2 0 2

Page 24 of 25Page 25 of 25 A - Although the guidance specifies only two trials (with an alysis of four samples from each trial), three trials will be required, since the guava trials will support the use on other commodities.

Additional notes:

• Since the time of the RED, the berry sub-group has been modified to include cranberries. If the registrant conducts the field trials as described below for berry group 13-07, field trials on cranbe rries will not be needed.

• In the DCI, trials on barley, rye, and oat grai n were required. If th e registrant completes the trials for the cereal grain representative commodities as described in the table below (crop group 15), then the trials on th ese grains will not be needed.

• Field trials on cherimoya are no longer needed ; data from atemoya may be translated to cherimoya.

• Field trials on pomegranate are no longer needed.