UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM February 21, 2006 SUBJECT: Piperonyl Butoxide HED Revised Risk Assessment for Reregistration Eligibility Document ( RED) PC Code No 067501; DP Barcode No. 326576 FROM: Becky Daiss Environmental Health Scientist Reregistration Branch 4 Health Effects Division ( 7509C)

THROUGH: Susan V. Hummel Branch Senior Scientist Reregistration Branch 4 Health Effects Division ( 7509C)

TO: Cathryn O'Connell Chemical Review Manager Reregistration Branch 2 Special Review and Registration Division ( 7508C)

Attached is Health Effects Division's ( HED's) risk assessment of piperonyl butoxide for purposes of issuing a Reregistration Eligibility Decision ( RED) Document for this active ingredient. This document updates the September 8, 2005 Piperonyl Butoxide HED Risk Assessment. The risk assessment has been revised to address public comments. The revised disciplinary science chapters and other supporting documents are included as appendices as follows:

Report of the Hazard Identification Assessment Review Committee, S. Ramasamy ( TXR No. 0052600, 6/ 8/ 04) ( Note: This is an archive data base document which cannot be revised. Revisions to the toxicology assessment have been addressed in the Risk Assessment) Report of the Metabolism Assessment Review Committee, T Morton, S. Ramasamy, W. Eckel ( D321269, 9/ 1/ 05) Product & Residue Chemistry Assessment, T. Morton ( D310030, 11/ 23/ 04) Occupational and Residential Exposure Assessment, B. Daiss ( D318743, 9/ 7/ 05), Occupational and Residential Exposure Assessment for the Use of Piperonyl Butoxide in Residential Outdoor Automatic Mister Systems, M. Crowley ( D315334, 8/ 30/ 05) Dietary Exposure and Risk Estimates for Tolerance Reassessment, T. Morton ( D310032, 11/ 23/ 04) Review of Pyrethrins Incident Reports  Second Revision, J. Blondell, Ph. D ( D320300, 8/ 16/ 04) Tier I Drinking Water Assessment, William Eckel ( D286223, 5/ 17/ 04) Page 2 of 61 TABLE OF CONTENTS pg. 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION . . . . . . . . . . . . . . . 8 3.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.1 Hazard Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.1.1 Toxicity Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1.2 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.2 FQPA Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3.3 Dose Response Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 3.3.1 Dietary Exposure Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.3.2 Occupational and Residential Exposure Endpoints . . . . . . . . . . . . . . . . . . . . . . 20 3.4 Endocrine Disruptor Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.0 DIETARY & DRINKING WATER EXPOSURE/ RISK ASSESSMENT . . . . . . . . . . 22 4.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.2 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2.2 Dietary Exposure/ Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.3 Drinking Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.3.1 Environmental Fate Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.3.2 Estimated Environmental Concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 5.0 RESIDENTIAL EXPOSURE/ RISK ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5.1 Residential Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5.1.1 Handler Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.1.2 Post application Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.2 Residential Exposure Data and Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.2.1 Application Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 5.2.2 Handler Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.2.3 Post application Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 5.2.4 Exposure Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 5.3 Residential Exposure and Risk Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 6.0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION . . . . . . . . 39 6.1 Acute Aggregate Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.2 Short term Aggregate Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 6.3 Chronic Aggregate Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 7.0 CUMULATIVE EXPOSURE AND RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 8.0 OCCUPATIONAL EXPOSURE/ RISK ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . 43 8.1 Occupational Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 8.1.1 Agricultural Handler Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 8.1.2 Pest Control Operator Handler Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 8.1.3 Mosquito Abatement Handler Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 8.1.4 Direct Application to Pets and Farm Animals . . . . . . . . . . . . . . . . . . . . . . . . . . 44 8.2 Occupational Exposure Data and Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 8.2.1 Exposure Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 8.2.2 Exposure Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 8.3 Occupational Exposure and Risk Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 9.0 INCIDENT REPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 10.0 UNCERTAINTIES AND RISK CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . 49 11.0 DATA NEEDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 11.1 Product Chemistry Data Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Page 3 of 61 11.2 Residue Chemistry Data Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 1.0 EXECUTIVE SUMMARY This assessment provides information to support the issuance of a risk management decision document known as a Reregistration Eligibility Decision ( RED) Document for piperonyl butoxide. EPA's pesticide reregistration process provides for the review of older pesticides ( those initially registered prior to November 1984) under the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) to ensure that they meet current scientific and regulatory standards. The process considers the human health and ecological effects of pesticides and incorporates a reassessment of tolerances ( pesticide residue limits in food) to ensure that they meet the safety standard established by the Food Quality Protection Act ( FQPA) of 1996.

Use Profile Piperonyl butoxide is an insecticide synergist. Synergists are chemicals that lack pesticidal effects of their own but enhance the pesticidal properties of other chemicals. Piperonyl butoxide is used in combination with a wide variety of insecticides in ratios ranging from 3: 1 to 20: 1 by weight. It is usually formulated with natural pyrethrins or synthetic pyrethroids and is an ingredient in 1600 to 1700 registered pest control products. It has numerous and varied commercial and residential applications, is available in a broad range of formulations, and is applied by wide variety of application methods. Commercial uses include pre and post harvest application to food and non food agricultural crops, applications in food and non food handling commercial and agricultural structures and outdoor premises, housing for veterinary and farm animals, and direct application to veterinary and farm animals. Piperonyl butoxide currently has 70 tolerances ( 40 CFR 180.127) in/ on various crop and livestock food commodities. Residentially, it is used to control insects both inside the home, and outside on gardens, lawns and ornamentals, patios, and other outdoor structures, and is directly applied to pets. As a synergist, it inhibits the mixed function oxidase system of insects and reduces the oxidative breakdown of other pesticides like pyrethrum and synthetic pyrethroids. Comprehensive information on use patterns and formulations is provided in the Piperonyl Butoxide Master Label which was submitted to the EPA by the Piperonyl Butoxide Task Force II. The risk assessments for piperonyl butoxide are based solely on the Master Label, since it only lists the uses that the Task Force II are supporting ( C. Rodia, Use Closure Memo, 11/ 17/ 03).

Screening level estimate of piperonyl butoxide usage performed by HED's Biological and Economical Analysis Division ( BEAD) indicates that 5,000 to 10,000 pounds of piperonyl butoxide are used annually in the U. S. for application to agricultural crops, with highest usage on potatoes ( 30% crop treated) and other uses at 5% or less. An estimated 100,000 to 200,000 pounds are used annually for non crop uses.

Regulatory History Page 4 of 61 Piperonyl butoxide is a FIFRA List B reregistration pesticide. The Phase 4 Reviews of available residue chemistry data were issued in February, 1991. Data Call In Notices for piperonyl butoxide were issued in May, 1991 and September, 1995 requiring the registrants to submit several residue chemistry studies in order to fulfill reregistration requirements. Reregistration of piperonyl butoxide is being supported by the Piperonyl Butoxide Task Force II, whose members are Prentiss, Inc., McLaughlin Gormley King Co., S. C. Johnson & Son, Inc., Takasago International Corp., Endura S. p. A., and Valent Biosciences Corp. Data has been submitted in response to data deficiencies outlined in the Phase 4 Reviews; to date, all studies have been reviewed.

Hazard Identification and Dose Response Assessment The toxicology data base is adequate to characterize the toxicity of piperonyl butoxide. Piperonyl butoxide has a low acute toxicity by oral, inhalation and dermal routes and it has been assigned toxicity Category IV by all exposure routes. In the acute studies, piperonyl butoxide has been identified as minimally irritating to eyes and skin.

The liver is primary target organ for piperonyl butoxide induced toxicity. Subchronic studies in rats showed increases in liver weight, increases in cholesterol and gamma glutamyl transpeptidase activity, and histopathological effects such as enlargement of hepatocytes, oval cell proliferation, bile duct hyperplasia, and focal necrosis. Similar effects occurred in subchronic mice study after 20 days. The liver effects ( increased liver weight, focal hyperplasia and changes in clinical parameters) appeared pronounced upon chronic exposure to piperonyl butoxide in rodents and dogs.

In a subchronic dermal toxicity study in rabbits, no systemic treatment related effects were observed. However, piperonyl butoxide was observed to be a mild irritant i. e., macro and micropathology of the tested sites exhibited dermal lesions associated with irritation. A subchronic inhalation toxicity study in rats showed histopathological changes in the respiratory tract indicated by metaplasia/ hyperplasia in the larynx in all treated groups.

In a combined chronic/ carcinogenic study in rats, positive carcinogenic effects were reported at doses where high incidence of ileocaecal ulcers were noticed. Liver adenomas and carcinomas were reported in Fischer 344 rats only when tested at excessive doses. A slight increase in thyroid follicular cell tumor alone was reported in Sprague Dawley rats when tested at adequate doses. A 1979 National Toxicology Program ( NTP) study reported negative effects for carcinogenicity in same strain of rats and in B6C3F1 mice. However, in CD 1 mice, piperonyl butoxide tested positive for liver tumor effects. Piperonyl butoxide is classified as a Group Cpossible human carcinogen with no cancer quantification required for piperonyl butoxide risk assessment.

The toxicity database is considered adequate for evaluation of risks to infants and children. Studies indicate that there is a low degree of concern for fetal susceptibility effects and no Page 5 of 61 evidence of residual uncertainties for pre and post natal toxicity from exposure to piperonyl butoxide. No developmental toxic effects were noted in guideline studies in rats and rabbits. Neurotoxic effects are not evident from the clinical signs reported in guideline developmental, reproductive and chronic studies. Therefore, the special FQPA safety factor is reduced from 10x to 1x.

Piperonyl butoxide tested negative in bacterial gene mutation assays. The in vitro mammalian cell mutation assays indicate a questionable positive effect for mutation. Piperonyl butoxide tested negative for chromosomal aberration and sister chromatid exchange in CHO cells and no induction of unscheduled DNA synthesis was observed in rat primary hepatocytes.

Piperonyl butoxide is well known to inhibit microsomal enzymes in insects. It also inhibits the microsomal enzymes in several other species ( e. g., rats, rabbits, mice). In the mammalian system, it is shown to exhibit initial inhibition followed by stimulation of microsomal enzymes upon continued exposure. The kinetics of piperonyl butoxide inhibition and/ or stimulation of microsomal enzymes in humans is not established. However, one study in humans reports no inhibition of microsomal enzymes ( measured as antipyrine half life in blood) at a dose of 0.7 mg/ kg.

Metabolism studies show the main route of piperonyl butoxide excretion in rats is via urine and feces ( 64 85% in feces, 11 30% in urine) with the majority of the radioactivity being excreted within 48 hours. The parent and the M3 metabolite ( parent with opened methylene dioxy ring) were the major compounds identified in feces ( approximately 20% of the radioactivity each).

Dietary, drinking water, and occupational and residential exposure scenarios are the relevant scenarios for exposure to piperonyl butoxide. The acute oral endpoint was selected based on a developmental toxicity study in rats. The chronic oral endpoint was selected based on a chronic oral toxicity study in dogs. No dose or endpoints were selected for dermal exposure because no systemic effects were observed at the limit dose in the 21 day dermal toxicity study in rabbits. The short, intermediate term and long term inhalation endpoints were selected based on a subchronic inhalation study in rats. Short and intermediate term incidental oral endpoints were selected based on a two generation reproduction study in rats. Endpoints used in the assessment are provided in Table 1.

Table 1. Endpoints Used for Piperonyl Butoxide Risk Assessment Dietary NOAEL mg/ kg/ day RfD mg/ kg/ day PAD mg/ kg/ day acute  all populations 630 6.3 ( UF= 100; FQPA = 1) 6.3 chronic  all populations 15.5 0.155 ( UF= 100; FQPA = 1) 0.155 Occupational and Residential NOAEL mg/ kg/ day MOE short intermediate & long term dermal NA NA short term incidental oral 89 100 Table 1. Endpoints Used for Piperonyl Butoxide Risk Assessment Page 6 of 61 short & intermediate term inhalation 4 300 long term inhalation 4 1000 Exposure Assessment Analysis of dietary, drinking water, occupational and residential exposure pathways were included in the piperonyl butoxide risk assessment. Sources of dietary exposure include pre and post harvest food crops, livestock, and food from treated food processing facilities and food storage warehouses. Drinking water exposure may occur due to run off from agricultural use, outdoor pest control, mosquito abatement and some direct aquatic uses ( e. g., carp bait). Occupational exposure may occur through use of piperonyl butoxide during application for agricultural, commercial and residential pest control, and mosquito abatement activities. Residential exposures may occur through homeowner use of piperonyl butoxide to control pests indoors, outdoors and on pets. For the occupational exposures, short, intermediate, and long term inhalation pathways were assessed based on label directed use patterns. For residential exposures, short and intermediate term inhalation and incidental oral pathways were assessed. Dermal exposures were not assessed because HIARC concluded that no quantitative dermal assessment is required because no systemic effects were observed at high doses in dermal toxicity studies.

Risk Assessment and Risk Characterization Risk assessments were conducted for dietary, drinking water, residential and occupational exposure pathways. An aggregate assessment of risk from the combined food and drinking water pathways was also conducted. Oral and inhalation residential exposures to piperonyl butoxide were not aggregated because the toxicity endpoints selected for these routes of exposure are not common. A cumulative risk assessment considering risks from other pesticides or chemical compounds having a common mechanism of toxicity has not been conducted for this RED because HED has not yet determined if there are any other chemical substances that have a mechanism of toxicity common with that of piperonyl butoxide.

Food Pathway Exposure and Risk HED conducted highly refined acute and chronic dietary exposure analyses using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database ( DEEMFCID   ) and the Lifeline model. Dietary analyses were conducted for the general U. S. population and all population subgroups.

Acute and chronic dietary risks are expressed as a percentage of the acute or chronic Population Adjusted Dose ( aPAD or cPAD). A dietary risk of 100% of the PAD is the target level of exposure that should not be exceeded, ( i. e., estimated risk less than 100% of PAD is not of concern). The PAD is the Acute reference dose ( RfD) or the Chronic RfD modified by the FQPA Safety Factor. The safety factor for both the acute and chronic dietary assessments is 1X. Page 7 of 61 Based on these analyses, acute and chronic dietary risk from existing and proposed uses of piperonyl butoxide are below HED's level of concern for the general US population and population subgroups. The 99.9th percentile acute exposure estimates were < 100% of the aPAD. The highest acute exposures ( 1.2 mg/ kg/ day) were in children 1 2 years old ( 20% aPAD). Chronic exposure estimates were also < 100% of the cPAD, with the highest chronic exposure ( 0.02 mg/ kg/ day) occurring in children 1 2 years old ( 12% cPAD).

Drinking Water Pathway Exposure and Risk The Environmental Fate and Effects Division ( EFED) performed a Tier I drinking water assessment for piperonyl butoxide in surface water and groundwater ( D286223, W. Eckel, 5/ 17/ 04). EFED used the FIRST ( FQPA Index Reservoir Screening Tool) model for estimating the upper bound on the concentrations that could occur in surface water source drinking water, and SCIGROW ( Screening Concentration in Ground Water) to estimate the concentrations in groundwater used for drinking water. The peak estimated drinking water concentration ( EDWC) of piperonyl butoxide in surface water is 240 ppb. The annual average drinking water EDWC in surface water is 60 ppb. The peak and annual average groundwater EDWCs are 0.26 ppb.

Aggregate Exposures and Risks Since there is potential for concurrent exposure via food and water, the combined exposures are estimated for the aggregate assessment. To assess aggregate risk, drinking water levels of comparison ( DWLOCs) are compared with model based EDWCs determined by EFED. The DWLOC is a theoretical concentration limit of a chemical in drinking water that would be acceptable as an upper limit in light of total aggregate exposure to that chemical from food, water, and residential sources. Aggregate risk for piperonyl butoxide exposure is calculated for acute and long term exposure. Acute and chronic DWLOCs include aggregate exposure from food and drinking water only. The short term DWLOC aggregates exposures from food, water and residential routes associated with application of piperonyl butoxide and is calculated when there is a common toxicity endpoint for each route of exposure.

The acute DWLOC is > 51000 ppb based on the food exposure from the most highly exposed subgroup ( children 1 2 years). The chronic DWLOC is > 1400 ppb also based on the food exposure for children 1 2 years. The short term DWLOC for children 1 2 years old is 8500 ppb. EFED's model based estimates for peak concentrations of piperonyl butoxide in surface and ground water are 240 and 0.26 ppb respectively; estimates for average surface and ground water concentrations are 60 and 0.26 ppb respectively. Since the model based estimates for concentrations in surface water and groundwater are well below the calculated acute, short term, and chronic DWLOCs, HED concludes that aggregate exposure to food and drinking water will not result in an unacceptable risk.

Occupational and Residential Pathway Exposure and Risk Page 8 of 61 O O O O CH 3 OC 4 H 9 Occupational exposure to piperonyl butoxide can occur from agricultural, pest control, mosquito abatement and veterinary and farm animal applications. Thirty two exposure scenarios were identified and assessed as representative of occupational exposure for piperonyl butoxide uses. Post application occupational exposure scenarios are not assessed because there is no endpoint for dermal exposure, the relevant route of exposure for post application activities. Residential exposure can occur from indoor and outdoor pest control uses and pet application. Fifteen residential handler and post application exposure scenarios were assessed. Short, intermediate and long term MOEs were calculated for this assessment as required based on scenario specific use/ exposure patterns.

Exposure data used for the piperonyl butoxide assessment are taken primarily from HED's Standard Operating Procedures for residential and occupational exposure. Risk estimates were conducted using maximum application rates from the Piperonyl Butoxide Master Label. A target Margin of Exposure ( MOE) of 300 is considered adequate for short and intermediate term occupational and residential exposure via inhalation routes. For long term occupational inhalation exposures, an adequate target MOE is 1000. The target MOE for residential incidental oral exposures is 100. Exposure estimates indicate MOEs of concern (< the target MOE) at the maximum application rate for ten of the occupational scenarios assessed. The results of the residential exposure assessment indicate that, with one exception, all of residential exposure scenarios assessed result in MOEs greater than the applicable target MOEs and are therefore below the level of concern. The short term residential bystander inhalation from use of piperonyl butoxide in residential outdoor automatic mister systems is the only scenario with risks of concern. An assessment of residential exposure from use of indoor metered release misters was not conducted due to data limitations. HED recommends that label restrictions provided in the master label be required for indoor automatic mister uses.

2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION The nomenclature and physicochemical properties of piperonyl butoxide are provided in Table 2.

TABLE 2. Piperonyl Butoxide Nomenclature Compound Chemical Structure Common name Piperonyl butoxide IUPAC name 5[ 2( 2 butoxyethoxy) ethoxymethyl] 6 propyl 1,3 benzodioxole or 2( 2 butoxyethoxy) ethyl 6 propylpiperonyl ether CAS name 5[[ 2( 2 butoxyethoxy) ethoxy] methyl] 6 propyl 1,3 benzodioxole TABLE 2. Piperonyl Butoxide Nomenclature Page 9 of 61 CAS # 51 03 6 Physicochemical Properties of the Technical Grade of Piperonyl Butoxide Parameter Value Reference Boiling point 202 204 ° C at 1.9 mm/ Hg D207185, 1/ 27/ 99, T. Morton 180 ° C at 1.0 mm/ Hg 2002 Farm Chemicals Handbook Molecular Weight 338.433 2002 Farm Chemicals Handbook pH Not applicable because the TGAI has low solubility in water Density, bulk density, or specific gravity 1.059 g/ mL at 20 ° C D172854, 11/ 30/ 92, A. Aikens Water solubility 14.34 : g/ mL at 25 ° C RD Memorandum, 12/ 31/ 90 ( cited under D207185, 1/ 27/ 99, T. Morton)

Solvent solubility Completely miscible ( 95% solution) in acetone, methanol, petroleum distillate, petroleum ether, methylene chloride, and isooctane D207185, 1/ 27/ 99, T. Morton Vapor pressure < 1 x 10 7 mm Hg at 25 ° C ( extrapolated from 1.59 x 10 7 mm Hg at 60 ° C D172854, 11/ 30/ 92, A. Aikens Dissociation constant, pKa Not applicable because the TGAI has low solubility in water Octanol/ water partition coefficient 4.51 x 104 RD Memorandum, 12/ 31/ 90 ( cited under D207185, 1/ 27/ 99, T. Morton)

log Kow = 4.95 D172854, 11/ 30/ 92, A. Aikens UV/ visible absorption spectrum Not available 3.0 HAZARD CHARACTERIZATION 3.1 Hazard Profile The toxicity data base for piperonyl butoxide is adequate for the selection of doses and endpoints for use in risk assessment. HED's Hazard Identification Assessment Review Committee ( HIARC) evaluated the available studies and established acute and chronic RfDs, as well as doses and endpoints for acute, and short, intermediate, and long term dermal and inhalation exposure scenarios. The Acute RfD is an estimate of a single day oral exposure level for the human population that is likely to be without an appreciable risk of deleterious effects. The chronic RfD is an estimate of a daily oral exposure level that is likely to be without an appreciable risk of deleterious effects during a lifetime. Acute and chronic RfDs are calculated by dividing the No Observable Adverse Effect Level ( NOAEL) by the Uncertainty Factors ( UF). UFs are used to account for differences between humans ( intraspecies variability) and for differences between the test animals and humans ( interspecies extrapolation). For occupational and residential exposures, UFs are used to determine adequate margins of exposure ( MOEs). The MOE is the ratio of the route appropriate NOAEL to the estimated exposure. The HIARC also evaluated available studies to determine if there was a special sensitivity for infants and children. The toxicological data for piperonyl butoxide are summarized in Tables 3 and 4. Page 10 of 61 3.1.1 Toxicity Profile Acute toxicity categories for piperonyl butoxide are shown in Table 3. Table 4 identifies guideline studies and open literature studies conducted for piperonyl butoxide and summarizes their results.

Table 3. Acute Toxicity Data on Piperonyl Butoxide Study/ Species MRID Results Classification 870.1100 Acute Oral, Rats 41969001 LD50 = 4570 mg/ kg ( m) 7220 mg/ kg ( f) Category IV ( Under Review)

870.1200 Acute Dermal, Rabbits 41969002 LD50 = > 2000mg/ kg Category IV ( Under Review)

870.1300 Acute Inhalation, Rats 41990001 LC50 = > 5.9 mg/ L Category IV 870.2400 Primary Eye Irritation, Rabbits 41969004 Minimally irritating Category III ( Under Review)

870.2500 Primary Skin Irritation, Rabbits 41969003 Minimally irritating Category III ( Under Review)

870.2600 Dermal Sensitization, Guinea pig 41969005 Negative Category IV ( Under Review)

Table 4. Piperonyl Butoxide Toxicity Study Profile Developmental/ Reproduction Toxicity Developmental Toxicity Rat 42380801 Doses: 0, 200, 500 and 1000 mg/ kg/ day Maternal NOAEL: 200 mg/ kg/ day Maternal LOAEL: 500 mg/ kg/ day Reduction in body weight gain and food consumption during 6 15 days of gestation Developmental NOAEL: 500 mg/ kg/ day ( HDT) Acceptable Guideline Developmental Toxicity Rabbit 00157157 Doses: 0, 50, 100, and 200 mg/ kg/ day Maternal NOAEL: 200 mg/ kg/ day ( HDT) Developmental NOAEL: 200 mg/ kg/ day ( HDT) Acceptable Guideline 2 Gen Reproduction Study Rat 00161118 Doses: 0, 300, 1000 and 5000 ppm 0, 27, 89, 469 mg/ kg/ day ( males) 0, 30, 102, 528 mg/ kg/ day ( females) Parental NOAEL: 89 mg/ kg/ day Parental LOAEL: 469 mg/ kg/ day Decreased body weight gain Reproductive NOAEL: 469 mg/ kg/ day Offspring NOAEL 89 mg/ kg/ day Offspring LOAEL: 469 mg/ kg/ day ( HDT) Decreased body weight gain in F1 and F2 pups Acceptable Guideline Table 4. Piperonyl Butoxide Toxicity Study Profile Page 11 of 61 Developmental Rats Kennedy et al., 1977 Doses: 0, 300, 1000 mg/ kg/ day Maternal NOAEL/ LOAEL: 300/ 1000 mg/ kg/ day Reduction in mean body weight gain during 6 20 days of gestation Developmental NOAEL 1000 mg/ kg/ day ( HDT) Non Guideline Developmental Rats Tanaka et al., 1995 Doses: 0, 630, 1065 or 1800 mg/ kg/ day Maternal NOAEL/ LOAEL: 630/ 1065 mg/ kg/ day Reduction in bodyweight gain ( 24 37%) during gestation Developmental NOAEL/ LOAEL: 630/ 1065 mg/ kg/ day, Limb deformities; HDT had increased resorption rate and decreased number of viable fetuses Non Guideline Developmental Mice Tanaka et al., 1994 Doses: 0, 1065, 1385, or 1800 mg/ kg/ day Maternal NOAEL: 1800 mg/ kg/ day ( HDT) Developmental NOAEL/ LOAEL: 1065/ 1385 mg/ kg/ day: Early and late fetal death and increased resorption rate; HDT had increased incidence of limb deformities Non Guideline Reproduction Single Generation Mice Tanaka, 1992 Doses: 0,1500, 3000, 6000 ppm Estimated Dose: 0, 225, 450, 900 mg/ kg/ day Offspring NOAEL/ LOAEL: 225/ 450 mg/ kg/ day Decreased weight of the pups at postnatal days 7 and 14 Neurobehavioral ( Parental) NOAEL/ LOAEL: 450/ 900 mg/ kg/ day Decreased ambulation and possibly rearing in F0 male mice at 900 mg/ kg/ day Neurobehavioral ( Offspring) NOAEL/ LOAEL: 225/ 450 mg/ kg/ day Decreased olfactory orientation in F1 mice Non Guideline Reproduction Two Generation, Mice Tanaka et al., 1992 Doses: 0,1000, 2000, 4000, 8000 ppm Chemical intake: 159, 317, 648,1237 mg/ kg/ day ( F0); 171, 319, 665, 1341 mg/ kg/ day ( F1) NOAEL/ LOAEL ( Parental): N/ A ( No measurements made) NOAEL/ LOAEL ( Offspring): 319/ 665 mg/ kg/ day; Reduction in litter size and litter weight in F2 generation and decreased weight of the F1 and F2 pups during lactation. Neurobehavioral NOAEL/ LOAEL ( Offspring): 171/ 319 mg/ kg/ day. Decreased olfactory orientation in F2 pups at postnatal day 14 Non Guideline .

Subchronic Oral Toxicity Table 4. Piperonyl Butoxide Toxicity Study Profile Page 12 of 61 Subchronic ( 13 weeks) Rats Fujitani et al., 1992 Doses: 0, 6000, 12000, or 24000 ppm ( diet) Estimated dose 0, 600, 1200, 2400 mg/ kg/ day NOAEL: < 600mg/ kg/ day LOAEL: 600 mg/ kg/ day based on 36 39 % increase in relative liver weight and 133 150% increase in gamma glutamyl transpeptidase Non Guideline Subchronic ( 12 weeks) Rats Fujitani et al., 1993a Doses: 0, 6000, 12000, or 24000 ppm ( diet) Estimated dose 0, 600, 1200, 2400 mg/ kg/ day NOAEL: < 600mg/ kg/ day LOAEL: 600 mg/ kg/ day based on increases in relative liver weight and in gamma glutamyl transpeptidase Non Guideline Subchronic ( 20 days) Mice Fujitani et al., 1993b Doses: 0,1000, 3000 or 9000 ppm ( diet) Estimated dose 0, 150, 450, 1350 mg/ kg/ day NOAEL/ LOAEL: 150/ 450 mg/ kg/ day based on increased cholesterol, gamma glutamyl transpeptidase and liver weights Non Guideline Subchronic ( 6 weeks) Mice Tanaka, 1993 Doses: 0, 1500, 3000 and 6000 ppm Equivalent to 0, 236, 448 and 880 mg/ kg/ day Neurobehavioral NOAEL:< 236 mg/ kg/ day LOAEL: 236 mg/ kg/ day based on effects on motor activity i. e., increased number of turnings and total distance traveled per 10 minutes Non Guideline Chronic Oral Toxicity 870.4100 Chronic Toxicity  Dogs 42926001, 42926002 Doses: 0, 100, 600 or 2000ppm 0, 2.9, 15.5, 52.8 mg/ kg/ day ( males), 0, 2.8, 16.3, or 71.0 mg/ kg/ day ( females) NOAEL: 15.5 mg/ kg/ day LOAEL: 52.8 mg/ kg/ day  Decreased body weight gain, increased in alkaline phosphatase and relative liver weights and hepatocellular hypertrophy ( 75 100% animals) Acceptable Guideline Combined Chronic Carcinogenicity 870.4300 Combined chronic toxicity/ carcinogenicity Rats 40323701 Doses: 0,30, 100 or 500 mg/ kg/ day NOAEL: 30 mg/ kg/ day LOAEL: 100 mg/ kg/ day  increased liver weight, increased cholesterol levels, gross and histopathological liver effects Negative for liver tumors Note: Butler et al., 1998 confirmed the negative tumor effects after reevaluation of pathological findings Acceptable/ Guideline Table 4. Piperonyl Butoxide Toxicity Study Profile Page 13 of 61 870.4300 Combined chronic toxicity/ carcinogenicity Rats 42839601, 42920201 Doses: 0, 547, 1052, 1877 mg/ kg/ day ( males) 0, 537, 1061, and 2002 mg/ kg/ day ( females) NOAEL: < 537 mg/ kg/ day LOAEL: 537 mg/ kg/ day  Decreased body weight gain, increased liver weights, effect on RBC parameters ( abnormal shaped erythrocytes), enlargement and hemorrhage effects in cecum Hepatocellular adenoma and carcinomas in both sexes Acceptable/ Non Guideline 870.4300 Combined chronic toxicity/ carcinogenicity Mice 42903701, 42978001 Doses: 0, 30, 100 or 300 mg/ kg/ day NOAEL: 30 mg/ kg/ day LOAEL: 100 mg/ kg/ day  Increased liver weight relative to body weight, and liver hypertrophy Hepatocellular adenomas and carcinomas in males and hepatocellular adenomas alone in females Note: Butler et al., 1998 confirmed the negative tumor effects after reevaluation of pathological findings Acceptable/ Guideline 2 year Carcinogenicity Rats NTP, 1979 Doses: 0, 5000 and 10,000 ppm ( diet) Negative for tumor effects Non Guideline 2 year Carcinogenicity Rats Maekawa et al., 1985 Doses: 0, 5000 and 10,000 ppm ( diet) Estimated Chemical Intake: 0, 500 and 1000 mg/ kg/ day Negative for tumor effects Non Guideline 1 year Carcinogenicity Mice Takahashi et al., 1994 Doses: 0, 6000 and 12,000 ppm ( diet) Dose dependent increase in hepatocellular adenomas and carcinomas; Hemangioendothelial sarcomas in males Takahashi et al., 1997reported similar findings in females. Non Guideline 11/ 2  year Carcinogenicity Mice NTP, 1979 Doses: 0, 6000 and 12,000 ppm ( diet) Negative for tumor effects Non Guideline Subchronic Dermal/ Inhalation Toxicity 21 Day Dermal Toxicity Rabbit 42218201 Doses: 0, 100, 300 and 1000 mg/ kg/ day Systemic NOAEL: $ 1000 mg/ kg/ day ( HDT) Dermal LOAEL: 100 mg/ kg/ day ( LDT) mild irritant , Very slight erythema, edema and desquamation and histpathological effects such as acanthosis, hyperkeratosis and chronic inflammation of the epidermis Acceptable/ Guideline Table 4. Piperonyl Butoxide Toxicity Study Profile Page 14 of 61 90 day Inhalation Toxicity Rat 42477101 Doses: 0, 0.015, 0.074, 0.155 and 0.512 mg/ L Systemic NOAEL: 0.155 mg/ L Systemic LOAEL: 0.512 mg/ L increased liver and kidney weights Respiratory NOAEL  Not Established Respiratory LOAEL 0.015 mg/ L ( LDT) metaplasia/ hyperplasia in the larynx Acceptable/ Guideline Metabolism Rat Metabolism 41998701 41998401 Most of the administered radioactivity was found in feces and urine in 48 hours after single oral dose of 50 or 500 mg/ kg bw. Less than 1.5% of the administered radioactivity was present in tissues after 168 hours. The highest levels were in the small intestine and liver. Acceptable Guideline Rat Metabolism 45582701 The dose administration was similar to the metabolism study above. PBO was excreted mainly in 0 48 hour urine and feces and less than 0.5% identified in tissues at 168 hours. Major metabolite in feces was identified as M3 i. e., PBO opened at the methylene dioxy ring ( approximately 20% of the radioactivity). Urine contained several radioactive peaks (~ 20 peaks) and none of these individual peaks exceeded 5% of the administered radioactivity. The urine metabolites are found conjugated with sulfate or glucuronide subsequent to oxidation of PBO in the methylenedioxy ring and/ or 2( 2 butoxyethoxy) ethoxymethyl side chain. Acceptable Guideline Mutation/ Genotoxicity 870.5100 Bacterial Reverse Mutation Assay 42004502 No evidence of mutagenicity in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 or TA100 in the presence or absence of metabolic activation Doses 100 5000 : g/ plate Acceptable Guideline 870.5100 Bacterial Reverse Mutation Assay NTP 00143499 No evidence of gene mutations in Salmonella typhimurium ( TA 1535, TA1537, TA98, TA100) with and without metabolic activation. Dose up to 10 mg/ plate Acceptable Guideline 870.5300 In vitro Mammalian Cell Gene Mutation Assay 00147693 Equivocal response in 75 : g/ ml only under nonactivated conditions in CHO cells. Doses10 100 : g/ ml ( without activation) Doses 25 500 : g/ ml ( with activation) Acceptable Guideline Table 4. Piperonyl Butoxide Toxicity Study Profile Page 15 of 61 870.5375 In vitro Mammalian Cell Chromosomal Aberrations Test 43013801 No induction of chromosomal aberration in CHO cells Doses in non activated condition: 15.0 30.0 : g/ mL for 10 or 20 hours Doses in S9activated condition: 12 120 : g/ mL for 2, 10, 20 or 30 hours Acceptable Guideline 870.5375 In vitro Mammalian Cell Chromosomal Aberrations Test NTP 00143499 No evidence of induction of chromosomal aberrations in CHO cells Acceptable Guideline 870.5550 Unscheduled DNA Synthesis in Rat Primary Hepatocytes 42004503 No evidence of induction of unscheduled DNA synthesis Dose Levels tested: 5,10, 25 and 50 : g/ ml Cytotoxic at $ 74.9 : g/ ml Acceptable Guideline 870.5900 In vitro Sister Chromatid Exchange Assay NTP 00143499 The study does not indicate sister chromatid exchanges in CHO cells with and without metabolic activation. Acceptable Guideline Microsomal Enzyme Inhibition/ Others In vitro study Liver microsomes Rats, Rabbits, Mice Franklin, 1972 Inhibition of ethylmorphine N demethylation by PBO is proportional to amount of Cytochrome P 450 and PBO metabolite complex Non Guideline Regulation of cytochrome P450 enzymes Mice Adams et al., 1993 Single i. p. dose at 0, 52, 104, 156, 208 or 400 mg PBO/ kg bw Induction of cytochrome P450 1a1mRNA, protein and enzyme activity at doses $ 104 mg/ kg at 24 hours Non Guideline Regulation of cytochrome P450 enzymes Mice Ryu et al., 1997 Single i. p. dose at 0, 400 mg PBO/ kg bw Induction of cytochrome P450 1a1and 1a2 mRNAs at 24 hours in liver by PBO treatment. Non Guideline WHO Report JMPR, 1995 PBO Toxicological Evaluation N/ A 3.1.2 Hazard Characterization Piperonyl butoxide has a low acute toxicity by oral, inhalation and dermal routes. It has been assigned toxicity Category IV by all exposure routes. In the acute studies, piperonyl butoxide has been identified as minimally irritating to eyes and skin. In the subchronic dermal study using rabbits, piperonyl butoxide is classified as a mild irritant. The dermal lesions include gross effects such as very slight erythema, edema and desquamation ( 30% of the animals) and histopathological effects such as acanthosis, hyperkerartosis and chronic inflammation of epidermis. Piperonyl butoxide is reported negative for dermal sensitization effects. In a Page 16 of 61 subchronic inhalation toxicity study, mild hyperplasia and metaplasia were noticed in the respiratory tract of rats The major target organ for piperonyl butoxide induced toxicity is the liver. Subchronic studies in rats showed piperonyl butoxide treatment caused increases in liver weight, and in clinical parameters such as cholesterol and gamma glutamyl transpeptidase activity compared to controls. Liver histopathological effects such as enlargement of hepatocytes with glassy cytoplasm, oval cell proliferation, bile duct hyperplasia, and focal necrosis were observed in treated rats. In ICR mice, similar effects ( increased liver weight, cholesterol and gamma glutamyl transpeptidase activity as well as liver histolopathological effects) occurred after 20 days of treatment. One year treatment of dogs with piperonyl butoxide also resulted in pronounced liver effects such as increased liver weight, hepatocyte hypertrophy and elevated serum alkaline phosphatase activity.

In combined chronic/ carcinogenic oral toxicity studies, liver tumorigenic effects were reported in rats only when tested at excessive doses. In Fisher 344 rats increases in liver adenomas and carcinomas were reported in both sexes of the rats at doses close to or higher than the limit dose. At these doses, hemorrhage effects in the stomach and cecum were also noticed. No liver tumor effects were reported in Sprague Dawley rats when tested at half limit dose. Maekawa et al. also reported negative carcinogenic effects in F344/ DuCrj rats even at doses where high incidence of ileocaecal ulcers were noticed. A 1979 NTP study also reported negative effects for carcinogenicity in same strain of rats. In chronic oral toxicity studies using CD 1 mice, statistically significant increases in hepatocellular adenomas, carcinomas and combined adenomas/ carcinomas in males and adenomas alone in females ( all at p< 0.01) were reported. The non guideline studies also reported increased incidences of hepatocellular adenomas and carcinomas and hemangioendothelial sarcoma in CD 1 mice treated with piperonyl butoxide. The NTP study reported negative effects for carcinogenicity in B6C3F1 mice. Piperonyl butoxide is classified as a Group C  possible human carcinogen. No cancer quantification is required for piperonyl butoxide uses.

No developmental toxic effects were noted in guideline studies using rats and rabbits. A few developmental studies in the open literature reported limb deformities, increased resorption and decreased number of viable fetuses in rodents at doses close to or higher than the limit dose. Neurotoxic effects of piperonyl butoxide are not evident from the clinical signs reported in developmental, reproductive and chronic studies submitted to the Agency.

Piperonyl butoxide tested negative in bacterial gene mutation assays. The in vitro mammalian cell mutation assays indicate a questionable positive effect for mutation. Piperonyl butoxide tested negative for chromosomal aberration and sister chromatid exchange in CHO cells and no induction of unscheduled DNA synthesis was observed in rat primary hepatocytes.

The main route of phenyl labeled piperonyl butoxide excretion in rats occurs via urine and feces. The amount of administered labeled radioactivity was found at 64 85% in feces, 11 30% in Page 17 of 61 urine and below 0.5% in tissues. The majority of the administered radioactivity was excreted in 0 48 hour urine and feces. The parent and the M3 metabolite i. e., piperonyl butoxide opened at the methylene dioxy ring were the major compounds identified in feces ( approximately 20% of the radioactivity for each). Several radioactive peaks (~ 20 peaks) were observed in urine samples and none of these individual peaks exceeded 5% of the administered radioactivity. The metabolites in the urine are polar and are found conjugated with sulfate or glucuronide subsequent to oxidation of piperonyl butoxide in the methylenedioxy ring and/ or 2( 2 butoxyethoxy) ethoxymethyl side chain.

Piperonyl butoxide is well known to inhibit microsomal enzymes in insects by direct binding to these enzymes and inhibit the breakdown of other insecticides such as pyrethrins and pyrethroids. It also inhibits the microsomal enzymes in several other species ( e. g., rats, rabbits, mice). The concentrations at which piperonyl butoxide binds to the enzyme and the affinity of binding to the enzyme and the stability of the cytochrome P450 piperonyl butoxide metabolite complex are some major factors that determine the potency of inhibition among different species.

Piperonyl butoxide is used as a classical compound in several pharmacological experiments to compare the therapeutical or toxicological effects of several drugs before or after metabolism in rodents. Although piperonyl butoxide is reported to inhibit the microsomal enzymes in mammalian system, it is shown to exhibit biphasic effects, i. e., initial inhibition followed by stimulation of microsomal enzymes upon continued exposure. Evidence from the published literature indicates that piperonyl butoxide is administered as a single dose at $ 100 mg/ kg bw in rats and mice ( with the exception of 5 25 mg/ kg bw in a couple of mice studies) to inhibit microsomal enzymes. Evidence suggests that the inhibition of microsomal enzymes is a transient effect in these drug interaction studies. As early as 24 hours after the dosing, the increase in microsomal enzymes are observed at the activity level as well as at mRNA and protein levels. The kinetics of the inhibition and/ or stimulation and the influence on the specificity of the microsomal enzymes affected upon exposure to piperonyl butoxide are not established in humans.

3.2 FQPA Considerations HIARC determined that the special FQPA safety factor should be reduced from 10x to 1x due to low degree of concern for the fetal susceptibility effects and no evidence of residual uncertainties for pre and postnatal toxicity. The FQPA safety factor recommended by the HIARC assumes that the exposure databases ( dietary food, drinking water, and residential) are complete and that the risk assessment for each potential exposure scenario includes all metabolites and/ or degradates of concern and does not underestimate the potential risk for infants and children.

There are no residual uncertainties identified in the exposure databases relevant to potential exposure to infants and children. The highly refined dietary food exposure assessment uses residue data from the USDA Pesticide Data Program, actual percent crop treated data from BEAD where available, and processing factors from processing study data. The drinking water Page 18 of 61 assessment utilizes water concentration values generated by model and associated modeling parameters which are designed to provide health protective, high end estimates of water concentrations which will not likely be exceeded. Use of piperonyl butoxide specific dietary food exposure data is intended to enhance the accuracy of the assessment but will not result in an underestimation of actual exposures/ risks. Therefore, these assessments will not underestimate the potential exposure to infants and children resulting from the use of piperonyl butoxide.

3.3 Dose Response Assessment Doses and toxicological endpoints selected for various exposure scenarios are summarized in Table 5.

Table 5. Endpoints selected by HIARC for Assessing Occupational and Residential Risks for Piperonyl Butoxide Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary General Population NOAEL= 630 mg/ kg/ day UF = 100 Acute RfD = 6.3 mg/ kg/ day FQPA SF = 1X aPAD = acute RfD FQPA SF = 6.3 mg/ kg/ day Developmental toxicity study, rats ( Tanaka et al., 1995)

LOAEL = 1065 mg/ kg/ day based on decrease in maternal body weight gain Acute Dietary Females 13 49 years N/ A N/ A Acute Dietary Endpoint for General Population is considered protective for this population. No separate endpoint is selected.

Chronic Dietary ( All populations) NOAEL= 15.5 mg/ kg/ day UF = 100 Chronic RfD = 0.16 mg/ kg/ day FQPA SF = 1X cPAD = chronic RfD FQPA SF = 0.16 mg/ kg/ day Chronic oral toxicity study, dogs LOAEL = 52.8 mg/ kg/ day based on decrease in body weight gain, and increases in alkaline phosphatase activity, liver weight and hepatocellular hypertrophy Short Term Incidental Oral ( 1 30 days) NOAEL= 89 mg/ kg/ day Residential MOE = 100 Occupational MOE = 100 Two generation reproduction study, rats LOAEL = 469 mg/ kg/ day based on the decrease in body weight gain of F1 and F2 pups at postnatal day 21 Intermediate Term Incidental Oral ( 1 6 months) NOAEL= 89 mg/ kg/ day Residential MOE = 100 Occupational MOE = 100 Two generation reproduction study, rats LOAEL = 469 mg/ kg/ day based on the decrease in body weight gain of F1 and F2 pups at postnatal day 21 Short Term Dermal ( 1 to 30 days); Intermediate Term Dermal ( 1 to 6 months); Long Term Dermal (> 6 months) N/ A N/ A No systemic, developmental and neurotoxicity concerns at the limit dose. Therefore, no quantification is required. PBO is classified as mild irritant. Contact should be avoided. Table 5. Endpoints selected by HIARC for Assessing Occupational and Residential Risks for Piperonyl Butoxide Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Page 19 of 61 Acute Inhalation (< 2 hrs) ( inhalation absorption rate = 100 %) NOAEL= 630 mg/ kg/ day Residential MOE = 100 Developmental toxicity study, rats ( Tanaka et al., 1995a) LOAEL = 1065 mg/ kg/ day based on decrease in maternal body weight gain Short Term Inhalation ( 1 to 30 days) Respiratory LOAEL= 3.91 mg/ kg/ day ( 0.015 mg/ L) Residential MOE = 300 Occupational MOE = 300 Subchronic inhalation toxicity study, rats Respiratory LOAEL = 3.91 mg/ kg/ day ( 0.015 mg/ L) based on laryngeal hyperplasia and metaplasia Intermediate Term Inhalation ( 1 to 6 months) Respiratory LOAEL= 3.91 mg/ kg/ day ( 0.015 mg/ L) Residential MOE = 300 Occupational MOE = 300 Subchronic inhalation toxicity study, rats Respiratory LOAEL = 3.91 mg/ kg/ day ( 0.015 mg/ L) based on laryngeal hyperplasia and metaplasia Long Term Inhalation (> 6 months) Respiratory LOAEL= 3.91 mg/ kg/ day ( 0.015 mg/ L) Residential MOE = 1000 Occupational MOE = 1000 Subchronic inhalation toxicity study, rats Respiratory LOAEL = 3.91 mg/ kg/ day ( 0.015 mg/ L) based on laryngeal hyperplasia and metaplasia Cancer NA NA Classified as " Group C carcinogen" with no quantification 3.3.1 Dietary Exposure Endpoints <IP_ADDRESS> Acute Reference Dose For acute dietary general population exposure, an oral NOAEL of 630 was selected from a rat developmental study based on maternal decrease in body weight gain during gestation at the LOAEL of 1065 mg/ kg/ day. Although the study reported the body weight changes after two gavage doses during gestation days 11 12, it is reasonable to assume that effects could have occurred after a single dose administration and thus are considered appropriate for acute RfD selection. The HIARC recommended a UF of 100x ( 10x for interspecies and 10x for intraspecies is extrapolation) which results in an RfD of 6.3 mg/ kg/ day. No separate endpoint was selected for the subpopulation of females, ages 13 49 years, because the study selected for the general population is considered protective for this subpopulation.

<IP_ADDRESS> Chronic Reference Dose Acute RfD ( General population) = 630 mg/ kg/ day ( NOAEL) = 6.3 mg/ kg/ day 100 ( UF) Page 20 of 61 For chronic dietary exposure for all populations, the toxicology endpoint was selected from a chronic oral toxicity study in dogs in which the NOAEL was 15.5 mg/ kg/ day and the LOAEL was 52.8 mg/ kg/ day, based on decreases in body weight gain, increased alkaline phosphatase activity and increased liver weight and hepatocellular hypertrophy. This study was selected because; 1) dogs appear to be the more sensitive species for the toxic effects of piperonyl butoxide than rats and mice, 2) it is appropriate for the duration and route of exposure, 3) it has endpoints similar to those reported in other chronic studies such as combined chronic and carcinogenicity studies in mice and rats 4) there are no developmental and reproductive concerns at the doses selected for risk assessment, and 5) it was also used for deriving the Acceptable Daily Intake ( ADI) of piperonyl butoxide by the Joint FAO/ WHO Meeting on Pesticide Residues in 1995. The HIARC recommended application of a conventional UF of 100 resulting in a chronic RfD of 0.155 mg/ kg/ day.

3.3.2 Occupational and Residential Exposure Endpoints <IP_ADDRESS> Dermal Exposure No dose or endpoints were selected for dermal exposure. HIARC concluded that no quantitative dermal assessment is required because no systemic effects were observed at the limit dose in the 21 day dermal toxicity study in rabbits. In the 21 day rabbit dermal toxicity study, dose levels of 1000 mg/ kg/ day produced no treatment related effect on mortality rate, food consumption, body weight gain, hematology, clinical chemistry, absolute/ relative organ weights, and histopathology. However, piperonyl butoxide was observed to be a mild irritant i. e., macro and micropathology of the tested sites exhibited dermal lesions associated with irritation. The dermal lesions include gross effects such as very slight erythema, edema and desquamation ( 30% of the animals) and histopathological effects such as acanthosis, hyperkeratosis and chronic inflammation of epidermis.

<IP_ADDRESS> Dermal Absorption Since no dermal endpoint was selected, a dermal absorption factor is not needed.

<IP_ADDRESS> Inhalation Exposure Acute, Short, Intermediate, and Long Term For acute inhalation exposure ( e. g., < 2 hours) the toxicology endpoint was selected from a rat developmental study in which the oral NOAEL was 630 mg/ kg/ day based on maternal decrease in body weight gain during gestation at the LOAEL of 1065 mg/ kg/ day. In the absence of appropriate acute inhalation toxicity studies, the default value of 100% for inhalation Chronic RfD = 15.5 mg/ kg/ day ( NOAEL) = 0.155 mg/ kg/ day 100 ( UF) Page 21 of 61 absorption was used for route to route extrapolations. The target margin of exposure ( MOE) for acute inhalation exposures to piperonyl butoxide is 100 based on the conventional uncertainty factor of 100X.

For short, intermediate and long term inhalation exposures, the toxicology endpoint was selected from a subchronic inhalation toxicity study in rats in which the LOAEL was 3.91 mg/ kg/ day based on the laryngeal hyperplasia and metaplasia. A respiratory NOAEL was not established because lesions in the larynx were present in all treated groups. The selected endpoint is considered appropriate for assessing all durations of inhalation exposure based on route and duration of the study.

A target MOE of 300 was determined by HIARC to be adequate for short and intermediate term inhalation exposures to piperonyl butoxide. The short and intermediate term target MOE includes the conventional uncertainty factor of 100X and an additional 3X uncertainty factor for the use of a LOAEL. For long term exposures, HIARC recommended a target of 1000. HIARC recommended that the long term target MOE be increased to 1000 to account for lesions in the respiratory tract that might progress into long term adverse effects ( e. g., cancer).

<IP_ADDRESS> Incidental Oral Exposure  Short and Intermediate Term For short and intermediate term incidental oral exposure, an oral NOAEL of 89 mg/ kg/ day was selected from a two generation reproduction study in rats based on the decrease in body weight gain of F 1 and F 2 pups at postnatal day 21 at the LOAEL of 469 mg/ kg/ day. Since the pup weights are affected significantly during lactation phase at postnatal day 21, and there is a trend for decrease in pup weight at postnatal day 4, the endpoints selected are considered appropriate for assessing risks to infants and children from this exposure scenario. A target MOE of 100 was selected as adequate for incidental oral exposures based on the conventional uncertainty factor of 100X.

<IP_ADDRESS> Common Toxicological Endpoints for Aggregate Exposure & Risk When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from oral, dermal and inhalation exposures. The toxicity endpoints selected for these routes of exposure may be aggregated if there are common toxicity endpoints ( clinical signs) via these routes. However, since the toxicity endpoints selected for oral and inhalation routes of exposure are not common, the risk may not be aggregated for piperonyl butoxide uses.

3.4 Endocrine Disruptor Effects EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may Page 22 of 61 have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP). In the available toxicity studies on piperonyl butoxide, there was no toxicologically significant evidence of endocrine disruptor effects.

When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, piperonyl butoxide may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

4.0 DIETARY AND DRINKING WATER EXPOSURE/ RISK ASSESSMENT 4.1 Summary of Registered Uses The food/ feed uses of piperonyl butoxide which are being supported by the Piperonyl Butoxide Task Force II for reregistration include; preharvest and postharvest uses on agricultural crops, direct and indirect treatments of livestock animals and premises, treatments of commercial and industrial facilities and storage areas where raw and processed food/ feed commodities are stored or processed, and mosquito abatement on agricultural fields, including aquatic areas. BEAD provided a screening estimate of usage based on 1997  2001 data from OPP's principal agricultural pesticide usage databases. Based on BEAD's estimates the highest usage of piperonyl butoxide is on potatoes ( 30% crop treated) with all other uses at 5% or less. Page 23 of 61 4.2 Dietary Exposure/ Risk Pathway 4.2.1 Residue Profile <IP_ADDRESS> Nature of the Residue  Plants and Livestock Plants The registrants have submitted acceptable plant metabolism studies on lettuce, cotton, and potatoes. The nature of the residue in plants is adequately understood. The HED Metabolism Assessment Review Committee ( MARC) concluded the terminal residues of concern in plants ( i. e., residues that need to be regulated or included in the tolerance expression) is piperonyl butoxide per se) ( T. Morton, D304469, 6/ 30/ 04). Metabolism studies conducted on lettuce, cotton, and potato indicated that parent is the only major residue (> 10% total radioactive residue ( TRR)). However, all the plant metabolism studies are poorly conducted in that only 20  40 % of the TRR were successfully identified. Only the lettuce study firmly identified any metabolites. The latter represented conjugates in which the polyether side chain had been hydroxylated or cleaved at one of the ether linkages. These conjugates are similar to some metabolites observed in the rat. MARC does not believe that these metabolites will be significantly more toxic than the parent, but can not exclude them as being significantly less toxic. Since these metabolites were present in lettuce at about the same level as the parent, MARC suggested that the risk assessment team use 2X the parent residue levels for risk assessment, unless field trial data on metabolites on related crops indicate as lower ratio is appropriate. For tolerance expression, parent only is adequate to serve as the misuse indicator.

Piperonyl butoxide is currently exempt from the requirements of tolerances when applied to growing crops in accordance with good agricultural practices ( 40 CFR § 180.1001( b)( 4)). Results of studies submitted by the Task Force II on preharvest uses for some crops ( based on a reduced number of field trials) show detectable and variable residues of piperonyl butoxide in/ on nearly all raw agricultural commodities tested. Therefore, additional residue data reflecting preharvest uses are required for reregistration and tolerance reassessment. When the requested data have been evaluated, HED will recommend revocation of the tolerance exemption in 40 CFR § 180.1001( b)( 4) along with the establishment of crop group tolerances, if appropriate. The established tolerances for plant commodities, resulting from postharvest uses, are currently expressed in terms of piperonyl butoxide per se. Plant tolerances range from 0.25 ppm ( potato and sweet potato) to 20 ppm ( most cereal grains). The available data are inadequate to support many of the established tolerances resulting from postharvest uses, and additional data are required.

Livestock The HED MARC concluded the terminal residue of concern in livestock is piperonyl butoxide per se. The qualitative nature of the residue in ruminants and poultry, resulting from Page 24 of 61 dermal treatments, is adequately understood. However, the nature of the residue in ruminants and poultry, resulting from oral treatments, is only partially understood. The oral metabolism studies may be upgraded to acceptable status pending further characterization/ identification of radioactive residues in certain matrices/ fractions ( data are under review) and radiovalidation of the enforcement or data collection method using samples from either the dermal or oral studies. The metabolism of PBO in lactating goat and hen poultry following dermal administration indicated that parent is the major metabolite (> 30% TRR except for goat kidney and liver). There are no specific toxicity concerns for all metabolites, which with few exceptions were present at < 10% TRR. Since the major route of exposure would most likely come from dermal treatment of livestock with piperonyl butoxide, MARC concluded that parent only is the residue of toxicological concern to be included in risk assessment and tolerance expression .

Tolerances of 0.25 ppm for milk fat, reflecting negligible residues in milk, and 0.1 ppm for the fat, meat, and meat byproducts of cattle, goats, hogs, horses, and sheep have been established. Tolerances of 1 ppm for eggs and 3 ppm for the fat, meat, and meat byproducts of poultry have been established. Additional data are required to reassess the established livestock commodity tolerances and estimate residues from all possible exposure scenarios which include direct application to livestock, premise treatment, and feeding of piperonyl butoxide treated livestock feed.

<IP_ADDRESS> Residue Analytical Method Plant Commodities The Pesticide Analytical Manual ( PAM) Volume II lists a colorimetric method ( Method II) for the enforcement of tolerances for residues of piperonyl butoxide per se in/ on plant commodities. An improved method, HPLC/ fluorescence method has been proposed to replace the existing colorimetric method. The new method can separately determine residues of piperonyl butoxide per se and piperonyl butoxide metabolites collectively determined as hydroxymethyl dihydrosafrol ( HMDS). The HPLC/ fluorescence method has been subjected to a successful independent laboratory validation and has been forwarded to ACL/ BEAD for method validation by Agency chemists. The data collection method used for the analysis of samples, harvested from recent studies pertaining to magnitude of the residue and storage stability studies, was the same HPLC/ fluorescence method.

Livestock Commodities Under Section 180.127, PAM Volume II lists several methods for the enforcement of tolerances for residues of piperonyl butoxide per se in animal commodities. The gas liquid chromatography methods ( Method I and Methods A and B) are preferred over the colorimetric methods ( Methods C and D). Using the GLC methods, residues in samples of milk and tissues are extracted with a mixture of ethyl alcohol, ether, and hexane. Determination is by GLC equipped with flame ionization detector for Methods I and B, and electron capture detector for Page 25 of 61 Method A. The sensitivity of each method is 0.005 ppm. A new GC/ MS method has been proposed for enforcement of piperonyl butoxide tolerances in livestock commodities. The LOQ is 0.01 ppm in milk and eggs and 0.05 ppm in livestock tissue.

<IP_ADDRESS>Multiresidue Methods According to PAM Volume I, piperonyl butoxide per se is completely recovered by multiresidue method Protocols A and D. A recent submission confirms that head lettuce gave acceptable recoveries for piperonyl butoxide per se when taken through the complete method in Protocol A using 401E1 + C1 + DL2.

<IP_ADDRESS> Storage Stability Data Plants The registrant has submitted the results of several studies which depict the freezer storage stability of piperonyl butoxide in/ on oilseeds, nonoily grains, leafy vegetables, root crops and fruits and fruiting vegetables. The available data indicate that fortified residues of piperonyl butoxide per se are reasonably stable under frozen storage conditions in some commodities but residues may also decline in some matrices. The Agency will make appropriate adjustments of maximum residues observed in the field trials, if needed, in order to compensate for losses resulting from storage. Storage stability data for piperonyl butoxide per se are required for oilseeds, nonoily grains, and root crops. The requested data for oilseeds and root crops should reflect maximum intervals of 30 and 21 months, respectively, and data for nonoily grains should reflect the storage intervals of samples from the outstanding field trials.

Processed Commodities Data on the storage stability of piperonyl butoxide residues on some processed commodities have been submitted. These data indicate that fortified residues of piperonyl butoxide per se are reasonably stable under frozen conditions for up to 12 months in bean cannery waste; tomato juice, puree, and wet and dry tomato pomace; orange juice, dried pulp, and molasses; and cotton meal, soapstock, and crude oil. The available data do not fully support the maximum intervals and conditions of samples from existing tomato, orange, and cotton processing studies. Therefore, additional storage stability data for the processed commodities of oilseeds, grains, and fruits/ fruiting vegetables are required. The requested data for the processed commodities of fruits/ fruiting vegetables and oilseeds should reflect a maximum interval of 31and 32 months, respectively. The Piperonyl Butoxide Task Force II has indicated that a storage stability study for many processed food/ feed items is ongoing. Page 26 of 61 Livestock Commodities No storage stability data are available for piperonyl butoxide residues of concern in milk, eggs, and livestock tissues. Therefore, storage stability data as well as information pertaining to the storage conditions and intervals of samples have been requested by HED Storage stability data is required to support the storage intervals and sample conditions from the following submitted studies; feeding studies for dairy cattle and poultry, cattle dermal study, and poultry premise study. For the dairy cattle and poultry oral feeding studies, the data should reflect the actual storage conditions of the samples, and therefore should include frozen storage as tissue/ eggs/ milk, storage as the dried extract, and storage as the reconstituted extract.

Water Water storage stability data indicate that fortified residues of piperonyl butoxide are reasonably stable in potable water under frozen storage conditions for up to  18 months. The collected potable water samples from the submitted field residue trials were stored frozen for  19 23 months prior to residue analysis. The registrants have indicated that additional fortified potable water samples will be analyzed to encompass the maximum storage interval of samples from the field trials.

<IP_ADDRESS>Magnitude of the Residue in Plants Overall, the available magnitude of the residue data for supported food/ feed commodities are inadequate to support these uses, and therefore, additional data are required for reregistration. The number of trials required to support preharvest uses is listed in the Product and Residue Chemistry assessment ( T. Morton, D288366, 6/ 29/ 04). Requirements are based on OPPTS 860.1500 GLN for data needed to establish crop group tolerances. Since the bulk of piperonyl butoxide end use products sold in the market are likely applied to field growing crops, the majority of the required trials reflect this use pattern. However, HED cannot estimate the residues expected following applications to greenhouses because data are not available. Therefore, the Agency recommends that additional side by side trials be conducted to determine the magnitude of residues from applications to greenhouse grown crops ( e. g., lettuce, pepper, and tomato). The postharvest uses of piperonyl butoxide on many crop commodities are also not supported by adequate residue data. The Agency prefers that residue data reflecting both preharvest uses and postharvest uses be submitted for crops with both uses.

Piperonyl butoxide is currently exempt from the requirements of tolerances when applied to growing crops in accordance with good agricultural practices ( 40 CFR § 180.1001( b)( 4)). When the requested data have been evaluated, HED will recommend revocation of the tolerance exemption and the establishment of crop group tolerances if appropriate. Page 27 of 61 <IP_ADDRESS>Magnitude of the Residue  Food Handling Adequate data on the magnitude of residues of piperonyl butoxide per se in food handling establishments and food storage areas are available. These data indicate that the established tolerance of 10 ppm will not be exceeded in representative food commodities and surfaces that had been covered during treatments using representative formulations. The Piperonyl Butoxide Master Label provides adequate instructions for removing or covering food during treatment, and for covering all food processing surfaces treatment and/ or thoroughly cleaned surfaces after treatment and before use.

No data are available to support uses of piperonyl butoxide on foods stored in multiwalled paper or cloth bags, and additional data are required for reregistration. The required data should depict the magnitude of residues of concern in representative food types stored in multiwalled paper or cloth bags following surface treatments followed by space treatments followed by bag/ container treatments at the maximum use rate for each application type. The bag/ container treatments should be in accordance with the conditions and specifications listed in 40 CFR § 180.127. Alternatively, the use of piperonyl butoxide on foods stored in multi walled paper or cloth bags may be removed from all product labels along with the revocation of the associated tolerance.

<IP_ADDRESS>Magnitude of the Residue in Processed Food/ Feed Studies depicting magnitude of the residues of piperonyl butoxide per se in the processed commodities of cotton, grape, orange, potato, sugar beet, and tomato are considered adequate pending submission of supporting storage stability data. These studies indicate that piperonyl butoxide may concentrate in certain processed commodities. At this time, HED is unable to recommend appropriate tolerance levels for processed commodities which showed residue concentration because the nature of the residue in plants has not been determined and the highest average field trial residue values for many crop commodities have not been determined. Processing studies for apple, barley, coconut, corn ( field), fig, flax, oat, peanut, pineapple, plum, rice, rye, and sorghum are required for reregistration. The required data should depict magnitude of residues of concern in each of the processed commodities for each of these crops. A wheat processing study has been submitted but deemed incomplete because no data were provided for wheat bran, middlings, shorts, and germ. A new wheat processing study is therefore also required for reregistration. The Piperonyl Butoxide Task Force II has indicated that a storage stability study for many processed food/ feed items is ongoing.

<IP_ADDRESS>Magnitude of the Residue in Meat, Milk, Poultry, and Eggs Based upon the initial results of studies depicting the magnitude of the residue in animals and observed residues in feedstuff from preharvest trials, piperonyl butoxide residues of concern are expected to occur in meat, milk, poultry, and eggs. Submitted ruminant studies reflecting dermal and oral treatments have been reviewed and deemed inadequate but upgradeable. The Page 28 of 61 reviewed studies suggest that the established tolerances for milk and ruminant tissues are too low. A premise spray treatment study with ruminants is also now required for reregistration because the results of the reviewed premise study with poultry suggest that detectable residues at or near the tolerance levels are expected at 1X. Submitted poultry studies reflecting oral and premise spray treatments have been reviewed and deemed inadequate but upgradeable. In addition, a study reflecting dip treatment of piperonyl butoxide on laying hens was reviewed and determined to be inadequate because it does not reflect the supported maximum use rate for direct application to poultry. Therefore, a study reflecting direct applications on poultry using a 10% dust formulation is required for reregistration.

HED would have preferred that the magnitude of the residue study for livestock reflect all possible exposure scenarios which include direct application to livestock, premise treatment, and consumption of treated feed. The Agency will add the residues from all possible exposure routes when the additional requested data have been submitted and reviewed.

<IP_ADDRESS> Magnitude of the Residue in Water, Fish, and Irrigated Crops Under current policy, EPA is not establishing tolerances for pesticides in potable water and no maximum contaminant level ( MCL) for piperonyl butoxide in potable water has been established. The Task Force II has submitted data depicting magnitude of the residue of piperonyl butoxide per se in potable water from trials conducted in aquatic environments simulating uses of the pesticide in flooded rice fields. In its review of the study, HED concluded that if the aquatic uses of piperonyl butoxide and pyrethrins are limited to flooded rice fields for the control of adult mosquitos only, then the reregistration requirements for GLN 860.1400 will be considered fulfilled pending label amendments to specify a minimum holding interval or EPA's Office of Water may wish to establish an MCL for piperonyl butoxide in potable water.

<IP_ADDRESS> Confined and Field Accumulation in Rotational Crops A confined rotational crop study ( OPPTS 860.1850) is required to determine the nature and amount of pesticide residue uptake in rotational crops as well as appropriate rotational crop restrictions. A field accumulation study in rotational crops ( OPPTS 860.1900) is required if the level of the total radioactive residue in the confined rotational crops is equal to or exceeds 0.01 ppm at the desired rotational interval or at 12 months, whichever is shorter, and once the nature of the residue in the rotational crops is understood.

<IP_ADDRESS> Codex Harmonization The Codex Alimentarius Commission has established several maximum residue limits ( MRLs) for residues of piperonyl butoxide. The Codex MRLs are expressed in terms of Piperonyl butoxide per se which is identical to the current U. S. tolerance expression. A numerical comparison of the Codex MRLs and the corresponding current U. S. tolerances for piperonyl Page 29 of 61 butoxide is presented in the Product and Residue Chemistry assessment ( T. Morton, D288366, 6/ 29/ 04).

4.2.2 Dietary Exposure/ Risk Assessment <IP_ADDRESS> Consumption Data and Dietary Risk Analysis Piperonyl butoxide chronic dietary exposure assessments were conducted using two peer reviewed software models, the Lifeline   model ( Version 2.0), and the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEM FCID   , Version 2.03). Both models incorporate consumption data from USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII), 1994 1996 and 1998. The 1994 96, 98 data are based on the reported consumption of more than 20,000 individuals over two non consecutive survey days.

The Lifeline   and DEEM   programs convert raw agricultural commodity ( RAC) residues into residues in/ on foods as eaten or consumed based on recipes of raw ingredients for each food item. Lifeline   converts the RAC residues by randomly selecting a RAC residue value from the residue distribution and calculating a net residue for that food based on the ingredients' mass contribution to that food item. Lifeline   models the individuals's dietary exposures over a season by selecting a new CSFII diary each day from a set of similar individuals based on age and season attributes and grouping the dairies based on age and the season. This probabilistic methodology is used to estimate both acute and chronic dietary exposures in Lifeline   .

In DEEM   , consumption data are averaged for the entire U. S. population and within population subgroups for chronic exposure assessment, but are retained as individual consumption events for acute exposure assessment. DEEM   estimates chronic dietary exposure by estimating the residue level in each treated food/ food form, multiplying that estimate by the average daily consumption estimate for that food/ food form, and summing residue intake estimates for all food/ food forms to arrive at a total average estimated exposure. For acute exposures DEEM   uses individual on day food consumption data on an individual by individual basis. The reported consumption amounts of each food item are matched in multiple random pairings with reside values and them summed in a probabilistic acute dietary exposure assessment.

Both the acute and chronic dietary exposure/ risk analyses for piperonyl butoxide were conducted using a highly refined dietary exposure assessment for all supported food uses. USDA Pesticide Data Program ( PDP) data were used for commodities which have a preharvest registered uses and for cereal grain crops which have a stored grain use. All other commodities were assigned residues from either the simulated warehouse space spray experiment or the simulated restaurant experiment. Residue data from dermal treatment of livestock studies were used for meat, milk poultry, and eggs because dermal treatment of livestock is the most likely route of exposure for humans. For risk assessment purposes, the terminal residues of concern for plants include the parent and a factor to account for metabolites. Based on recommendations Page 30 of 61 from the HED MARC, residues were estimated at 2X the parent residue to account for metabolites unless field trial data on metabolites on related crops indicate that a lower ratio is appropriate. For risk assessment purposes, the terminal residue of concern in livestock is piperonyl butoxide, per se. Available data from processing studies were used for processed commodities. Percent crop treated ( CT) was used for all commodities for which % CT data are available. Where no percent CT data are available, the dietary analyses assumes 100% CT. ( T. Morton, 6/ 30/ 04, D296887).

<IP_ADDRESS> Acute Dietary Exposure/ Risk Assessment The highly refined probabilistic acute dietary exposure assessment was conducted for all supported piperonyl butoxide food uses and dietary risk estimates are provided for the general U. S. population and various population subgroups. This assessment concludes that for all supported commodities, the acute dietary exposure estimates are below HED's level of concern. The acute dietary exposure estimate for the highest exposed population subgroup, children 1 2 years of age, is 20% of the aPAD. Results of the acute dietary exposure analysis are presented in Table 6.

Table 6. Piperonyl Butoxide Acute Dietary ( Food) Exposure Estimate and Percent of Acute RfD Population Subgroup aPAD ( mg/ kg/ day) Exposure ( mg/ kg/ day) 99.9th percentile % aPAD 99.9th percentile DEEM FCID Lifeline DEEM FCID Lifeline General U. S. Population 6.3 0.2825 0.3761 4 6 All Infants (< 1 year old) 0.1550 0.3908 2 6 Children 1 2 years old 0.6473 1.2296 10 20 Children 3 5 years old 0.4805 0.8027 8 13 Children 6 12 years old 0.3639 0.4112 6 7 Youth 13 19 years old 0.2005 0.3446 3 5 Adults 20 49 years old 0.1772 0.3030 3 5 Adults 50+ years old 0.1818 0.2865 3 5 Females 13 49 years old 0.1768 0.3467 3 6 <IP_ADDRESS> Chronic Dietary Exposure/ Risk Assessment The highly refined chronic dietary exposure assessment was conducted for all supported piperonyl butoxide food uses for the general U. S. population and various population subgroups. This assessment concludes that for all supported commodities, the chronic dietary exposure estimates are below HED's level of concern. The chronic dietary exposure estimate for the highest exposed population subgroup, children 1 2 years of age, is 12% of the cPAD. Results of the chronic dietary exposure analysis are presented in Table 7. Page 31 of 61 Table 7. Piperonyl Butoxide Chronic Dietary ( Food) Exposure Estimate and Percent of Chronic RfD Population Subgroup cPAD ( mg/ kg/ day) Exposure ( mg/ kg/ day) % cPAD DEEM FCID Lifeline DEEM FCID Lifeline General U. S. Population 0.155 0.0078 0.0075 5 5 All Infants (< 1 year old) 0.0034 0.0057 2 4 Children 1 2 years old 0.0182 0.0185 12 12 Children 3 5 years old 0.0169 0.0163 11 11 Children 6 12 years old 0.0130 0.0117 8 8 Youth 13 19 years old 0.0062 0.0059 4 4 Adults 20 49 years old 0.0063 0.0064 4 4 Adults 50+ years old 0.0060 0.0066 4 4 Females 13 49 years old 0.0063 0.0070 4 5 4.3. Drinking Water Exposure/ Risk Pathway 4.3.1. Environmental Fate Assessment Environmental fate studies indicated that piperonyl butoxide is moderately mobile in soilwater systems. Lab studies indicated that piperonyl butoxide degrades in the environment by photolysis in water ( half life 8.4 hours), and is metabolized by soil microorganisms ( half life 14 days). The aqueous photolysis route may be significant for piperonyl butoxide due to its use in mosquito control applications over intermittently flooded areas. The major degradates of piperonyl butoxide are piperonyl butoxide alcohol,  aldehyde, and  acid ( Attachment 1). These degradates are expected to be more soluble in water and therefore more mobile in soil water systems than the parent, based on their lower molecular weights and hydrophilic moieties. Based on the structural similarity, HED's MARC believes that these three degradates will likely share the same toxicity as the parent. Therefore, MARC recommended that these three degradates be included in the drinking water assessment. There are no specific toxicity concerns for all other minor metabolites ( T. Morton, D304469, 6/ 30/ 04).

4.3.2 Estimated Environmental Concentrations Monitoring data are not available to assess residues of piperonyl butoxide and piperonyl butoxide in drinking water. Therefore, the EFED performed a Tier I drinking water assessment for piperonyl butoxide in surface water and groundwater ( W. Eckel, D286223, 5/ 17/ 04). EFED used the FIRST model for estimating the upper bound on the concentrations that could occur in surface water source drinking water, and the SCI GROW model to estimate the concentrations in ground water used for drinking water. The drinking water assessment focuses on the terrestrial agricultural uses of piperonyl butoxide since they are considered more likely to contaminate drinking water sources. The cranberry, mosquito adulticide and carp bait uses are not considered, although each has the potential to contaminate water, because EFED does not have standard Page 32 of 61 methods for estimating drinking water contamination from these use patterns. Estimated drinking water concentrations are presented in Table 8.

Table 8. Drinking Water EDWCs for Piperonyl Butoxide Drinking Water Source Acute ( ug/ L) Chronic( ug/ L)

Surface Water 240 60 Groundwater 0.26 0.26 <IP_ADDRESS> Surface Water The FIRST model was used to estimate environmental concentrations in drinking water from surface water. FIRST is a screening model and produces upper bound values of drinking water concentrations. It is based on a real reservoir in Illinois. It is a single event model which assumes that a single run off moves a percentage of the applied pesticide into the pond. Input parameters used for the surface water analysis are summarized in Table 9. The peak and mean surface water EDWCs for piperonyl butoxide are 240 and 60 ug/ L respectively.

<IP_ADDRESS> Groundwater EFED used the Screening Concentration in Ground Water ( SCI GROW) model to estimate piperonyl butoxide concentrations in groundwater contaminated by terrestrial uses. SCIGROW is a regression based model that uses few input parameters: pesticide's organic carbon partition coefficient ( K oc ), aerobic soil degradation half life, and product label application rate and frequency ( Barrett, 1997). It provides a groundwater screening concentration for use in determining potential risk to human health from drinking water contaminated with a pesticide. The groundwater concentration is estimated based on the maximum application rates in areas where groundwater is exceptionally vulnerable to contamination. These vulnerable areas are characterized by high rainfall, rapidly permeable soil, and shallow aquifer. Input parameters are summarized in Table 9. The peak and mean groundwater EDWCs for piperonyl butoxide are 0.26 ug/ L.

Table 9. FIRST and SCI GROW Input Parameters for Piperonyl butoxide Input Parameter Value Application Rate 0.5 lb, ten times, at 3 day intervals Application type Aerial spray ( 16% drift) or ground spray ( 6.4% drift) Unincorporated Laboratory Soil Metabolism Half life 73 days ( 3 x single value of 24.2 days)

Laboratory Aerobic Aquatic Metabolism Half life 399 days ( 3 x single values of 133 days)

Laboratory Hydrolysis Half life ( pH 7) stable Laboratory Aqueous Photolysis Half life 5.07 days Table 9. FIRST and SCI GROW Input Parameters for Piperonyl butoxide Input Parameter Value Page 33 of 61 Soil Water Partitioning Coefficient ( Koc) FIRST: 399 ( lowest non sand Koc) SCI GROW: 599 ( median Koc)

Solubility 14.3 ppm ( parent)

Percent Cropped Area 87%

5.0 RESIDENTIAL EXPOSURE AND RISK Based on the Master Label, 14 residential exposure scenarios have been assessed for this RED. Only inhalation and incidental ingestion exposure assessments have been conducted for the residential scenarios. Dermal exposures were not assessed because no dose or endpoints were selected for dermal exposure. Acute, and short and intermediate term exposures are expected/ assessed for residential exposure scenarios based on use and exposure patterns. Acute exposures are assessed for post application inhalation exposure to aerial and curbside mosquito abatement applications and for exposures during and after application of aerosol space sprays indoors. Short and intermediate term exposures are assessed for all other handler and postapplication exposure scenarios. ( B. Daiss, D313107, 8/ 05; M Crowley, D315334, 8/ 05)

5.1 Residential Exposure Scenarios The residential exposure assessment includes three handler and eleven post application residential exposure scenarios. The term " handler" applies to individuals who mix, load, and apply the pesticide product. The term " post application" describes individuals who are exposed to pesticides after entering areas previously treated with pesticides. Based on information provided in the Master Label regarding current registrant supported uses, HED assessed the following residential exposure scenarios for the piperonyl butoxide RED.

Application of dust with shaker can, bulb duster, and power duster, a relevant and potentially significant exposure scenario, was not assessed due to lack of dust specific or adequate surrogate data on inhalation exposure associated with this activity. Additionally, HED did not conduct a quantitative assessment of potential exposure from indoor misters due to data limitations. However, HED recommends that the use restrictions, both general and specific, prescribed by the master label be required for all labels for indoor misters that contain PBO. These restrictions include the following: general use restrictions  do not apply when other persons are present, do not apply when pets ( except fish) are present, remove or cover exposed food and wataer before application, remove or cover dishes, utensils, food processing equipment, and food preparation surfaces or wash them thoroughly before use, do not breathe dust, vapors, or spray mist; specific metered release application use restrictions  do not use in nurseries or rooms where infants, ill or aged persons are confined, do not place metering device directly over or within 8 feet of exposed foods, dishes, utensils, food processing equipment, and food handling or prepartion areas. It should be noted that a screening assessment of indoor misters was Page 34 of 61 conducted for the pyrethrin risk assessment. HED believes the pyrethrin assessment provides support for the label restrictions listed above for indoor misters. ( T. Dole, D318630, 9/ 05)

5.1.1 Handler Exposure Scenarios 1) Mixing, loading, and applying liquid spray formulation by low pressure handwand for indoor surface spray application 2) Mixing, loading, and applying liquid spray formulation by low pressure handwand for indoor crack and crevice treatment 3) Mixing, loading, and applying liquid spray formulation by hose end sprayer for lawn and garden application 4) Mixing and loading liquid formulations for the systems' holding tanks for outdoor automatic mister systems 5.1.2 Postapplication Exposure Scenarios 1) Inhalation exposure from application of mosquito adulticide from fixed wing aircraft and/ or helicopter 2) Inhalation exposure from application of mosquito adulticide from ULV truck mounted sprayer 3) Toddler incidental ingestion of residue from treated turf grass via hand to mouth activities 4) Toddler incidental ingestion of residue via object to mouth activity while on treated turf grass 5) Toddler incidental ingestion of soil from treated area 6) Toddler incidental ingestion of residues deposited on carpet via hand to mouth activities after use of total release foggers 7) Toddler incidental ingestion of residues deposited on vinyl flooring via hand to mouth activities after use of total release foggers 8) Toddler incidental ingestion of residues on pets via hand to mouth activities after pet treatment 9) Inhalation exposure to aerosol spray during and after space spray application 10) Bystander acute inhalation exposure during outdoor automatic mister applications 11) Bystander short term inhalation exposure during outdoor automatic mister applications 5.2 Residential Exposure Data and Assumptions 5.2.1 Application Parameters Application rates for all of the exposure scenarios assessed are based on information provided in the Piperonyl Butoxide Master Label submitted to the Agency by the Piperonyl Butoxide Task Force II in February 2003. The Master Label provides application parameters including type of application, maximum application rate or concentration, and use restrictions pertinent to human exposure and environmental exposure. The Piperonyl Butoxide Master Label Page 35 of 61 lists all of the uses that the Piperonyl Butoxide Task Force II members are supporting. Therefore, it is important all labels be revised to reflect the supported uses and maximum allowable application rates provided in the Master Label. For the outdoor automatic mister scenario, the application rate ( lb ai/ gal soln) used is from a product label assumed to represent typical automatic mister systems.

5.2.2 Handler Exposure Data It is the policy of the HED to use data from the Pesticide Handlers Exposure Database ( PHED) or Occupational and Residential Exposure Task Force ( ORETF) data to assess handler exposures for regulatory actions when chemical specific monitoring data or other handler specific data are not available. PHED was designed by a task force of representatives from the US. EPA, Health Canada, the California Department of Pesticide Regulation, and members of the American Crop Protection Association. Currently, the database contains values for over 1,700 monitored individuals ( i. e., replicates). The ORETF completed four studies which were designed to provide representative surrogate exposure data for pesticide handler risk assessment. The studies monitored professionals applying granular formulation by push spreader and various formulations by pressurized hose end " handgun" or spray gun; and volunteers representing non professional consumers applying granular formulation by push spreader and liquid formulations by garden hose end sprays. Overall, the four ORETF studies were well conducted and the data for all scenarios is considered of better quality and quantity than what is currently contained in PHED.

Data from the PHED and/ or ORETF data bases were used to assess residential handler exposures. Default application assumptions regarding areas treated or amounts applied for residential handler scenarios are documented in the HED Science Advisory Committee on Exposure SOP 12: " Recommended Revisions To The Standard Operating Procedures For Residential Exposure Assessment" ( 2/ 22/ 2001).

5.2.3 Post application Exposure Data <IP_ADDRESS> HED Residential Exposure SOPs The default factors used for the assessment are taken from the Exposure Science Advisory Committee SOP 12. SOP 12 provides values to assess post application inhalation and non dietary ingestion exposure to lawn care pesticides, and indoor broadcast and crack and crevice treatments.

<IP_ADDRESS> Non Dietary Exposure Task Force Exposure Data Primary assumptions for assessing post application exposure to use of foggers and aerosols in indoor residential settings were based on data provided by the Non Dietary Exposure Task Force ( NDETF). The NDETF was formed in 1996 from members of the Pyrethrin Joint Page 36 of 61 Venture ( PJV) and Piperonyl Butoxide Task Force II, Task Forces set up in the 1980s by producers, formulators, and marketers of the AIs to respond to reregistration needs. NDETF includes; Bayer CropSciences, Botantical Resources Australia, Endura S. p. A, McLaughlin Gormley King Company, Pyrethrum Board of Kenya Prentiss Inc., S. C. Johnson and Son, Inc., and Valent BioSciences Corporation. NDETF's purpose is to produce scientifically sound data on non dietary exposures to pyrethrin, the pyrethroids, piperonyl butoxide, and MGK 264.

<IP_ADDRESS> Spray Drift Task Force Exposure Data HED used the AgDRIFT model to calculate airborne concentrations from aerial ULV applications. The model was developed by the Spray Drift Task Force, a coalition of pesticide registrants whose primary objective was to develop a comprehensive data base of off target spray drift information along with an appropriate modeling system. The model has been peer reviewed by EPA's Science Advisory Panel and has been used in previous mosquito adulticide exposure assessments ( e. g. carbaryl, malathion).

5.2.4 Exposure Assumptions The following assumptions were used in estimating risks from residential exposure to piperonyl butoxide:

° Average body weight of an adult is 70 kg ° Average body weight of an toddler is 15 kg ° Exposure is assessed on day of application ( i. e., day zero) ° Exposure duration is short and intermediate term unless otherwise indicated ( i. e., acute exposures for mosquito and indoor space spray scenarios) ° Maximum application rates as provided by the Piperonyl Butoxide Task Force II were used for all types and methods of application For outdoor automatic mister systems, application rates ( lb ai/ ft3) from product labels are assumed to represent typical automatic systems ° Maximum daily volumes handled and/ or area treated are as follows  0.5 acre is used to represent the surface area treated for broadcast applications to lawns using garden hose end sprayer;  average home treated with space spray or crack and crevice treatment has 1600 square feet of surface area  holding tank size for outdoor automatic mister systems is 55 gallons and 250 gallons based on information provided to SRRD from the registrants. It is assumed that a homeowner can prepare the dilute solution and re fill the holding tank; 1 holding tank is filled per day. ° Mosquito Abatement Scenario  for aerial application @ fixed wing aircraft release height is 100 feet @ rotary aircraft release height is 30 feet Page 37 of 61 @ average droplet size is 50 microns ( per label and/ or Public Health Pesticide Applicator Manual ( 25 50 microns))

@ wind speed is 2 mph ( per label and/ or Applicator Manual (< 10 mph))

@ temperature is 86 ° F ( per label and/ or pesticide Applicator Manual ( 50 95 ° F))  for truck mounted ULV spray application a dilution factor of 0.01 is applied to the airborne concentration at the maximum application rate ( i. e., 1% of product released is available for exposure)  breathing zone airborne concentration is estimated to be approximately 4 6 ft from the ground  adult breathing rate is 1.0 m3 per hour; child breathing rate is 0.8 m3 per hour ( NAFTA breathing rates for light activity)  exposure duration is < 2 hours  exposure is assessed as an acute exposure ° Toddler Outdoor ( turf) and Indoor Fogger ( carpet and vinyl) Hand to Mouth Scenario  estimated turf transferable residue is assumed to be 5% of the maximum application rate for sprays  indoor surface residue is 10 µ g/ cm2 based on NDETF study data and a maximum application rate of 0.033 lbs ai/ 1000 ft3 for indoor foggers  hand transfer efficiency is 13% for carpet; 8% for vinyl based on NDETF data  saliva extraction factor is 50 percent  surface portion of hand put in mouth is 20 cm2  hand to mouth exposure frequency is 20 times per hour  saliva extraction factor is 50 percent  Exposure duration is 2 hours ° Toddler Object to Mouth Scenario  object to mouth transfer efficiency is equal to 20% of the application rate  ingestion rate of residues from mouthing turf or a small object is 25 cm2 ° Toddler Incidental Soil Ingestion Scenario  soil ingestion rate is 100 mg/ day  fraction of ai available in uppermost cm of soil ( fraction/ cm) is 100 percent based on soil incorporation into top 1 cm of soil after application ° Toddler Pet Treatment Hand to Mouth Scenario  one half of a 16 oz spray container is used to treat each animal  transferable residue from a treated pet is assumed to be 20% of the maximum application rate for sprays  surface area of a treated ( 30 lb) dog is 6000 cm2 ( EPA 1993 Wildlife Exposure Factors Handbook  carbaryl)  saliva extraction factor is 50 percent  surface portion of hand put in mouth is 20 cm2  frequency of hand to mouth events is one per day ( frequency modified to reflect transferable residue assumption which is based on a 5 minute heavy rubbing/ petting technique that would lead to significantly higher hand concentrations than would result from a single contact) Page 38 of 61 ° Inhalation during and after aerosol space spray application  @ one 16 oz spray can containing likely maximum of 2.5% ai is used per application @ one application per home  adult breathing rate is 1.0 m3 per hour; child breathing rate is 0.8 m3 per hour  exposure duration is < 2 hours ° Acute inhalation exposure to residential bystanders from outdoor automatic misters  all active ingredient is assumed to be " thrown up" in the air immediately and available for exposure ( 100% active ingredient available) for the entire exposure duration  adult breathing rate is 1.0 m3 per hour; child breathing rate is 0.7 m3 per hour  nozzle height outdoors is assumed to be 8 feet from the ground  exposure duration is assumed to be 1 minute per day ( 0.0167 hours/ day)   the entire duration of a nozzle spray  exposure is assumed to encompass 1, 1 minute spray event that occurs in the morning or evening ( i. e., exposure is to air concentration following 1, 1 minute spray event). Note: this is assumed to be a conservative estimate for acute exposure duration ( i. e., labels indicate spray durations may be less   20, or 30 seconds) ° Short term inhalation exposure to residential bystanders from outdoor automatic misters  all active ingredient is assumed to be " thrown up" in the air immediately and available for exposure ( 100% active ingredient available) for the entire exposure duration  adult breathing rate is 1.0 m3 per hour; child breathing rate is 0.7 m3 per hour  nozzle height outdoors is assumed to be 8 feet from the ground  exposure duration is assumed to be 5 hours per day for adults and 3 hours per day for toddlers  Exposure is assumed to encompass 2, 1 minute, or 2, 30 second spray events that occur in the morning or evening and are also assumed to occur within the 5 hour or 3 hour exposure duration interval ( i. e., exposure is to total air concentration following 2, 1 minute, or 2, 30 second spray events)

Non Standard Exposure Assumptions Substance and scenario specific data from the NDETF study was used to determine deposition of piperonyl butoxide on vinyl and carpet flooring following use of a total release indoor fogger. Post fogger release floor concentration was estimated based on data from NDETF Study Volume 2, " Post Application Deposition Measurements for Pyrethrins & Piperonyl Butoxide Following Use of a Total Release Indoor Fogger". Transfer of piperonyl butoxide from fogger treated carpet was assumed to be 13% of deposition based on data from Volume 29 of the NDETF Study, " Measurement of Transfer of Permethrin and Piperonyl Butoxide Residues from Vinyl and Carpet Flooring Treated with a Fogger Formulation to DSS Wetted Hands Following a Single Hand Press". Indoor air concentration for the period during and after aerosol space spray application was assumed to be 6 mg per cubic meter based on data from Volume 18 of the NDETF Study, " Measurement of Air Concentration , Dermal Exposure, and Deposition of Pyrethrin and Piperonyl Butoxide Following the Use of an Aerosol Spray". Page 39 of 61 The approach for estimating air concentrations from truck mounted ULV spray applications is based on a modification of the SOP for residential exposure assessment for inhalation exposure from use of an outdoor space spray for pest control.

Specific reference to " automatic mister systems" is not made in the Piperonyl Butoxide Master Label however there is reference to use of PBO in outdoor domestic sites as a general, crack and crevice, or spot surface spray. Four PBO containing products ( EPA Reg. No. 1021 1785, 21165 24,1021 1800, and 655 797) identified in a Consumer Specialty Products Association ( CSPA) discussion paper ( CSPA, 2005), reference specific nozzle spray systems used in outdoor residential sites. The following is additional general use information from the CSPA discussion paper: holding tanks or reservoirs are typically plastic with 30, 55, or 250 gallon capacity; nozzle height is approximately 8   10 feet; nozzle spacing is approximately 10   15 feet apart along fences or foliage ( i. e., perimeter separation); automatic dispersions are set for 2 to 4 times per day for 30 to 60 seconds per event; systems can be activated manually by homeowners.

5.3 Residential Exposure and Risk Estimates A target MOE of 100 is considered adequate for acute exposure via inhalation and for short and intermediate term incidental ingestion exposures. A target MOE of 300 is considered adequate for short and intermediate term inhalation exposures. Mosquito abatement postapplication and indoor aerosol space spray application scenarios are assessed as acute exposures. All other residential handler and post application exposure scenarios are assessed as short and intermediate term exposures. Exposure and risk estimates for each scenario are summarized below and a more detailed summary of risk calculations, critical assumptions, and results is provided in Tables 13 21 on pages 53 56 of this document.

The results of the residential exposure assessment indicate that with one exception, all residential exposure scenarios assessed based on master label specified uses result in MOEs greater than the applicable target MOEs i. e., all but one result in exposures below the level of concern. The short term residential bystander inhalation risk from outdoor automatic misters is the only scenario of concern. Bystander inhalation risk for toddlers is of concern when exposure is to the piperonyl butoxide air concentration resulting from 2, 1 minute spray durations ( MOE Toddlers = 190). When exposure is to 2, 30 second spray durations, risk is not of concern ( MOE Toddlers = 370).

6.0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION The aggregate risk assessment integrates the assessments conducted for dietary, drinking water, and residential exposure. Since there is potential for concurrent exposure via the food, water and residential pathways, the combined exposures are estimated using the methodology described below and are compared with modeling based estimates of drinking water contamination determined by EFED. Page 40 of 61 For the aggregate exposure assessment, DWLOCs were calculated and compared with the estimated drinking water concentrations of piperonyl butoxide in ground water and surface water. The DWLOC is the concentration of a chemical in drinking water that would be acceptable as an upper limit in light of total aggregate exposure to that chemical from food, water, and residential sources. The acute and chronic DWLOCs for piperonyl butoxide consider aggregate exposure from food and water only. The short term DWLOC aggregates exposures from food, water and residential routes associated with application of piperonyl butoxide and is calculated only if there is a common toxicity endpoint for each route of exposure.

6.1 Acute Aggregate Risk Assessment Acute DWLOCs were calculated based on acute dietary exposure estimates and default body weights and water consumption figures. The Agency's default body weight/ water consumption assumptions are 70 kg/ 2 L ( adult male), 60 kg/ 2 L ( youth 13 19 and adult female) and 10 kg/ 1 L ( infants and children < 12 years). To calculate the DWLOC, the acute dietary food exposure is subtracted from the aPAD. Acute DWLOCs and EDWCs are provided in Table 10.

Table 10. Piperonyl Butoxide  Drinking Water Levels of Comparison for Acute Dietary Exposure Population Subgroup Acute PAD ( mg/ kg/ day) Food Exposure ( mg/ kg/ day) 99.9th percentile Acute Water Exposure ( mg/ kg/ day) DWLOC acute* ( ug/ L) Surface Water EDWC ( ug/ L) Ground Water EDWC ( ug/ L)

US Population 6.3 0.38 6 210000 240 0.26 All Infants 0.39 6 59000 240 0.26 Children 1 2 1.23 5 51000 240 0.26 Children 3 5 0.80 5.5 55000 240 0.26 Children 6 12 0.41 6 59000 240 0.26 Youths 13 19 0.35 6 180000 240 0.26 Adults 20 49 0.30 6 210000 240 0.26 Females 13 49 0.35 6 180000 240 0.26 Adults 50+ 0.29 6 210000 240 0.26 * DWLOCacute = [ acute water exposure ( mg/ kg/ day) x ( body weight)] [ consumption ( L) x 10 3 mg/ µ g] where, acute water exposure ( mg/ kg/ day) = [ aPAD  ( acute food ( mg/ kg/ day)]

The EDWCs for both surface water and groundwater are well below the acute DWLOCs for the general U. S. population and all other population subgroups indicating that acute aggregate exposure to piperonyl butoxide in food and water is less than HED's level of concern for these populations.

6.2 Short Term Aggregate Risk Assessment The short term aggregate risk is the estimated risk associated with aggregated risks from Page 41 of 61 average food exposures, average drinking water exposures, and short term oral, dermal and inhalation exposures. The toxicity endpoints selected for the dietary, drinking water , and incidental oral routes of exposure may be aggregated because of the common toxicity endpoints ( decreased body weight gain) via these routes. Inhalation exposures are not included in the short term aggregate risk estimate because the toxicity endpoints selected for the chronic dietary/ drinking water routes of exposure and those selected for inhalation route of exposure are not based on common effects i. e., the chronic dietary endpoint is based decreased body weight gain and liver effects and the short term inhalation endpoint is based on laryngeal hyperplasia and metaplasia. The short term aggregate risk for piperonyl butoxide is calculated by adding exposure estimates from dietary, drinking water, and incidental oral exposure pathways for children age 1 2 and comparing them with model based EDWCs determined by EFED. The calculated short term DWLOC and EDWCs are presented in Table 11.

Table 11. Piperonyl Butoxide  Short Term Aggregate Risk and DWLOC Calculations Population Target Aggregate MOE1 MOE food2 MOE Incidental Oral3 Aggregate MOE ( food & residential) 4 MOE water5 Allowable water exposure6 ( mg/ kg/ day) Ground Water EDWC ( ug/ L) Surface Water EDWC ( ug/ L) DWLOC7 ( ug/ L)

Child 1 2 100 4800 4700 2400 100 0.85 0.26 60 8500 1 Target MOE based on UF of 10 for intraspecies variation and 10 for intraspecies extrapolation 2 MOE food = [( short/ intermediate term incidental oral NOAEL = 89 mg/ kg/ day)/( chronic dietary exposure = 0.0185 mg/ kg/ day)] 3 MOE incidental oral = [( short or intermediate term oral NOAEL = 89 mg/ kg/ day)/( incidental oral residential exposure = 0.019 mg/ kg/ day)]; 4 Aggregate MOE ( food and residential) = 1 ÷ [( 1 ÷ MOE food) + ( 1 ÷ MOE incidental oral)] 5 Water MOE = 1 ÷ [( 1 ÷ Target Aggregate MOE)  ( 1 ÷ Aggregate MOE ( food and residential)] 6 Allowable water exposure = Short or Intermediate Term Oral NOAEL ÷ MOE water 7 DWLOC ( ug/ L) = [ allowable water exposure ( mg/ kg/ day) x body weight ( kg)] BW = 10 kg [ water consumption ( L) x 10 3 mg/ ug] Daily Water Consumption = 1L EFED's model based estimates for average concentrations of piperonyl butoxide in surface and ground water are 60 and 0.26 ppb respectively. The short term DWLOC for children 1 2 years old is 8500 µ g/ L. Since the model based estimates for allowable concentrations in surface water and groundwater are below the calculated short term DWLOC, HED concludes that aggregate exposure to food and drinking water will not result in an unacceptable risk.

6.3 Chronic Aggregate Risk Assessment/ DWLOCs Chronic DWLOCs were calculated based on the chronic dietary exposure estimates and default body weights and water consumption figures. Calculated chronic DWLOCs and EDWCs are provided in Table 11. To calculate the chronic DWLOC, the chronic dietary food exposure is subtracted from the chronic PAD.

Table 12. Drinking Water Levels of Comparison for Chronic Dietary Exposure Population Subgroup Chronic PAD ( mg/ kg/ day) Food Exposure ( mg/ kg/ day) Max. Water Exposure ( mg/ kg/ day) DWLOC ( ug/ L) Surface Water Annual Avg EDWC ( ug/ L) Ground Water Annual Avg EDWC ( ug/ L)

US Population 0.155 0.0078 0.15 5200 60 0.26 Table 12. Drinking Water Levels of Comparison for Chronic Dietary Exposure Population Subgroup Chronic PAD ( mg/ kg/ day) Food Exposure ( mg/ kg/ day) Max. Water Exposure ( mg/ kg/ day) DWLOC ( ug/ L) Surface Water Annual Avg EDWC ( ug/ L) Ground Water Annual Avg EDWC ( ug/ L)

Page 42 of 61 All Infants (< 1 year) 0.155 0.0057 0.15 1500 60 0.26 Children 1 2 years 0.155 0.0185 0.14 1400 60 0.26 Children 3 5 years 0.155 0.0169 0.14 1400 60 0.26 Children 6 12 years 0.155 0.0130 0.14 1400 60 0.26 Youth 13 19 years 0.155 0.0062 0.15 4500 60 0.26 Adults 20 49 years 0.155 0.0064 0.15 5200 60 0.26 Females 13 49 years 0.155 0.0070 0.15 4500 60 0.26 Adults 50+ 0.155 0.0066 0.15 5200 60 0.26 DWLOCchronic = [ chronic water exposure ( mg/ kg/ day) x ( body weight)] [ consumption ( L) x 10 3 mg/ µ g] where, chronic water exposure ( mg/ kg/ day) = [ cPAD  ( chronic food ( mg/ kg/ day)]

The average EDWCs for both surface water ( 60 ug/ L) and groundwater ( 0.26 ug/ L) are less than the chronic DWLOCs, indicating that chronic exposure to piperonyl butoxide in food and water is less than HED's level of concern.

7.0 CUMULATIVE RISK Section 408( b)( 2)( D)( v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider " available information" concerning the cumulative effects of a particular pesticide's residues and " other substances that have a common mechanism of toxicity."

EPA does not have, at this time, available data to determine whether piperonyl butoxide has a common mechanism of toxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to piperonyl butoxide and any other substances and, piperonyl butoxide does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that piperonyl butoxide has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ fedrgstr/ EPA PEST/ 2002/ January/ Day 16/.

8.0 OCCUPATIONAL EXPOSURE AND RISK Page 43 of 61 Based on the Master Label, 31 occupational exposure scenarios have been assessed for this RED. Only inhalation exposures have been assessed for each of the occupational scenarios. Dermal exposures were not assessed because no dose or endpoints were selected for dermal exposure. Short, intermediate, and long term exposures are expected/ assessed for occupational exposure scenarios based on use patterns. Agricultural handler exposures are assessed as shortand intermediate term. Pesticide control operator exposures are assessed as short, intermediateand long term. Mosquito abatement exposures are assessed as short and intermediate term for aerial and backpack spray applications and short, intermediate, and long term for truck mounted ULV spray applications. ( B. Daiss, D313107, 3/ xx/ 04)

8.1 Occupational Exposure Scenarios Only occupational handler scenarios were assessed for the piperonyl butoxide RED. The term " handler" applies to individuals who mix, load, and apply the pesticide product. Occupational post application scenarios were not assessed because there is no endpoint for the dermal exposure, the only relevant route of concern for post application worker exposure. Based primarily on information provided in the Master Label regarding current registrant supported uses, HED assessed the following scenarios for agricultural, professional pest control operator, and mosquito control applications for the piperonyl butoxide RED. Application of dust with shaker can, bulb duster and power duster, a relevant and potentially significant exposure scenario was not assessed due to lack of dust specific or adequate surrogate data on inhalation exposure associated with this activity.

8.1.1 Agricultural Handler Scenarios 1) mixing and loading liquids for aerial and/ or chemigation application to field crops 2) mixing and loading liquids for groundboom application to field crops 3) mixing and loading liquids for airblast application to field crops 4) mixing and loading wettable powders for aerial and/ or chemigation application to field crops 5) mixing and loading wettable powders for groundboom application to field crops 6) mixing and loading wettable powders for airblast application to field crops 7) applying liquids aerially to field crops 8) applying liquids with ground boom sprayer to field crops 9) applying liquids with airblast sprayer to field crops 10) mixing, loading and applying liquids with high pressure hand wand for greenhouse application 11) mixing, loading and applying liquids with backpack sprayer or low pressure handwand for greenhouse application 12) mixing loading and applying wettable powder with backpack sprayer or low pressure hand wand for greenhouse application 13) mixing, loading and applying liquids with backpack sprayer or low pressure hand wand for Page 44 of 61 agricultural premise and equipment application 14) flagging for aerial spray application 8.1.2 Pesticide Control Operator Handler Scenarios 1) mixing, loading and applying liquids indoors for surface spray application with low pressure handwand; 2) mixing, loading and applying liquids indoors for crack and crevice application with low pressure handwand; 3) mixing, loading and applying wettable powders indoors for surface spray application with low pressure handwand; 4) mixing, loading and applying wettable powders indoors for crack and crevice application with low pressure handwand; 5) mixing, loading and applying liquids with backpack sprayer or low pressure hand wand for general outdoor sites; 6) mixing, loading and applying liquids for hand gun sprayer application to lawns; 7) mixing, loading and applying liquids for groundboom application to golf courses 8) mixing, loading and applying liquids for back pack sprayer or low pressure handwand application to stored grain 9) mixing, loading and applying liquids for high pressure handwand application to stored grain 1) mixing, loading and applying liquids for low pressure handwand application to warehouse stored produce 11) applying liquids to golf courses with groundboom sprayer 12) aerosol spray application indoors 13) mixing and loading liquid formulations for the systems' holding tanks for outdoor automatic mister systems 8.1.3 Mosquito Abatement Scenarios 1) mixing, loading liquids for aerial application 2) mixing, loading liquids for ULV truck mounted spray application 3) mixing, loading, applying liquids with truck mounted ULV ground spray ( airblast sprayer unit exposure used as surrogate) 4) mixing, loading, applying liquids with back pack sprayer 8.1.4 Direct Application to Pets and Farm Animals ( by veterinarians and groomers)

C spray application Page 45 of 61 8.2 Occupational Exposure Data and Assumptions 8.2.1 Exposure Data <IP_ADDRESS> Application Parameters Application rates for all of the occupational exposure scenarios assessed are based on information provided in the Piperonyl Butoxide Master Label which lists all of the uses that Piperonyl Butoxide Task Force II members are supporting. Therefore, it is important all labels be revised to reflect the supported uses and maximum allowable application rates provided in the Master Label.

<IP_ADDRESS> Handler Exposure Data Data from the PHED or ORETF data bases were used to assess occupational handler exposures. Default application assumptions regarding areas treated or amounts applied for agriculture and mosquito abatement handler exposure scenarios are documented in the HED Science Advisory Committee on Exposure's SOP 9, " Standard Values for Daily Acres Treated in Agriculture" ( 7/ 5/ 2000). Information on how pest control operators use pesticide products was obtained from a survey conducted by the National Pest Management Association ( NPMA). NPMA sponsored a " Pest Control Operators ( PCO) Product Use and Usage Information Survey".

8.2.2 Exposure Assumptions The following assumptions were used in estimating risks to occupational handlers from exposure to piperonyl butoxide:

° Average body weight of an adult handler is 70 kg ° Exposure duration is short term and intermediate term for agricultural handlers and short, intermediate and long term for PCOs and mosquito control applicators ° Baseline inhalation exposure ( no respiratory protection) ° Maximum application rates as provided by Piperonyl Butoxide Task Force II were used for all types and methods of application; rates used for exposure assessment are provided in Table 3 of the Occupational Exposure Assessment ( B. Daiss, D310033, 11/ 04) Outdoor automatic mister systems  application rate ( lb ai/ gal soln) used is from a product label assumed to represent typical automatic mister systems ( M. Crowley, D315334, 8/ 05) ° Maximum daily volumes handled and/ or area treated used for the scenarios assessed are as follows  aerial applications @ 350 acres per day for typical acreage field crops; 1200 for high acreage field crops ( e. g., corn, rice, wheat)

@ 7500 acres per day for mosquito control adulticide applications  groundboom applications Page 46 of 61 @ 80 acres treated per day for field crops @ 40 acres treated per day for golf course turf  airblast applications  40 acres treated per day for agricultural applications;  ULV truck mounted sprayer  3000 acres treated per day for mosquito control ( airblast used as surrogate)  pet groomer/ veterinary applications @ 8 pet animals are treated per day @ one half of a 16 oz spray container used to treat each animal  high pressure handwand application  10 acres treated or 1000 gallons of spray solution used per day  backpack sprayer or a low pressure handwand sprayer applications @ 2 acres treated or 40 gallons spray solution used per day for agricultural premise/ mosquito control/ general outdoor site applications @ 5 grain storage bins treated per day with cross sectional area of 1000 square feet per bin @ 5 food produce storage warehouses treated per day, area treated per warehouse is 10,000 square feet  pest control operator applications @ a maximum of 7 commercial buildings or residential homes treated per day for general pest control management activities @ average area treated per building is 1600 square feet for surface spray and crack and crevice treatment and 12800 cubic feet for space spray application ( EPA Exposure Factors Handbook)

@ for outdoor automatic mister systems, holding tank size is 55 gallons and 250 gallons based on information provided to SRRD from the registrants; handlers ( i. e., system maintenance workers) are assumed to fill 5 holding tanks per day Non Standard Exposure Assumptions ° Assumptions used for veterinary and grain storage treatments are not included in the Occupational Exposure SOPs but represent values that have been used by the Agency in previous assessments ( e. g., carbaryl, cyfluthrin). ° Assumptions used for daily area treated for produce storage warehouses are based on best professional judgement. ° Assumptions used for general pest control applicators are based data from the NPMA survey. Based on BEAD's review of the NPMA survey, PCOs conducting general pest control activities would treat an average of between 6 and 7 buildings per day, assuming an 8 hour work day. ° Airblast application unit exposure data was used to assess exposure resulting from truck mounted ULV application of mosquito adulticide. In the absence of more equipment specific data, airblast unit exposure data is thought to provide reasonable surrogate exposure information based on the similarity of the two application methods and has been used for this purpose in previous HED occupational exposure assessments ( e. g., carbaryl). Page 47 of 61 ° Specific reference to " automatic mister systems" is not made in the Piperonyl Butoxide Master Label however there is reference to use of PBO in outdoor domestic sites as a general, crack and crevice, or spot surface spray. Four PBO containing products ( EPA Reg. No. 1021 1785, 21165 24,1021 1800, and 655 797) identified in a Consumer Specialty Products Association ( CSPA) discussion paper ( CSPA, 2005), reference specific nozzle spray systems used in outdoor residential sites. The following is additional general use information from the CSPA discussion paper: holding tanks or reservoirs are typically plastic with 30, 55, or 250 gallon capacity; nozzle height is approximately 8   10 feet ( i. e., off the ground); nozzle spacing is approximately 10   15 feet apart along fences or foliage ( i. e., perimeter separation); automatic dispersions are set for 2 to 4 times per day for 30 to 60 seconds per event; systems can be activated manually by homeowners.

8.3 Occupational Exposure and Risk Estimates A target MOE of 300 for the inhalation route is considered adequate for short and intermediate term occupational exposure and risk. A target MOE of 1000 is considered adequate for long term worker exposure via the inhalation route. Agricultural handler exposures are assessed as short and intermediate term. Pesticide control operator exposures are assessed as short, intermediate and long term. Mosquito abatement worker exposures are assessed as shortand intermediate term for aerial and backpack spray applications and short, intermediate, and long term for truck mounted ULV spray applications. Exposure and risk estimates for each scenario are summarized below and a more detailed summary of exposure and risk calculations, critical assumptions, and results is provided in Tables 22 26 on pages 56 61 of this document.

The results of the worker exposure assessment indicate that the following agricultural application exposure scenarios result in MOEs less than the target MOE of 300 for inhalation for short and intermediate term exposure.

 Mixing and loading wettable powders for aerial and/ or chemigation application to field crops. The MOE at the maximum application rate of 0.5 lb ai/ acre for typical acreage field crops is s 40; the MOE for high acreage field crops is 11. MOEs greater than the target MOE of 300 result at an application rate of 0.06 lb ai/ acre for the typical acreage field crop scenario and 0.018 lb ai/ acre for the high acreage scenario.