Docket Number EPA

- HQ-OPP-20 12-0682 www.regulations.gov



# 4-tertiary-Amylphenol and Salts Final Work Plan

Registration Review:

Case Number 3016

March 2013

Approved by:

Date: Susan Lewis Acting Director Antimicrobials Division

Page 1 of43Page 2 of 43 4- tertiary- Amylphenol and Salts Regi stration Review Team

Human Health & Environmental Effects Srinivas Gowda Timothy Dole Zoë Layton Jonathan Chen James Breithaupt Pat Jennings

Risk Management Seiichi Murasaki Lance Wormell

Office of General Counsel Philip RossPage 3 of 43 

### Table of Contents
1 Introduction .................................................................................................................. ........... 4 1.1 Statutory and Regulatory Authority ................................................................................. 4 1.2 Updates to the Work Plan ................................................................................................. 5 1.3 Case Overview ................................................................................................................. 7 1.4 Chemical Identification and Properties ............................................................................ 7 1.5 Use/Usage Description ..................................................................................................... 8 1.5.1 Summary of Regist ered Uses .................................................................................... 8 1.5.2 Usage Information .................................................................................................... 9 1.6 Incidents ..................................................................................................................... ...... 9 1.6.1 Human Health ........................................................................................................... 9 1.6.2 Ecological ............................................................................................................... 10 2 Anticipated Data Needs ........................................................................................................ 10 3 Human Health Risk Assessment ........................................................................................... 13 3.1 Existing Toxicological Endpoints .................................................................................. 13 3.2 Dietary Exposure ............................................................................................................ 1 4 3.2.1 Food ........................................................................................................................ 1 4 3.2.2 Drinking Water ....................................................................................................... 14 3.3 Occupational and Residential Exposures ....................................................................... 15 3.3.1 Occupational Handler Exposure ............................................................................. 15 3.3.2 Residential Handler Exposures ............................................................................... 15 3.3.3 Residential Post-Applic ation Exposures ................................................................. 16 3.4 Aggregate and Cumulative Exposure ............................................................................. 17 3.4.1 Aggregate Exposures .............................................................................................. 17 3.4.2 Cumulative Exposures ............................................................................................ 17 4 Environmental Risk Assessment........................................................................................... 17 4.1 Environmental Conceptual M odel Exposure Pathways ................................................. 17 4.2 Ecological Effects Assessment ....................................................................................... 18 4.2.1 Mechanism of Action .............................................................................................. 19 4.2.2 Measures of Effect (Ecotoxicology Endpoints) ...................................................... 19 4.3 Exposure Analysis Plan .................................................................................................. 21 4.3.1 Aquatic and Terrestrial Wild life Exposure Estimates ............................................ 21 4.3.2 Screening Level Down-the-Drain Analysis ............................................................ 21 4.4 Effects Analysis Plan ..................................................................................................... 22 5 Endocrine Disruptor Screen ing Program (EDSP) ................................................................. 22 6 Next Steps .................................................................................................................... ......... 23 7 References .................................................................................................................... ......... 24

Appendix A Toxicology Profile ............................................................................................... 26 Appendix B Environmental Fate ............................................................................................. 30 Appendix C Ecotoxicology Profile .......................................................................................... 32 Appendix D Screening Level Down-the-Drain Analysis ........................................................ 40 Appendix E Comments Received Concerning th e Preliminary Work Plan ............................ 43

List of Tables Table 1 – Summary of Anticipated Ri sk Assessments and Data Needs ......................................... 6Page 4 of 43 Table 2 – Anticipated Regist ration Review Schedule .................................................................... 6 Table 3 – Chemical Identification of p- tertiary- Amyl Phenol (PTAP) .......................................... 7 Table 4 – Physical-Chemical and Fate Properties for PTAP and salts ........................................... 7 Table 5 – Summary of PTAP Registered Uses ............................................................................... 8 Table 6 – Studies Anticipated as Needed for the Registration Review of PTAP ......................... 11 Table 7 – Existing Toxicological Endpoints ................................................................................. 13 Table 8 – Occupational Handler Ex posure Scenarios for PTAP .................................................. 15 Table 9 – Residential Handler Exposure Scenarios for PTAP ..................................................... 16 Table 10 – Residential Post-Applicati on Exposure Scenarios for PTAP ..................................... 16 Table 11 – Existing Effects Endpoints for Risk Assessment of PTAP ......................................... 19 Table 12 – Summary of Screening Level Down-the-Drain Analysis Results .............................. 21 Table 13 – Acute Toxicity Studies for PTAP ............................................................................... 26 Table 14 – Aquatic Organism PTAP Toxicology ......................................................................... 33 Table 15 – Examples of PTAP Affecti ng the Endocrine System in Fish ..................................... 35

List of Figures Figure 1 – Conceptual Model for Ecological E xposure and Effects of PTAP and Its Major Reaction Products/Degradates to Aqua tic and Terrestrial Organisms .......................................... 18


## 1 Introduction

This document is the Environmen tal Protection Agency’s (EPA or “the Agency”) Final Work Plan (FWP) for the registration review of the 4 -tertiary- Amylphenol and Salts Case. The FWP document explains what EPA's Office of Pesticide Programs knows about the chemicals, highlighting anticipated data and assessment need s, identifying the types of information that would be especially useful to the Agency in conducting the review, and providing an anticipated timeline for completing their review. This work plan also addresses public comments received concerning the Preliminary Work Plan (PWP), which was posted in the 4 -tertiary- Amylphenol and Salts registration review docket (EPA- HQ-OPP-2012-0682). Further, this document makes final the work plan for the 4 -tertiary- Amylphenol and Salts regist ration review process.



## 1.1 Statutory and Regu latory Authority
The Food Quality Protection Act (FQPA) of 1996 mandated a regi stration review program. All pesticides distributed or sold in the United St ates generally must be registered by the U.S. Environmental Protection Agency (USEPA, EPA, or the Agency ) based on scientific data showing that they will not cause unreasonable ri sks to human health or the environment when used as directed on product labeling. The regist ration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet th e statutory standard of no unreas onable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the Agency periodically reevaluates pesticides to make sure that as change occurs , products in the marketpl ace can be used safely. Information on this program is provided at http://www.epa.gov/oppsrrd 1/registration_review/.

The Agency is implementing the registration revi ew program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registeredPage 5 of 43 pesticide every 15 years to determine whether it continues to meet th e FIFRA standard for registration. The regulations governing registra tion review begin at 40 CFR 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the Agency’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registrati on review decision. The 4

- tertiary- Amylphenol and Salts Preliminary Work Plan (PWP) was published on September 26, 2012 and the 60-day comment period ended on November 26, 2012.

Documents associated with this registration re view can be viewed at http://www.regulations.gov in docket EPA-HQ-OPP-2012-0682. Below is a summ ary of the issues relevant to this registration review case.



## 1.2 Updates to the Work Plan
Since the publication of the PWP, the agency has made the following updates:

• Deleted anticipated data requirements no l onger required to support registration review since these are to be addressed in the subm ission of the remaining anticipated exposure data requirements:

o 875.1600: Data Reporting and Calculations

o 875.2900: Data Reporting and Calculations

• Added the following anticipated data requirement

o 850.1075 Fish Acute Toxicity Test. Results from this study are needed to calculate an acute-to-chronic ratio for freshwater fish.

• Clarified throughout the document that additiona l tolerances may need to be established as determined during the planned risk assessments.

• Moved information on Regulatory Hist ory from Section 1.6 to Table 3.

• Added information on Description of Formulation Process to Table 4.

• Updated Table 6 to clarify th at (a) results from tests c onducted according to OECD 223 1
or OCSPP Guideline 850.2100 can be submitted fo r consideration to address the Avian Acute Oral Toxicity Test requirement and (b) results from tests conducted according to OECD 443 2 or OCSPP Guideline 870.3800 can be subm itted for consideration to address the Reproductive Toxicity Study requirement. These updates were made in response to comments received during the public comment period (see Appendix E ).

• Corrected formatting and typographical errors

The Agency received two comments on the initial docket. The comments rece ived did not affect the data needs (except as noted in the next two sentences), work plan and timeline described in the PWP. One comment requested that the Agen cy consider the possibility that two data requirements could possibly be addressed by te sting results obtained from use of OECD guidelines. The Agency considered this possibl e approach and agrees that the OECD methods referenced in the comment could be considered for use in the subject te sting. A summary of the comments received and the Agency’s res ponses are presented in Appendix E .

1 http://www.oecd-ilibrary.org/environment/test-no-22 3-avian-acute-oral-toxicity-test_9789264090897-en
2 http://www.oecd-ilibrary.org/environment/test-no-44 3-extended-one-generation-reproductive-toxicitystudy_9789264122550-enPage 6 of 43 Table 1 – Summary of Anticipated Risk Assessments and Data Needs

Risk Assessment Assessment Necessary to Support Registration Review Date of Most Recent Assessment Type of Assessment Required (New/Updated) Data Anticipated as Needed (See Table 6 for details)

Dietary (food) Yes 5/26/2005 Updated Surface / Dietary Residue Reproductive Toxicity Developmental Toxicity Dietary (drinking water) No (see 3.2.2) 5/26/2005 None None

Occupational Handler Yes 5/26/2005 Updated Indoor Exposure Inhalation Toxicity

Residential Handler Yes 5/26/2005 Updated Indoor Exposure Inhalation Toxicity Residental Post Application - Incidental Oral and Dermal Yes 5/26/2005 Updated Surface Residue

Residental Post Application - Inhalation Yes 5/26/2005 Updated Indoor Exposure Inhalation Toxicity

Aggregate Yes 5/26/2005 Updated Surface Residue Reproductive Toxicity Developmental Toxicity

Cumulative No (see 3.4.2) N/A None None

Tolerance Review Yes N/A New None

Ecological Yes N/A New Invertebrates, aquatic plants, and avian Toxicity Fish life-cycle Reproductive Toxicity Environmental Fate N/A = Not applicable Table 2 – Anticipated Regi stration Review Schedule
Anticipated Activity Target Date* Completion Date Phase 1: Openin g the Docket Open Docket and 60-Day Comment Period for Preliminary Work Plan 2012-09 2012-09-26 Close Public Comment Period 2012-11 2012-11-26 Phase 2: Case Development Issue Final Work Plan 2013-03 2013-03-13 Issue Data Call-In (DCI) 2014-03 Receive Data to be Considered in Risk Assessment 2016-03 Open 30-Day Public Comment Period for Pr eliminary Risk Assessm ent(s) 2017-09 Close Public Comment Period 2017-10 Phase 3: Registration Review Decision and Implementation Open 60-Day Public Comment Period for Proposed Decision 2018-03 Close Public Comment Period 2018-05 Issue Final Decision 2018-09 Begin Post-Decision Followup 2018 Total (years) 6
*The anticipated schedule will be revised as necessary (e.g., n eed arising under the Endocrine Di sruptor Screening Program with respect to the active ingredients in this case).Page 7 of 43 

## 1.3 Case Overview

The docket for the 4 -tertiary- Amylphenol and Salts Case (Cas e 3016) has been established at http://www.regulations.gov in doc ket number EPA-HQ-OPP-2012-0682.



## 1.4 Chemical Identification and Properties

Table 3 presents the three active ingred ients to be assessed in Case 3016: 4 -tertiary- amylphenol (PC Code 064101); p -tertiary- amylphenol, potassium salt (PTAP-K, PC Code 064111); and p

tertiary- amylphenol, sodium salt (PTAP-Na, PC C ode 064112). Except where otherwise noted, the three active ingredients in this case w ill be referred to collectively as “PTAP.”

Table 3 – Chemical Identification of p- tertiary- Amyl Phenol (PTAP)

Chemical Name 4- tert -Amylphenol p - tert -Amylphenol, potassium salt (PTAP-K) p - tert -Amylphenol, sodium salt (PTAPNa) Classification Alkyl Phenol Alkyl Phenol Alkyl Phenol
PC Code 064101 064111 064112
CAS No. 80-46-6 53404-18-5 31366-95-7 Molecular Formula C 11 H 16 O C 11 H 15 KO C 11 H 15 NaO Molecular Weight 164.25 g/mol 202.3345 g/mol 186.23 g/mol First registered in US 1962 1967 1986 Reregistration Eligibility Decision (RED) issued 3 2005 2005 2005
Registered Products (as of 02/12/2013) 31 1 1 Tolerances 4 40 CFR 180.940(c) None None

The PTAP product chemistry inform ation relevant to risk assessm ent is summarized in Table 4.

Table 4 – Physical-Chemical and Fa te Properties for PTAP and salts

OPPTS Guideline No. Physical and Chemical Properties 4 -tertiary- amylphenol PTAP-K PTAP-Na

830.1550 Product identity and composition Refer to Table 3. Refer to Table 3. Refer to Table 3.

830.1650 Description of Formulation Process Confidential Business Information (CBI) CBI CBI

830.1800 Enforcement analytical method GC MS GC MS GC MS
830.6302 Color White crystals White White 830.6303 Physical State So lid; Flakes Solid Solid 830.6304 Odor Slight phenolic odor Slight phenolic odor Slight phenolic odor

3 EPA anticipates issuing the post-RED DCI soon.
4 PTAP (expressed as Phenol, 4-(1,1-dimethylpropyl)-) has a tolerance exemption in 40 CFR 180.940(c) as a foodcontact sanitizer for use in food-processi ng equipment and utensils at a use dilu tion not to exceed a limit of 80 ppm. The need for additional tolerances or tolerance exemptions will be determined during the risk assessment stage of this registration review.Page 8 of 43 OPPTS Guideline No. Physical and Chemical Properties 4 -tertiary- amylphenol PTAP-K PTAP-Na

830.6313 Stability to sunlight, normal and elevated temperature, metals/metal ions Stable under normal temperatures and
pressures. Stable under normal temperatures and
pressures. Stable under normal temperatures and
pressures. 830.7000 pH 6.5 - 7 (0.1% aq.sol.) N/A N/A
830.7050 UV/Visible Absorption Limited absorbance above 290 nm Limited absorbance above 290 nm Limited absorbance above 290 nm 830.7200 Melting point 91-94°C; 95° C 206 °C (EPI Suite) 205.87 °C (EPI Suite)
830.7220 Boiling point 262.5 °C at 760 mmHg 262.5°C at 760 mmHg 262.5°C at 760 mmHg 830.7300 Density 0.96 g/cm 3 at 20 °C N/A N/A 830.7370 Dissociation Constant pKa = 10.43 NA NA

830.7550 Partition coefficient ( n

octanol/water) log Kow = 4.03 (Measured) 1.23 (EPI Suite) 1.23 (EPI Suite)

830.7840 Solubility in water 168 mg/L at 25°C (Measured) 3,811 mg/L (EPI Suite) 4,595 mg/L (EPI Suite)

830.7860 Solubility in organic solvents Soluble in alcohol, ether, benzene, chloroform, DMSO, Acetone N/A N/A

830.7950 Vapor pressure 2.0 x 10 -3 mm Hg at 25° C (Measured) 7.7 x10 -10 at 25° C (EPI suite) 7.7 x10 -10 at 25° C (EPI suite)

N/A Henry's Law Constant 2.6 x 10 -6 atm-m 3 /mole at 25 o C (Calculated) 5.4 x 10 -14 atmm 3 /mole at 25 o C (EPI Suite) 4.1 x 10 -14 atmm 3 /mole at 25 o C (EPI suite)



## 1.5 Use/Usage Description

1.5.1 Summary of Registered Uses

Table 5 presents a summary of the registered us es of PTAP that will be assessed in this registration review. PTAP can be applied by the following application methods: mop, wipe, spray, fogging, soaking, and immersion.

Table 5 – Summary of PTAP Registered Uses

Use Application Method Application Rate Agricultural Premises and Equip ment – Indirect Food Contact

Non-porous surfaces in: Animal and poultry farms, egg handling areas, aquaculture greenhouses and mushroom farms 5 Fogger, Thermal Unknown 6
Fogger, Total Release 0.5 mg/m 3

Mop, Soak or Wipe 76 to 598 ppm

5 Labels specify that use is not permitted in milking stalls, milking parlors or milk houses.
6 Labels specify a fogging solution concentration ( i.e., 5000 ppm) and an application time ( i.e., fog for three minutes per 2000 ft 3 ). The labels do not indicate how much fogging solution should be applied per unit volume (i.e., three ounces per 1000 ft 3 ).Page 9 of 43 Use Application Method Application Rate

Shoe Baths 78 to 156 ppm Commercial, Industrial, Institutional, Premises and Equipment

Non-porous surfaces - Floors, walls, fini shed woodwork, chairs, countertops, sinks, garbage cans, cabinets. Fogger, Total Release 0.2 to 1.4 mg/m 3
Mop, Spray, Wipe 28 to 598 ppm Food Handling/Storage Establis hments Premises and Equipmen t – Indirect Food Contact

Non-porous surfaces Fogger Unknown 6
Mop, Spray, Wipe 78 to 450 ppm

Residential and Public Access Premises Non-porous surfaces 37 Fogger, Thermal Unknown 6
Fogger, Total Release 0.2 to 0.5 mg/m 3
Spray, Mop, Wipe 76 – 740 ppm Carpets Spray 375 ppm Human Footwear (ski boots etc) Spray 450 ppm Medical/Dental/Veterinary Premises and Equipment

Non-porous surfaces Fogger Unknown 6
Spray, Mop, Wipe 28 to 781 ppm

Fiberglass bath and therapy Units Circulate then Drain 195 ppm

Barber and Beauty Shop Instruments Immersion 35 to 580 ppm Dental Handpieces Immersion 580 ppm

Medical Instruments Immersion 598-1197 ppm



### 1.5.2 Usage Information

According to the Kline Biocides Report for 2004/2005 (Kline, 2005), PTAP makes up less than 1 percent of the estimated U.S. consumption of sp ecialty biocides in hous ehold disinfectant and sanitizer products. Production vo lume data in the EPA Section Seven Tracking System (SSTS) for the years 2004 through 2008 indicate that no mo re than 100,000 kilograms of PTAP are sold per year in the United States 8

.


## 1.6 Incidents

1.6.1 Human Health

No PTAP human poisoning incidents have been re ported in OPP’s Incident Data System (IDS) for the time period spanning 2005 to 2012.

7 Labels specify that fogger use is not permitted in a room 5ftx5ft or smaller.
8 Data for the years 2009 through 2011 were not used in this estimate since data collection is still in progress.Page 10 of 43 

### 1.6.2 Ecological

No PTAP incidents ecological inci dents have been reported in the Agency’s Ecological Incident Information System (EISS) for the time period spanning 2005 to 2012.


## 2 Anticipated Data Needs

Table 6 presents a summary of the data anticipate d as being needed to su pport this registration review.Docket Number EPA-HQ-OPP-2012-0682www.regulations.govPage11of43Table 6 – Studies Anticipated as Neededfor the Registration Review of PTAPGLNStudy NameTestSubstanceTime Frame(Measured inmonths fromDCI Receipt)RiskAssessment(s)Data WillSupportUse Site(s)TriggeringAnticipated DataRequirementApplicable Exposure ScenarioStudies Anticipated to be Required through the Registration Review DCI835.1110Activated Sludge SorptionIsothermTGAI 24 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.835.3220Porous Pot Test TGAI 24 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.835.3280Simulation Tests to Assess theBiodegradability of ChemicalsDischarged to WastewaterTGAI 24 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.835.3240Simulation Test – Aerobic SewageTreatment: A. Activated SludgeUnitsTGAI 24 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.850.1035Acute marine/estuarineinvertebrate toxicity (shrimp)9TGAI 12 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.850.1075 Fish acute toxicity (freshwater)10TGAI 12 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.850.1500 Fish life-cycle (freshwater)10TGAI 24 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.850.1025 or850.1055Acute estuarine/marineinvertebrate toxicity (mollusk)TGAI 12 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.850.1350Chronic marine/estuarineinvertebrate toxicity (shrimp)9TGAI 24 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.850.210011Avian acute oral toxicity test TGAI 12 EcologicalHard SurfaceDisinfectionBirds ingesting aquatic animals that have absorbedor ingested PTAP850.4400Aquatic plant toxicity test usingLemna gibbaTGAI 12 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.OECD 209or 850.3300Activated Sludge RespirationInhibition or Modified ActivatedSludge Respiration InhibitionTGAI 24 EcologicalHard SurfaceDisinfectionDown the drain; hard surface disinfectants areoften rinsed down the drain.9Results using the same species as that used in the chronic studyare anticipated to be requiredto calculate an acute-to-chronic ratio.10An acceptable acute 96-h LC50value for the same species tested for thefull life cycle test is expected to be required to calculate an acute-to-chronic ratio.11OECD TG 233 using the "LD50- slope test" or "limit dose test" can be submitted for consideration instead of OCPSS 850.2100 for certain species and conditions(e.g., causes no delayed effects, causes no regurgitation). Details on the species and conditions under which TG 233 would notfulfill the data requirement aredescribed at http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/terrestrial_biology_tech_team/review_avian_acute_oral_oecd_tg223.htmPage12of43GLNStudy NameTestSubstanceTime Frame(Measured inmonths fromDCI Receipt)RiskAssessment(s)Data WillSupportUse Site(s)TriggeringAnticipated DataRequirementApplicable Exposure Scenario870.3465 90-day inhalation toxicity study TGAI 24OccupationalandResidentialAir Sanitization,HVAC Treatments,Hard SurfaceDisinfectionAll scenarios that involveinhalation exposures.870.380012Reproduction and Fertility EffectsstudyTGAI 24Dietary,EcologicalFood ContactSurfacesDietary exposures from indirect and direct foodcontact uses.875.1200 Indoor Exposure, Dermal TGAI 24OccupationalandResidentialHard SurfaceDisinfection(1) Trigger pump sprayer, low pressure handwand,high pressure handwand, mop, and wipe13and (2)Hand held fogger875.1400 Indoor Exposure, Inhalation TGAI 24OccupationalandResidentialHard SurfaceDisinfection(1) Trigger pump sprayer, low pressure handwand,high pressure handwand, mop, and wipe13and (2)Hand held fogger875.1700 Product Use Information TGAI12 All AllAll scenarios.875.2300Indoor Surface ResidueDissipation14TGAI 24 ResidentialSurface disinfectionof household floorsand carpetsDermal and incidental exposures to PTAP areexpected for toddlers who sit or play on householdfloors or carpets after they are disinfected withPTAP products.875.2500Post Application Exposure,InhalationTGAI 24 ResidentialAir Sanitization,HVAC TreatmentsInhalation exposure following the use of airdeodorizers or HVAC treatments.875.3700 Developmental Toxicity in Rabbits TGAI 24 DietaryFood ContactSurfacesDietary exposures from indirect and direct foodcontact uses.Studies Expected to be Required through the Anticipated Post-RED DCI870.310090-day Oral Subchronic in Rats(including neurotoxicity andendocrine endpoints)TGAI 24 DietaryFood ContactSurfacesDietary exposures from indirect and direct foodcontact uses.875.2800 Descriptions of Human Activity TGAI 24 All AllAll scenarios.SpecialStudyDietary-Residues in Food fromTreating Countertops with 4-tAmylphenol (FDA Wipe StudyMethodology)TGAI 24 DietaryFood ContactSurfacesDietary exposures from indirect and direct foodcontact uses.12Results from a multi-generation (EPA guideline 870.3800) oran extended one-generation reproductive and fertility effects study using OECD TG 443(http://www.oecd-ilibrary.org/environment/test-no-443-extended-one-generation-reproductive-toxicity-study_9789264185371-en) maybe submitted forconsideration in response to this requirement.13It may be possible to use proprietary surrogate exposure data if data compensation issues are appropriately and adequately addressed.14In the absence of surface residue data, EPA will need to estimate riskutilizing a transfer fate of 100%.Docket Number EPA-HQ-OPP-2012-0682 www.regulations.gov

Page 13 of 43 

## 3 Human Health Risk Assessment

The Agency anticipates the need to conduct a human health risk assessment for PTAP. The Agency expects to require additional data for use in conducting the registration review.



## 3.1 Existing Toxicological Endpoints
EPA anticipates the need to revise the existing t oxicological endpoints as pa rt of this registration review. Table 7 presents the endpoints used in EP A’s most recent human health risk assessment in support of the 2005 RED. As previously stated, toxicological studies we re identified as data gaps in the RED and identified in the registra tion review as anticipat ed data needs based on currently registered uses. All av ailable information including existing toxicology studies, valid scientific literature, and the studies that are expe cted to be required for registration review will be considered in establishing the endpoints to be us ed in the registration re view risk assessment. A detailed description of the toxicity studies is provided in Appendix A .

Table 7 – Existing Toxicological Endpoints

Exposure Scenario Dose Used in Risk Assessment (mg/kg/day) Target Margin of Exposure (MOE), UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects

Acute Dietary Females 13+ b.w. = 60kg No Observed Adverse Effect Level (NOAEL) = 200 mg/kg/day UF = 3000 (10x inter-species extrapolation, 10x intra-species variation) FQPA SF= 10 DB UF = 3 Acute PAD =0.067 mg/kg/day Developmental toxicity study in the rat NOAEL of 200 mg/kg/day, based on skeletal effects and decreased fetal body weight at 500 mg/kg/day

Chronic Dietary All populations b.w. = 70 kg NOAEL = 50 mg/kg/day UF = 3000 (10x inter-species extrapolation, 10x intra-species variation) FQPA SF= 10 DB UF = 3 Chronic PAD =0.017 mg/kg/day Developmental toxicity study in the rat NOAEL of 50 mg/kg/day, based on clinical signs, decreased body weight and body weight gain, and decreased food consumption in maternal animals at 200 mg/kg/day

Incidental Oral (short and intermediate term) NOAEL =50 mg/kg/day MOE = 3000 (10x interspecies extrapolation, 10x intraspecies variation, 10x FQPA , 3x database UF) Developmental toxicity study in the rat NOAEL of 50 mg/kg/day, based on clinical signs, decreased body weight and body weight gain, and decreased food consumption in maternal animals at 200 mg/kg/day
Dermal (short andintermediateterm) (occupational and residential) NOAEL = 25 mg/kg/day (HDT) MOE (occupational) = 100 MOE (residential) =1000 (10x interspecies extrapolation, 10x intraspecies variation, 10x FQPA) Subchronic dermal toxicity in the rat No systemic effects identified up to and including the high dose of 25 mg/kg/day

Dermal (long-term) (occupational and residential) NOAEL = 25 mg/kg/day (HDT) MOE (occupational) = 300 MOE (residential) =3000 (10x interspecies extrapolation, 10x intraspecies variation, 10x FQPA, 3X for subchronic to chronic duration) Subchronic dermal toxicity in the rat No systemic effects identified up to and including the high dose of 25 mg/kg/dayPage 14 of 43 Exposure Scenario Dose Used in Risk Assessment (mg/kg/day) Target Margin of Exposure (MOE), UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects

Inhalation All time periods (occupational and residential) NOAEL = 50 mg/kg/day MOE (occupational) = 300 MOE (residential) = 3000 (10x interspecies extrapolation, 10x intraspecies variation, 10x route extrapolation, 3x database uncertainty) Developmental toxicity study in the rat NOAEL of 50 mg/kg/day, based on clinical signs, decreased body weight and body weight gain, and decreased food consumption in maternal animals at 200 mg/kg/day
Cancer No cancer data available for PTAP



## 3.2 Dietary Exposure
The Agency anticipates the need to revise th e dietary (food) assessment conducted in support of the 2005 RED. Uses of PTAP that may result in dietary exposures incl ude countertops, food or feed contact surfaces, agricultural commodities, surfaces in livestock premises and poultry premises including hatcheries and application to food-grade eggs.

Dietary risk is characterized in terms of the Population Adjusted Dose (PAD), which reflects the reference dose (RfD), either acute or chronic, that has been adjusted to account for the FQPA Safety Factor (SF). This calculation is perf ormed for each population subgroup for which an endpoint exists. A risk estimate th at is less than 100% of the ac ute or chronic PAD is not of concern. Acute dietary risk for PTAP will be assessed by comparing dietary exposure estimates expressed in mg/kg/day to the acute Population Adjusted Dose (aPAD) and chronic Population Adjusted Dose (cPAD).



### 3.2.1 Food

EPA anticipates the need to revise the acute and chronic dietary food assessment conducted in support of the 2005 RED. In the RED, EPA consid ered exposures to residues on various hard nonporous surfaces such as countertops, sinks and stoves and did not identify any dietary risks of concern. At that time, EPA assumed a residue tran sfer factor of 10%, provided that registrants submit confirmatory residue data. In the absence of these confirma tory data (the Nature of the Residue on Surfaces and Migration Studies expect ed to be required through the post-RED DCI), EPA will need to estimate risk utilizing a transfer rate of 100%.

The acute and chronic assessments will estimate dietary exposure for all population subgroups.

PTAP has a tolerance exemption in 40 CFR 180.940( c) as a food-contact sanitizer for use in food-processing equipment and utensils at a use dilution not to exceed 80 ppm.



### 3.2.2 Drinking Water

EPA does not anticipate the need to revise the drinking water assessment conducted in support of the 2005 RED because dietary exposure from drinki ng water is not expected to occur based on PTAP’s sorption to soils and sediments and lack of persistence (see Appendix B ) and a range finding assessment of down the drai n exposures (see Appendix D ).Page 15 of 43 

## 3.3 Occupational and Residential Exposures
The Agency anticipates the need to revise the occupational and residential assessments conducted in support of the 2005 RED since Margins of Exposure (MOE)s were calculated using assumptions that possibly underestimates exposure and will need to be reassessed using updated values. Uses of PTAP that may result in o ccupational handler and residential handler/postapplication exposure are presented in Table 8, Table 9, and Table 10.



### 3.3.1 Occupational Handler Exposure

EPA anticipates the need to revise the occupa tional handler assessment conducted in support of the 2005 RED. Occupational handler dermal and i nhalation exposures to PTAP were assessed in the RED for applications using low pressure ha ndwands, high pressure handwands, aerosol cans, trigger sprayers, mops and wipes. These exposur es were assessed using unit exposure data from the Pesticide Handler Exposure Database (PHE D) and Chemical Manufacturer’s Association (CMA) data. In all cases, the respective dermal and inhalation MOEs were not of concern. Occupational handler exposures were assessed for the pouring of liquid concentrate into the fogger, but exposures while operating the fogger were not assessed. Occupational post application inhalation exposures we re assessed for the applicati on of fogging solutions to poultry houses and the risks were found to be acceptable if the re-entry interval was longer than two hours.

All of the handler scenarios that were assesse d in the RED will need to be revised during registration review upon r eceipt of the unit exposure data that is anticipated to be required to supplement or replace the unit exposure data that we re used in the RED. It will also be necessary to reassess the fogger handler e xposures for fogging applications that are made using hand held foggers and it will be necessary to reassess post application expos ures once the ap plication rates are clarified. Occupational handler scenarios to be assessed are presented in Table 8.

Table 8 – Occupational Handler Exposure Scenarios for PTAP

Scenario Exposure Route(s) Duration
Occupational Exposures Applying disinfectant using low pressure handwands, high pressure handwands, aerosol cans, trigger sprayers, mops and wipes. Dermal Inhalation Short, Intermediate, and Long Term
Applying disinfectant using handheld foggers or misters Dermal Inhalation Short and Intermediate Term



### 3.3.2 Residential Handler Exposures
EPA anticipates the need to revise the resident ial handler assessment conducted in support of the 2005 RED. Residential handler dermal and inhala tion exposures to PTAP were assessed in the RED for spraying, mopping and wiping surfaces and for aerosol spray can application for “air sanitization.” In all cases, the respective dermal and inhalation MOEs were not of concern.

Residential exposure may occur during applicati on of PTAP products used as a hard surface disinfectant (e.g., walls, floors, tabl es, fixtures), to textiles (e. g., clothing, diapers, mattresses,Page 16 of 43 bedding) and to carpets. PTAP produ cts are widely used disinfectants and have a large number of use patterns. As such, the Agency has selected re presentative scenarios for each use site that are believed to be representative of the PTAP uses , based on end-use product application methods and use amounts. The quantitative exposure/risk assessment to be developed for residential handlers will be based on the following scenarios presented in Table 9.

Table 9 – Residential Handler Exposure Scenarios for PTAP

Scenario Exposure Route(s) Duration
Residential Exposures Applying disinfectant to hard surf aces and carpets using aerosol cans, trigger sprayers, mops and wipes Dermal Inhalation Short and Intermediate Term
Applying disinfectant to the air using aerosol cans Inhalation Short and Intermediate Term



### 3.3.3 Residential Post-Application Exposures
EPA anticipates the need to revise the reside ntial post-application a ssessment conducted in support of the 2005 RED. Residential post applica tion dermal exposures can occur when adults and children come in contact with PTAP in ar eas where PTAP has been applied to floors and carpets. Incidental oral exposures to children can also occur fr om hand to mouth contact with treated floors and carpets. Inhalation exposures ca n occur following the application of PTAP.

Residential post-application exposur es to residues arising from th e hard surface disinfection of floors, treated diapers, treated clothing and sanitized air were assessed. The Margins of Exposure (MOE)s were not of concern for hard surface di sinfection of floors but they were calculated using an assumption of solution coverage ( 1000 square feet per ga llon) that possibly underestimates exposure and will have to be reassessed using updated values. The MOEs were of concern for the clothing and diaper use. The de rmal MOEs for the trea ted clothing ranged from <1 when 100 percent residue transfer was assume d to 17 when 5 percent transfer was assumed. Based on these concerns, the RED specified that th e diaper use was ineligible for reregistration and that label statements be added requiring ot her treated textile arti cles be washed after treatment. The MOEs for air sa nitization were not of concern. The quantitative exposure/risk assessment to be developed for residential handlers will be based on the following scenarios presented in Table 10.

Table 10 – Residential Post-Application Exposure Scenarios for PTAP

Scenario Exposure Route(s) Duration
Residential Exposures Post application exposure to floors and carpets cleaned with preserved household cleaning solutions. Dermal Incidental Oral Short and Intermediate Term Post application exposure to aerosols and vapors released from air deodorizing treatments Inhalation Short and Intermediate TermPage 17 of 43 

## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

EPA anticipates the need to revise the aggr egate assessment conducted in support of the 2005 RED. Upon a reevaluation and sel ection of toxicological endpoint s, combined with the human health exposure assessments expected as a part of this registration review case, aggregate exposures will need to be assessed. This asse ssment will include dietary (food) exposures and residential exposures.



### 3.4.2 Cumulative Exposures

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a cumulative risk approach based on a common me chanism of toxicity, EPA has not made a common mechanism of toxicity finding as to PTAP and any other substances and PTAP does not appear to produce a toxic metabolite produced by other substances. For the purposes of this registration review, ther efore, EPA has not assumed that PTAP has a common mechanism of toxicity with other s ubstances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity a nd to evaluate the cumulative effects of such chemicals, see http://www.epa .gov/pesticides/cumulative/.


## 4 Environmental Risk Assessment

The Agency has not conducted a risk assessmen t that supports a complete endangered species determination for PTAP. The ecological risk as sessment planned during registration review will allow the Agency to determine whether PTAP’s use has 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or their designa ted critical habitats. When an assessment concludes that a pesticide’s use 'may a ffect' a listed species or its designated critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services), as appropriate.



## 4.1 Environmental Conceptual Model Exposure Pathways

PTAP and its salts are active ingredients in antimic robials that can be used as disinfectants or sanitizers on hard inanimate su rfaces in a variety of settings. Antimicrobials that are used to disinfect or sanitize surfaces are often rinsed do wn the drain with potable water in order to remove residues and therefore have the potential to reach aquatic organisms, if they are not removed by wastewater treatment plants. Although the half-life for PTAP is reported to be relatively short, ranging fr om 1 to 5 days in air, water, and soil, this half-life is not short enough that PTAP would be expected to be apprecia bly degraded prior to entering Waste Water Treatment Plants (WWTPs). Data on the hal f-life of PTAP in environmental media do not provide specific information on the potential fo r PTAP to be removed during the wastewater treatment process in which conditions are presen t that tend to promote removal of chemical substances from WWTPs, particularly via proc esses such as biodegradation and sorption (MRID 43733201).Page 18 of 43 Because pesticide residues have the potential to reach the hab itat of aquatic organisms it is necessary to determine the risk to aquatic fish, invertebrates, and plants that may occur from exposure to these chemicals. PTAP has been found in an effluent sample from a municipal waste water treatment plant (Ellis et al. 1982) which further solidifies the necessity for assessing aquatic exposure for PTAP. There are no outdoor uses for this compound, and therefore the only environmental exposures will be from any resi dues that go down-the-drain. An ecological conceptual model summarizing exposure pathways for PTAP and its reaction products/degradates is provided in Figure 1.

The indoor fogging applications are not expected to result in direct or indirect exposure of aquatic or terrestrial systems because of containment within structures.

Figure 1 – Conceptual Model for Ecological Exposure and Effects of PTAP and Its Major Reaction Products/Degradates to Aquatic and Terrestrial Organisms



## 4.2 Ecological Effects Assessment

Ecological effects data are used as measures of di rect and indirect effect s to biological receptors. Acute and chronic toxicity data from studies submitted by pesticide registrants along with the available open literature will be used to evaluate the potential direct and indirect effects of PTAP and its degradates to aquatic and terrestrial receptors. The Agency does not have ecological effects data for PTAP. Data discussed here-in we re found in the peer-reviewed literature as well

Stressor

Source

Receptors and Exposure
Routes

Attribute Change(s) Individual organisms Reduced survival Reduced growth Reduced reproduction Food chain Reduction in algae Reduction in prey Modification of PCEs related to prey availability Habitat integrity Reduction in primary productivity Reduced cover Community change Modification of PCEs related to habitat Aquatic Animals Invertebrates Vertebrates Exposure Media

Ingestion Ingestion Uptake/gills or integument

Aquatic Plants Non-vascular Vascular Uptake or sorption by

cells, roots, leaves,

Piscivorous* Invertebrates Vertebrates Phytoplanktivore/ Herbivore Invertebrates Vertebrates

*As used here this term refers to animals (terrestrial or aquatic) that eat not just fish but any aquatic animal ( e.g ., amphibians, mollusks, crustaceans, etc.) Ingestion Waste Water Treatment Plant (WWTP)

Key Most likely

exposure pathway contributing to risk Low likelihood of contributing to risk In-Service Use of Disinfectants or Sanitizers on Hard Inanimate Surfaces

WWTP microorganisms Uptake or sorption

Population Respiration inhibition Waste Water Disposal Down-the-Drain

Surface Water

SedimentPage 19 of 43 as OPPT’s High Production Volume (HPV) Cha llenge (http://www.epa.gov/HPV/) or estimated using modeling as described below and in Appendix C .



### 4.2.1 Mechanism of Action

PTAP and its salts are broadly categorized wi thin the alkylphenols chemical category. For ecotoxicological purposes the alkylphenols are classi fied as polar narcotics. Aquatic toxicities for the alkylphenols appear to be related to their de gree of lipophilicity and increases rela tive to their log K ow values. PTAP has a log K ow value of 4.03 and therefore surpasses the Agency's threshold of concern (K ow value of 3.0) and indicates a potential for bioaccumulation in fatty tissues. However, the bioconcentration factors range from 177-230, which is less than the level of concern (1,000) indicating signi ficant degradation and/or depu ration (removal) is occurring. Using alkylphenols with comparable lipophilicity, it is possible to use EC OSAR data to support available experimental data in this case (EPA HPV, 2006).

Additionally since PTAP is consid ered an ecoestrogen there is concern about the possibility of endocrine disruption in fish. PTAP’s estrogenic properties were documented 15 in several studies on carp ( Cyprinus carpio ).



### 4.2.2 Measures of Effect (Ecotoxicology Endpoints)

Current selected ecotoxicol ogical endpoints are summarized in Table 11. All available information including existing toxi cology studies, valid scientific lit erature, and the studies that are expected to be required for registration review will be considered in establishing the endpoints to be used in the regi stration review risk assessment. A more detailed description of the ecotoxicity studies ar e provided in Appendix C .

Table 11 – Existing Effects Endpoints for Risk Assessment of PTAP

Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint

as a.e. Comment Reference

Freshwater fish Rainbow trout ( Oncorhyncus mykiss ) Acute 96-hr LC 50 = 849 ppb* Supplemental information, preferred sensitive species estimated using Web-ICE and lowest acute fathead minnow, see comments for chronic freshwater fish Web-ICE v. 3.1 see Appendix C

Generic fish Acute 96-hr LC 50 = 817 ppb Supplemental information, see comments for chronic freshwater fish ECOSAR v1.11

15 Gimeno, S., Komen, H., Venderbosch, P.W., and Bowner, T. (1997) Disruption of sexual differentiation in genetic male carp ( Cyprinus carpio ) exposed to an alkyphenol during different life stages. Environ. Sci. Technol. 31(10): 2884-2890. Gimeno, S., Komen, H., Gerritsen, A.G., and Bowner, T. (1998a): Feminisation of young males of the common
carp, Cyprinus carpio , exposed to 4- tert -pentyphenol during sexual differentiation. Aquatic Toxicology (Amsterdam) 43: 77-92. Gimeno, S., Komen, H., Jobling, S., Sumpter, J., and Bown er, T. (1998b): Demasculinisation of sexually mature male common carp, Cyprinus carpio , exposed to 4- tert -amylphenol during spermatogenesis. Aquatic ToxicologyPage 20 of 43 Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint

as a.e. Comment Reference

Generic fish Chronic ChV = 111 ppb Supplemental information, use will underestimate chronic ri sks, because there are endocrine disruption con cerns a full life-cycle study is anticipated to be required rather than an early life-stage study (ChV values are early life-stage), an acute test conducted on the same test species would allo w for the calculation of an acute-to-chronic ratio ECOSAR v 1.11

Freshwater invertebrates Waterflea ( Daphnia spp. ) Acute 48-hr EC 50 = 169 ppb* Supplemental information, preferred sensitive species estimated using Web-ICE and lowest acute fathead minnow, un certainty is expected to be low, no additional studies are anticipated to be required at this time Web-ICE v. 3.1, see Appendix C

Acute LC 50 = 608 ppb Supplemental information, uncertainty is expected to be low, no additional studies are anticipated to be required at this time ECOSAR v 1.11

Chronic ChV = 115 ppb Supplemental information, use will underestimate chronic risk but ChV value for invertebrates includes reproduction and uncertainty is expected to be low, ACR will be applied to Web-ICE v. 3.1 value, no additional studies are anticipated to be required at this time ECOSAR v 1.11

Estuarine / Marine fish Sheepshead minnow Acute 96-hr LC 50 = 1010 ppb* Supplemental information, use will underestimate acute risk, ACR from freshwater data requirements will be used to estimate values, no additional studies are anticipated to be required at this time Web-ICE v. 3.1, see Appendix C

Generic Fish (SW) Acute ChV = 253 ppb See above ECOSAR v 1.11 Sheepshead minnow Chronic No data available See above

Estuarine / Marine invertebrates Shrimp ( Crangon septemspinosa ) Acute 96-hr LC 50 = 1700 ppb* Acute shrimp study anticipated to be required

Chronic No data Chronic shrimp study anticipated to be required Mollusk Acute No data Acute mollusk study anticipated to be required

Algae Green Algae Chronic EC 50 = 2,294 ppb Supplemental information, exceedances not expected, uncertainty is expected to be low, no additional studies are anticipated to be required at this time ECOSAR v 1.11

Chronic ChV = 1,050 ppb See above ECOSAR v 1.11 Aquatic Vascular plants Lemna gibba Chronic 7-day EC 50 = 353 ppb Supplemental information, exceedances expected, Lemna gibba study anticipated to be required ECOSAR v 1.11

Birds Acute No data available Acute oral study anticipated to be requiredPage 21 of 43 Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint

as a.e. Comment Reference

Mammals Acute LD 50 >2000 mg/kg-bw 46616601

Chronic Will use two-generation reproduction data anticipated to be required.



## 4.3 Exposure Analysis Plan

4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates In order to address the risk hypot hesis, the potential for adverse effects on the environment will be estimated. For down-the-drain (DtD) risk estima tes, an approach that estimates the number of days a concentration-of-concern (COC) is exceeded, also referre d to as a probabilistic dilution model (PDM) approach is used to assess risk to aquatic organisms. A screening DtD assessment using this approach was conducted to evaluate if PTAP uses resulting in DtD releases could potentially be identified as minimal use and unlikely to result in effects. Th e results of the screen are provided in Appendix D. Base d on the results of the screen, where at even low end estimates of release there is potential for endangered spec ies levels of concern to be exceeded, there is a need to conduct a more refined DtD assessment. The environmental fate and effects data anticipated to be required to conduct a more refi ned DtD assessment are included as part of the work plan.



### 4.3.2 Screening Level Down-the-Drain Analysis
The Down-the-Drain (DtD) module of E-FAST (E xposure and Fate Assessment Screening Tool) was used to screen for the potential for aquati c organisms downstream of domestic wastewater treatment plants to be exposed to PTAP. Inputs used in this screening level DtD module run included concentrations of con cern (COCs) for aquatic organisms, zero percent removal during
wastewater treatment 16 , and two wastewater treatment plan t influent volume scenarios. The results of the DtD module are expressed as numbe r of days of exceedance of COCs for aquatic organisms. A detailed descrip tion is provided in Appendix D .

Table 12 – Summary of Screening Leve l Down-the-Drain Analysis Results

Influent Volume Freshwater fish acute (COC = 409 ug/L) Endangered Freshwater fish (COC = 41 ug/L) Freshwater fish chronic (COC = 111 ug/L) 1,000,000 kg/year Exceeded <1 day per year Exceede d 22 days per year Exceeded 3 days per year 100,000 kg/year No exceedances No exceedances No exceedances

Influent Volume Freshwater fish acute (COC = 425 ug/L) Endangered Freshwater fish (COC = 42.5 ug/L) 1,000,000 kg/year Exceeded <1 day per year Exceeded 20 days per year 100,000 kg/year No exceeda nces No exceedances

Influent Volume Freshwater invertebrates acute (COC = 304 ug/L) Endangered Freshwater invertebrates (COC = 30.4 ug/L) Freshwater invertebrates chronic (COC = 115 ug/L) 1,000,000 kg/year Exceeded <1 day per year Exceede d 34 days per year Exceeded 3 days per year

16 In the absence of data concerning removal of PTAP during wastewater treatment, no removal of PTAP during wastewater treatment was assumed.Page 22 of 43 100,000 kg/year No exceedances No exceedances No exceedances

Influent Volume Freshwater invertebrates acute (COC = 180 ug/L) Endangered Freshwater invertebrates (COC = 18 ug/L) 1,000,000 kg/year Exceeded 1 day per year Exceeded 65 days per year 100,000 kg/year No exceedances Exceeded 1 day per year



## 4.4 Effects Analysis Plan
Additional open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) database 17 , which employs a literature search engine for locating chemical toxicity data for aquatic life, terrestrial plants, and wildlife. Th e ECOTOX database will be searched when the risk assessment for PTAP is prepared. Endpoints mo re sensitive than those already selected will be reviewed.

Data from an ECOTOX run for PTAP and its degradates will be evaluated for possible quantitative and/or qualitative incl usion in the risk assessment in support of Registration Review.


## 5 Endocrine Disruptor Screening Program (EDSP)

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

EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must scre en all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/dat a call-ins for the firs t group of 67 chemicals,

17 http://cfpub.epa.gov/ecotox/Page 23 of 43 which contains 58 pesticide activ e ingredients and 9 inert ingred ients. PTAP is not among the group of 58 pesticide active ingredients on the in itial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP screening assays for PTAP.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening ba ttery, please visit our website: http://www.epa.gov/endo/.


## 6 Next Steps

A DCI will be developed regarding the da ta needs listed under the “Anticipated Data Needs” section of this document. The Agency expects to issue the DCI in March 2014. The Agency will conduct human health and environmental fate and ecological hazard assessments for all uses.Page 24 of 43 

## 7 References

Ellis DD et al; Arch Environ Contam Toxicol 11: 373 – 82, 1982 Gimeno, S., Gerritsen, A., Bowmer, T., and Ko men, H. (1996) Feminization of male carp. Nature 384:221-222. Gimeno, S., Komen, H., Venderbos ch, P.W., and Bowner, T. (1997) Disruption of sexual differentiation in genetic male carp ( Cyprinus carpio ) exposed to an alkyphenol during different life stages. Environ. Sci. Technol. 31(10): 2884-2890. Gimeno, S., Komen, H., Gerritse n, A.G., and Bowner, T. (1998a ): Feminisation of young males of the common carp, Cyprinus carpio , exposed to 4-tert-p entyphenol during sexual differentiation. Aquatic Toxico logy (Amsterdam) 43: 77-92. Gimeno, S., Komen, H., Jobling, S ., Sumpter, J., and Bowner, T. (1998b): Demasculinisation of sexually mature male common carp, Cyprinus carpio , exposed to 4-tert-amylphenol during spermatogenesis. Aquatic Toxicology (Amsterdam) 43: 93-109. Holcombe, G.W., Phipps, G.L., Knuth, M.L., and Felhabert, T. (1984) The acute toxicity of selected substituted phenols, benzenes and benzoic acid ester to fathead minnows Pimephales promelas . Environ. Pollut. Ser. A Ecol. Biol. 35(4): 367-381. Hornung, M., Ankley, G.T., and Schmieder, P. (2003) Induction of an estrogen-responsive reporter gene in rainbow trout hepatoma cells (RTH-149) at 11 or 18C. Environ Toxicol. Chem. 22:866-871. McLeese, D.W. (1981) Lethality and accumulation of alkylphenols in aquatic fauna. Chemosphere 10(7): 723-730. Miller et al; Estogenic Activity of Phenolic A dditives Determined by an In Vitro Yeast Bioassay, Environmental Health Perspectives, Volume 109, Number 2, pp. 133-138, February, 2001 Routledge and Sumpter; Structural Features of Alkylphenolic Chemi cals Associated with Estrogenic Activity, Journal of Biologi cal Chemistry, Volume 272, Issue 6, pp 3280- 3288, February 7, 1997. Russon, C.L., Bradbury, S.P., Broderius, S.J ., Hammermeister, R.A., and Drummond, R.A. (1997) Predicting modes of toxic action from ch emical structure: ac ute toxicity in the fathead minnow ( Pimephales promelas ). Environ. Toxicol. Chem. 16:948-967. Seki, M., Yokota, H., Matsubara,H., Maeda, M.., Tadokoro, H., and Kobayashi, K. (2003) Fish full life cycle testing for the weak estrogen 4-1-pentylophenol on medaka ( Oryzias latipes ). Environ Toxicol Chem 22:1487-1496. Smeets, J.M.W., van Holsteijn, I., Giesy, J., Sein en, W., and van den Berg, M. (1999) Estrogenic potencies of several environmental pollutants, as determined by v itellogenin induction in a carp hepatocyte assay. Toxico logical Sciences 50: 206-213. Soto, AM et al: The E-Screen Assay as a Tool to Identify Estrogen - An Update on Estrogenic Environmental Pollutants, Environmental Health Perspectives,Vol. 103, Supplement 7, pp 113-122, October 1995 Tapper, M., Sheedy, B., Denny, J., and Schmiede r, P. (2005) Rainbow trout estrogen (ER) binding and ER-mediated vitellogenin produc tion in a trout liver slice assay. [Measurements made at the EPA/ORD/NHE ERL/Midcontinent Ecology Division (MED) Duluth, MN]Page 25 of 43 Tollefsen et al; Estrogenicity of Alkylphenols a nd Alkylated Non-Phenolic s in a Rainbow Trout ( Oncorhynchus mykiss ) Primary Hepatocyte Culture. Ecotoxicology and Environmental Safety 71, pp 370-383, 2008 U.S. Environmental Protection Agency (E PA). 2002. ECOTOX User Guide: ECOTOXicology Database System. Version 3.0. Availa ble: http://www.epa.gov/ecotox/ U.S. Environmental Protection Agency. High Pr oduction Volume Information System (HPVIS). http://www.epa.gov/hpvis/ Yamasaki et al; Immature Rat Uterotrophic Assa y of 18 Chemicals and Hershberger Assay of 30 Chemicals. Toxicology 183, pp 93-115, 2003. Yokota, H., Abe, T., Nakai, M., Murakami, H., Et o, C., and Yakabe, Y. (2005) Effects of 4-tertpemtyulphenol on the gene expression of P 450 11B-hydroxylase in the gonad of medaka. Aquatic Toxicology 71:121-132.Page 26 of 43 

# Appendix A Toxicology Profile Acute Toxicity for Product Labeling

As listed in Table 13, PTAP is a primary dermal ir ritant (Category I) and is in Category III for acute oral toxicity based on guide line studies. It is likely an ey e irritant (Category I), and is believed to be Category III for acute dermal toxic ity according to data from the open literature. However, acceptable guideline acute studies are no t available for dermal, inhalation, primary eye irritation or dermal sensitization, and the literature data protocol s were inadequate. These studies were identified as data gaps in the RED.

Table 13 – Acute Toxicity Studies for PTAP

Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100/ Acute oral toxicity 46616601 LD50 >2000 mg/kg for males and females III

870.1200/ Acute dermal toxicity N/A
N o studies were submitted and studies in the literature do not meet applicable guidelines. Th ese studies were identified as data gaps in the RED. III

870.1300/ Acute inhalation toxicity N/A Unknown

870.2400/ Acute eye irritation N/A I

870.2500/ Acute dermal irritation 46616602 Corrosive following 4 hour application; scar tissue noted 14 days after treatment I

870.2600/ Skin sensitization N/A N o study is available. This study was identified as a data gap in the RED. Unknown

N/A=Not available 

## Subchronic Toxicity

There is one rat 90-day dermal study (MRID 42470301) in the toxicology database and this study is summarized below. A subchr onic oral rodent toxicity test is expected to be required for the indirect food uses of PTAP and this study wa s identified as a data gap in the RED. In addition, due to high volatility, a subchronic inhalation study is also anticipated as needed for registration review.

90-day Rat Dermal Study (MRID 42470301) Nipacide Amylphenol was administ ered to the clipped skin of Sprague Dawley rats (10 males and 10 females/group) at dose levels of 0, 2.5, 10 and 25 mg/kg, 6 hr/day, five days/week for 13 weeks. The test substance was dissolved in a 50% v/v solution of ethanol in distilled water; all doses were administered at a constant volume of 6.0 ml/kg. No treatment-related deaths or clinical signs were observed.

Dermal irritation was not observed in controls or at 2.5 mg/kg/day. At 10 and 25 mg/kg/day, both sexes exhibited dose-related dermal irrita tion, such as erythema and desquamation which progressed to eschar formation with subsequent eschar exfoliation. The incidence and severity of the dermal irritation were increased in the 25 mg/kg/day group where the eschar formationPage 27 of 43 progressed to cover 50 - 75% of the application si te in two males and five females. Ulcerations were also observed within the exposure site of three males and five females in the 25 mg/kg/day group. Eschar formation in the 10 mg/kg/day gr oup progressed to cover 10 - 25% of the application site in one male and three females. Histopathological observations were limited to the treated skin of rats in the 10 and 25 mg/kg/ day groups. These changes included minimal to marked acanthosis, minimal to mild chronic or acute dermatitis, inflammatory exudate on the epidermal surface and occasional ulcers. The incide nce and severity of the dermal changes were dose dependent. The dermal NOAEL is 2.5 mg/kg/d ay. The LOAEL is 10 mg/kg/day based on histopathological changes, dermal irritation characteri zed by erythema, desquamation, eschar formation and subse quent eschar exfoliation.

No significant changes in body we ight or body weight gain were observed at any dose level. No significant changes in food consumption were ob served. A transient increase (p<0.05) in food consumption was noted during study days 8 - 15, but was small (+8%), and not accompanied by a corresponding change in body weight. No treatmen t-related ocular effect s were noted in test animals. Hematological parameters showed no si gnificant changes due to the test substance. Clinical chemistry parameters were not affected significantly by treatment with the test substance. Organ weights were not affected by treat ment with the test subs tance. No other gross pathological findings were made. The systemic NOAEL is 25 mg/kg/day which was the highest dose tested. 

## Developmental Toxicity

There is one developmental study for PTAP and summary of the study is included below: The single developmental study is adequate only fo r the non-food uses of PTAP. An additional developmental study in another sp ecies (i.e., rabbits) is anticipat ed as needed for registration review of indirect or direct food uses.

Prenatal Developmental Toxicity Study in Rats (MRID 41920002) Nipacide Amylphenol was administ ered by gavage to pregnant Sprague-Dawley rats (25/dose) from gestation days (GD) 6 to GD 15 at dos e levels of 0, 50, 200, and 500 mg/kg/day. Animals were sacrificed on GD 20, and dams and litters we re examined for signs of toxicity. Maternal toxicity, observed at 200 and 500 mg /kg/day, was manifested as incr eased incidences of clinical signs (mucoid/soft stools, urine stains, rales, hair loss, salivation). Decreased body weight (p<0.05, p<0.01) and decreased body weight gain of 10 - 50% (p<0.05, p<0.01) were observed at several periods during gestation in the 200 a nd 500 mg/kg/day groups, respectively. Similarly, mean food consumption was decreased 9 - 58% respectively during gestation at 200 and 500 mg/kg/day. No adverse maternal effect s were observed at 50 mg/kg/day. The maternal NOAEL is 50 mg/kg/day, and the LOAEL is 200 mg/kg/day, based on clinical signs, decreases in body weight and body we ight gain, and decreases in food consumption.

Effects in the conceptus were observed at 500 mg/kg/day and included decreased fetal body weight (-5.6%, p<0.05, measured as fetal weight/li tter) and an increased in cidence of bent ribs (p<0.05). No adverse developmental effect s were observed at 50 or 200 mg/kg/day. The developmental NOAEL is 200 mg/kg/day, and the LOAEL is 500 mg/kg/day, based on decreased fetal body weight and increased incidence of bent ribs.Page 28 of 43 

## Reproductive Toxicity

There is no reproductive toxicity study available and such a study is normally required to support indirect or direct food uses. In addition, there are other toxicological c oncerns for PTAP that need to be evaluated in a reproductive study. A two generation reproduc tion study is therefore anticipated to be needed for registration review. 

## Chronic Toxicity

The data base for chronic toxicity is adequate fo r the indirect food uses of PTAP. Tier II chronic toxicity studies are typically re quired for direct dietary uses or long-term, high-level uses (e.g., metal working fluids) and are not expected to be needed for the registered uses of PTAP. 

## Carcinogenicity

The data base for carcinogenicity is adequate for the indirect food uses of PTAP. Tier II carcinogenicity studies are typically required for direct dietary uses or long-term, high-level uses (e.g., metal working fluids) and are not expected to be needed for the registered uses of PTAP. 

## Mutagenicity

The data base for mutagenicity is considered adequate based on EPA's 1991 mutagenicity guidelines and indicates that PTAP is not mutage nic or genotoxic. In a submitted bacterial study (MRID 41438401) and in a study identified in the lit erature (Zeiger et al . 1988), PTAP was not mutagenic to the bacteria in the presence or absence of mammalian me tabolic activation. An assay using cultured mouse lymphoma cells also proved negative (MRID 41572701). Finally, a mouse micronucleus test using male and fe male CD-1 mice also was negative (MRID 41710801). 

## Other Toxicological Effects

There are studies in the literatur e that indicate PTAP has other t oxicological effects in both in vitro and in vivo testing systems. In Akahori et al. 2008, which was a comparison of Estrogenic Receptor (ER) binding and the uterotrophic assay, PTAP was positive in both. In an uterotrophic assay reported in Yamasaki et al., 2003, PTAP wa s positive as an agonist at 200 mg/kg. Soto et al. (1995) found PTAP to be estrogenic in the E-SCREEN assay, which assesses the estrogenicity of a compound by meas uring its proliferative effect on estrogen-sensitive cells. The cell number achieved by similar inocula of MCF-7 cells (estrogen-sensitive human breast cancer cells) in the absence of estrogens (nega tive control) and in the presence of 17 β -estradiol (positive control) is compared with the number of cells achi eved with a range of conc entrations of the test chemical. For PTAP, a concentration of 10 pM wa s the lowest concentra tion needed for maximal cell yield. For the positive control 17 β -estradiol, the lowest concentration needed was 30 pM. The relative proliferative effect (RPE) is calculated as 100 x (PE-1) of the test compound divided by (PE-1) of 17 β -estradiol. A value of 100 i ndicates that the compound test ed is a full agonist of the estradiol; a value of 0 indi cates that the compound lacks estr ogenicity at the doses tested. Intermediate values suggest that th e compound is a partial agonist of 17 β -estradiol. For PTAP,Page 29 of 43 an RPE of 105 was estimated. Both Routledge and Sumpter, 1997 and Miller et al., 2001, demonstrated estrogenic activity of PTAP gene activation in hER in yeast reporter system. Hornung et al., 2008 studied the gene activation in rainbow trout ER in a reporter cell line; PTAP showed positive results. Tollefsen et al., 2008 studied the binding of chemical to rainbow trout ER; PTAP showed positive results. Femini zation of young male common carp was observed when treated with PTAP (Gimeno S, Komen H, and Gerritsen AGM, Bowmer T. 1998).Page 30 of 43 

# Appendix B Environmental Fate Environmental Fate Properties

Except as noted, the environmenta l fate properties of PTAP were based on the predictions of EPI-WEB 4.0 along with the Hi gh Production Volume documents from the Office of Toxic Substances. Biodegradation of PTAP is the a pparent route of dissipation, which will form CO 2 and tightly sorbed residues.

Parent substance, PTAP

PTAP, with a pKa of 10.43, ionizes (loses hydrog en) at a higher pH value than phenol, which has a pKa value of 10. The pKa is the pH in wa ter at which 50% of the compound is ionized and 50% is not ionized. In the environmental relevant range of pH 5 to 9, virtually all PTAP will be in the un-ionized (protonated) state. The un-ionized state is less likely to move from soil by leaching to ground or runoff to surfa ce water than the ionized state.

It has a high vapor pressure (2.0 x 10 -3 mm Hg at 25 o C), a water solubility of 168 mg/l, and a Henry’s Law Constant of 2.57 x 10 -6 atm m 3 /mol. Based on this water solubility and Henry’s Law Constant, it is soluble but wi ll not volatilize significantly from water. However, it will have the tendency to volatilize from solid surfaces in to air based on the vapor pressure of 2.0 x 10 -3 mm Hg, which is greater than 1 x 10 -6 mm Hg (level of concern for volatility) (EPI-WEB 4.0, MRID 43733201).

PTAP is stable to hydrolysis (no hydrolysable func tional groups) and essentially stable to direct photodegradation because of limited light ab sorption (>290 nm). However, indirect photodegradation in air is more rapid. The reporte d half-life due to indi rect photodegradation in air (oxidation with photosensitizers such as nitr ate) is only 3 hours because of enhanced light energy sorption. The half-lives in water and soil are 1-9 and 5 days , respectively (MRID 43733201).

The estimated sorption values to organic materials (Koc) range from 1,798-3,802 ml/g, indicating that water column concentrations will te nd to partition to soil and sediment (EPI-WEB 4.0).

The Log Kow for PTAP ranges from 3.91-4.03, which is greater than the bioconcentration level of concern of Log Kow of 3 (40 CFR 158.630, 2009, pp. 122-125, Subpart G, Environmental Effects). This level of concern refers to a Kow of 1,000, which is greater than the observed bioconcentration factors of 177-230 (EPI-Web 4.0).

PTAP is not readily biodegradable in sewage sl udge with only 52% degradation after 10 days (> 60% is criteria for rapid biodegradability ) in a sewage biodegradation study (MRID 46624701). By the end of the study (28 days) 73 % of PTAP had mineralized, while 86% of sodium benzoate mineralized to CO 2 . In a monitoring study of organic constituents of mutagenically active secondary effluents from 10 industrial plants and publicly owned treatmentPage 31 of 43 works in Illinois, PTAP was detected at only one si te (final effluent from a trickling filter plant partially inoperative in Roselle, IL) although co ncentrations and detection limits were not reported (Ellis et al. , 1982).

Reaction Products/Degradates

The only degradation products identified were CO 2 , which occurred in sewage sludge. However, the phenolic nature of the compound indicates that CO 2 and tightly sorbed residues are formed (MRID 46624701).Page 32 of 43 

# Appendix C Ecotoxicology Profile Toxicity to Terrestrial Receptors

Birds

For indoor uses, an acute oral t oxicity study using the technical grade of the active ingredient (TGAI) is anticipated to be needed for use in es tablishing the toxicity of PTAP and its salts to birds. The 2005 RED indicated this data gap but the DCI has not yet gone out. The preferred test species is either mallard duck (a waterfowl) or northern bobwhite quail (an upland game bird). Two avian acute toxicity studies were found in th e Agency's files for PTAP and its salts. The tests were conducted in 1974 using the bobw hite quail (MRID 00049836) and mallard duck (MRIDs 00049838 and 00096236). The tests were conduc ted using antiquated procedures. The results showed moderate toxicity, which high lights the importance of obtaining a study that satisfies the current guideline requirements (850.2100).

A single acute oral is anticipate d to be required to support hazard labeling. Furthermore, since PTAP is expected to reach surface water, these da ta are anticipated as needed for use in a risk assessment for examining risks to bird s ingesting water containing PTAP. 

## Toxicity to Aquatic Receptors

Freshwater Fish

Two fish studies were found in the Agency’s files, but no studies have been submitted by registrants to support regist ration of PTAP. The first st udy (MRID # 240116619) was conducted in 1974 and tested both rainbow trout and bluegi ll sunfish in the same study. The second study (MRID # 444742-08) was conducted in 1992 using zebra fish, but only tested one concentration of TGAI. Neither of these studies meets current guidelines, and cannot be used in a risk assessment. However, as explained below, the agency intends to use values estimated from surrogate species and does not an ticipate the need to require addi tional studies for these specific fish species.

In the 2005 RED, results from freshwater fish ac ute toxicity studies with fathead minnow were obtained from peer-reviewed literature. The fathea d minnow acute toxicity values ranged from 2,500 μg/L to 16,000 μg/L (Holcombe et al. 1984 and Russon et al ., 1997). The first study (Holcombe et al. , 1984) was conducted using criteria simila r to OPPTS guidelines and is more likely to be used in a risk assessmen t than the subsequent study (Russon et al ., 1997) which did not provide any information on how the study was c onducted. The data indicate that PTAP is at least moderately toxic to warmwater species, such as the fathead minnow. The fathead minnow is considered to be less sensitive than the pref erred warmwater bluegill and that of the coldwater species, rainbow trout.

Where results with only nonprefe rred species are available, speci es uncertainty factors may be applied or models may be used to estimate toxi city values for the pref erred sensitive indicator species. The Web-based Interspecies Correlati on Estimation (Web-ICE) application estimatesPage 33 of 43 acute toxicity to a desired aquatic species, for which data are missing, from data for a different species. Web-ICE version 3.1 was used to estimate the toxicity to blueg ill sunfish (1,560 μg/L; 95% C.I. 1,068 – 2,280 μg/L) and the rainbow tr out (1,160 μg/L; 95% C.I. 849 – 1,588 μg/L). Web-ICE includes polar narcosis compounds w ithin its model data for development of correlation estimates. For the fathead minnow the toxicity value for PT AP falls within the midrange of the fathead mi nnow toxicity model data.

The HPV Information System (HPV IS) contains an estimated acute ecotoxicity value for PTAP to fish. Fish is an amalgamation of a number of different species, and does not represent a specific species. The estimated acute 96-hr LC 50 fish value calculated using ECOSAR v.0.99e is 1,600 μg/L. ECOSAR v.1.11, the most recent vers ion of ECOSAR, estimated an acute 96-hr LC 50 of 817 μg/L and a chronic value of 111 μg/L. ECOSAR v.1.11 estimates will be used in the ecological risk assessment unless acute and chroni c affects data for PTAP are submitted to the agency. Because of these available estimates, acute and chronic (early life stage) fish data are not anticipated to be required.

The Web-based Interspecies Correlation Estim ation (Web-ICE) application estimates acute toxicity to a desired aqua tic species, for which data are missing, from data for a different species. Web-ICE version 3.1 released January 2010 was used to estimate the toxicity to bluegill sunfish and rainbow trout (see below). Polar narcosis substa nces are part of the m odel data domain used to develop the ICE values. Because the model allows prediction for a specific species and includes polar narcosis compounds in the model da ta set, the 95% lower confidence limit of 849 μg/L for rainbow trout will be used to asse ss acute risks to freshwater fish species.

Table 14 – Aquatic Organism PTAP Toxicology

Test Organisms Exposure Scenario and Comments Test Substance (% Purity) Toxicity Endpoint (95% C.I.) Study Classification/ Toxicity Classification Reference

Rainbow trout Freshwater PTAP Unacceptable MRID 240116619 Bluegill sunfish Freshwater PTAP Unacceptable MRID 240116619 Zebrafish Freshwater PTAP Unacceptable MRID 44474208

Fathead minnow ( Pimephales promelas ) Freshwater flowthrough; -necrosis observed in surviving fish PTAP 96-hr LC 50 = 2,500 (1,870 – 3,340) moderately toxic Holcombe, G W et al . 1984

Rainbow trout Freshwater -- 96-hr LC 50 = 849* highly toxic Web-ICE v.3.1 (see calculations below) Fathead minnow ( P. promelas ) freshwater PTAP 96-hr LC 50 = 16,000 (NR) slightly toxic Russon, C L et al

. 1997 Shrimp ( Crangon septemspinosa ) estuarine PTAP 96-hr LC 50 = 1,700 (NR) moderately toxic McLeese, D W 1981 *95% lower confidence limit value from Web-ICE calculations

Web-ICE version 3.1 Calculator - Aquatic Species (Freshwater Fish)
Surrogate Species: Fathead minnow ( Pimephales promelas ) Predicted Species: Rainbow trout ( Oncorhynchus mykiss ) Surrogate Acute Toxicity (log value) Predicted Acute Toxicit y (lo g value)Page 34 of 43 μ g/L (3.39) 1160.75 μ g/L (3.06)

Select Confidence Interval : Lower Limit Upper Limit

848.67 μ g/L 1587.59 μ g/L

Model Information Intercept: -0.095072 Slope: 0.929919 Degrees of Freedom (N-2): 79 R 2 : 0.825954 p-value: 0.000000 Average value of surrogate (log value): 2307.11 (3.36) Minimum value of surrogate (log value): 1.18 (0.075366) Maximum value of surrogate (log value): 10600000.00 (7.02) Mean Square Error (MSE): 0.389762 Sum of Squares (S xx ): 168.97 Cross-validation Success (%): 87.65 Taxonomic Distance: 4

Surrogate Species: Fathead minnow ( Pimephales promelas ) Predicted Species: Bluegill ( Lepomis macrochirus ) Surrogate Acute Toxicity (log value) Predicted Acute Toxicit y (lo g value)

μ g/L (3.39) 1560.46 μ g/L (3.19)

Select Confidence Interval : Lower Limit Upper Limit

1068.19 μ g/L 2279.58 μ g/L

Model Information Intercept: 0.022235 Slope: 0.933218 Degrees of Freedom (N-2): 66 R 2 : 0.790938 p-value: 0.000000

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95%

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95%Page 35 of 43 Average value of surrogate (log value): 1843.51 (3.26) Minimum value of surrogate (log value): 1.18 (0.075366) Maximum value of surrogate (log value): 10600000.00 (7.02) Mean Square Error (MSE): 0.475436 Sum of Squares (S xx ): 136.31 Cross-validation Success (%): 80.88 Taxonomic Distance: 4

Endocrine Disruption

Data from the open literature th at was identified in the 2005 RED indicates that PTAP is an endocrine disruptor (see the fo llowing Table). For known reproduc tive toxicants, fish full life cycle testing is required rather than early life stages. There ar e no early life stage or fish life cycle data submitted in support of PTAP. There is a chronic estimate fo r PTAP from ECOSAR, but it is an estimate based on early life stage da ta, and represents an estimate of the geometric mean of a NOAEC and LOAEC value, whereas a NOAEC value is required for this assessment. The estimated chronic value from ECOSAR v1. 11 is 111 μg/L. The ECOSAR estimated chronic value provides supplemental inform ation, but it is not adequate to conduct a risk assessment for PTAP. Since estimated chronic values based on ear ly life stages are not adequate as substitutes for full life cycle values, the agen cy anticipates the need to re quire a fish life-cycle study.

Table 15 – Examples of PTAP Affect ing the Endocrine System in Fish
Organism/ Age Results Comments Reference

Male common carp ( Cyprinus carpio )/ - exposed embryos and fingerlings at various
ages - caused formation of oviducts in male fish and reduced the number of primordial germ cells in gonads - identified as an ecoestrogen - test concentration 140 ppb Gimeno et al . 1997 Environ Sci Technol 31(10): 2884-2890.Page 36 of 43 Organism/ Age Results Comments Reference

Male common carp ( C. carpio ) - 30-day EC 50 for oviduct formation = 63 ug/L NOEC for oviduct formation <36 ppb primordial germ cells lower in treated fish NOEC for vitellogenin induction =90-256 ppb - identified as causing endocrine disruption effects - 120 male carp tested - nominal concentrations of 100, 320, and 1000 ppb - 160 day test duration - intermittent flow through system Gimeno, S. et al

. 1998a, Aquatic Toxicology (Amsterdam) 43:77- 92.

Cultured hepatocytesfrom geneticallyuniform, all male, F 1 - hybrid progenies of common carp ( C. capio ) - vitellogenin induction in carp hepatocytes with LOEC ranging from 5-50 uM, - cytotoxic at 100 uM - identified as causing endocrine disruption effects -six month old hepatocytes with fully
mature testes containing mature
sperm Smeets, J. M. et al

. 1999. Toxicol. Sci. 50(2): 206-213.

Trout RTH 149 Recombinant trout-ER - Estrogenic LOEC = -6 log M; IC 50 = 7.6x10 -7 M - identified as causing endocrine disruption effects - relative potency is 0.036 approx. 75% of maximum E 2 Hornung et al . 2003

Partial life cycle carp ( C. carpio ) - Estrogenic LOEC = -6.2 log M - identified as causing endocrine disruption effects - oviduct development in male Gimeno et al . 1996

Partial life cycle Medaka ( Oryzias latipes ) - Estrogenic LOEC = -5.8 log M - identified as causing endocrine disruption effects - sex reversal; - Inhibition of P450 11B hydroxylase mRNA levels Yokota et al . 2005

Full life cycle Medaka ( O. latipes ) - Estrogenic LOEC = -6.5; - cytoxicity = - 5.2 F 0 and -5.8 F 1 - identified as causing endocrine disruption effects - Vtg induction at -6.5 log M Seki et al . 2003

Rainbow trout cytosol ER competitive binding - Estrogenic LOEC = -5 log M; IC 50 = 2.2x10 -4 M; - RBA 0.004 % - identified as causing endocrine disruption effects Tapper et al . 2005

Male rainbow trout liver slice/Vtg gene expression - elevated levels of vitellogenin, inhibition of spermatogenesis, disappearance of speratozoa and spermatogenic cysts, reduced diameter of seminiferous lobules, reduced spermatocrit values and early appearance of ovo-testes LOAEL= 32 ppb - identified as causing endocrine disruption effects and no mortality or growth effects - 3 month test duration - nominal concentrations of 32, 100, 320 and 1000 ppb were tested Gimeno et al . 1998b

Freshwater Invertebrates

No freshwater invertebrate toxicity studies were submitted in support of PTAP or identified from peer-reviewed literature in the 2005 RED. As with fish, the HPVIS contains estimated ecotoxicity values for PTAP to aquatic invert ebrates using ECOSAR. Estimated values were calculated using ECOSAR v.0.99e. As with the chr onic fish data, the chr onic value in ECOSAR represents the geometric mean of the NOAEC and LOAEC, rather than the NOAEC used in this assessment. The values are as follows:Page 37 of 43  Acute Toxicity to Aquati c Invertebrates: 48 hour LC 50 =1500 μg/L ( Daphnia sp. )

 Chronic Aquatic Invertebrate Toxicity: 21 day ChV=170 μg/L ( Daphnia sp. )

ECOSAR v.1.11 estimates are as follows:

 Acute Toxicity to Aquati c Invertebrates: 48 hour LC 50 = 608 μg/L ( Daphnia sp. )

 Chronic Aquatic Invertebrate Toxicity: ChV = 115 μg/L ( Daphnia sp. )

Web-ICE version 3.1 provides an acute 48-hr EC 50 estimate for Daphnia magna of 357 μg/L (95% C.L. 169 – 755 μg/L), which is lower than the value estimated from ECOSAR.

The most conservative estimates will be used in the ecological risk assessment unless acute and chronic affects data for PTAP ar e submitted to the agency. Because of these available estimates, the agency does not anticipate the need to require acute and chroni c invertebrate data.

Web-ICE version 3.1 Calculator - Aquati c Species (Freshwater Invertebrates)
Surrogate Species: Fathead minnow ( Pimephales promelas ) Predicted Species: Daphnid ( Daphnia magna ) Surrogate Acute Toxicity (log value) Predicted Acute Toxicit y (lo g value)

μ g/L (3.39) 357.39 μ g/L (2.55)

Select Confidence Interval : Lower Limit Upper Limit

169.15 μ g/L 755.09 μ g/L

Model Information Intercept: -0.499292 Slope: 0.898321 Degrees of Freedom (N-2): 85 R 2 : 0.404881 p-value: 0.000000 Average value of surrogate (log value): 6752.64 (3.82) Minimum value of surrogate (log value): 1.49 (0.176091) Maximum value of surrogate (log value): 26500000.00 (7.42) Mean Square Error (MSE): 2.16 Sum of Squares (S xx ): 155.05 Cross-validation Success (%): 34.48 Taxonomic Distance: 6

2500

95%Page 38 of 43 Estuarine/Marine Fish

Web-ICE version 3.1 Calculator - Aqua tic Species (Estuarine/Marine Fish)
Surrogate Species: Fathead minnow ( Pimephales promelas ) Predicted Species: Sheepshead minnow ( Cyprinodon variegatus ) Surro g ate Acute Toxicit y (lo g value) Predicted Acute Toxicit y (lo g value)

μ g/L (3.39) 2258.55 μ g/L (3.35)
Select Confidence Interval: Lower Limit Upper Limit

1010.64 μ g/L 5047.35 μ g/L

Model Information Intercept: 1.62 Slope: 0.507579 Degrees of Freedom (N-2): 12 R 2 : 0.536675 p-value: 0.002883 Average value of surrogate (log value): 2230.26 (3.34) Minimum value of surrogate (log value): 2.68 (0.428134) Maximum value of surrogate (log value): 186000.00 (5.26) Mean Square Error (MSE): 0.358983 Sum of Squares (S xx ): 19.36 Cross-validation Success (%): 78.57 Taxonomic Distance: 4

Estuarine/Marine Invertebrates

No studies on marine/estuarine invertebrates were found in the ECOTOX database (EPA, 2002). One study was found in the peer-reviewed literat ure. The peer reviewed study (McLeese, 1981) measured the acute toxicity to shrimp was LC 50 =1,700 μg/L. This indicates that PTAP is

2500

95%Page 39 of 43 moderately toxic to shrimp. The study does not meet current guideline requirements and cannot be used in a risk assessment. An acute freshwater invertebrates toxicity study is anticipated to be required for registration review.Page 40 of 43 

# Appendix D Screening Level Down-theDrain Analysis

The Down-the-Drain (DtD) module of E-FAST (E xposure and Fate Assessment Screening Tool), version 2 was used to screen for the potentia l for aquatic organisms downstream of domestic wastewater treatment plants to be exposed to PTAP. The Down-t he-Drain module uses daily per capita release of household wastewat ers, stream dilution factors, and wastewater treatment plant removal efficiency to provide both high-end and median (average) time-averaged surface water concentrations of chemicals discharged by domes tic wastewater treatment plants. The high-end scenario uses surface water concentrations downstr eam of domestic wastewater treatment plants based on the 10 th percentile stream dilution factor (SDF); the average scenario uses surface water concentrations based on the 50 th percentile SDF. SDF is defined as the ratio of the stream flow downstream of a wastewater treatment plant to th e wastewater treatment plant flow. Inputs used to run the DtD module included concentrations of concern (C OCs) for aquatic organisms, percent removal during wastewater treatment, and hypothetical wastewater treatment plant influent volumes. The results of the DtD module are expressed as number of days of exceedance of COCs for aquatic organisms. COCs for acute effects were determined by dividing LC 50 values from acute toxicity tests on aquatic vertebrates and invertebrates by 2. COCs for chronic effects for non-listed species were based on No Observ ed Adverse Effects Concentration (NOAEC) values from tests on aquatic vertebrates and invertebrates. COCs for listed endangered and threatened aquatic organisms were determined by dividing LC 50 values from acute toxicity tests on aquatic vertebrates and invertebrates by 20. In the absence of data on removal of PTAP during wastewater treatment, no removal of PT AP during wastewater treatment was assumed. The Down-the-Drain module was first run using a high-end scenario to determine whether the model predicted exceedances of concentrations of concern. If the high-end scenario predicted exceedances of the concentration of concern, the model was also run using the average scenario. The Down-the-Drain module was run using ecoto xicology endpoints for freshwater fish and invertebrates that were estimated using two different tools: ECOS AR, version 1.11, and WebICE, version 3.1. For freshwater fish, ECOSAR estimated an acute t oxicity endpoint of 0.817 ppm (LC 50 = 817 ug/L) and a chronic toxicity endpoi nt of 0.111 ppm (111 ug/ L). For freshwater invertebrates, ECOSAR es timated an acute ecotoxicity endpoint of 0.608 ppm (LC 50 = 608 ug/L) and a chronic toxicity endpoint of 0.115 pp m (115 ug/L). Web-ICE estimated an acute ecotoxicity endpoint of 849 ug/L (LC 50 = 849 ug/L) for freshwater fish and 357 ug/L (LC 50 = 357 ug/L) for freshwater invertebrates. Web -ICE does not estimate chronic ecotoxicity endpoints.

For freshwater fish, the ecotoxicology endpoint s estimated from ECOSAR corresponded to an acute COC of 409 ug/L (LC 50 /2), an endangered species COC of 41 ug/L (LC 50 /20), and a chronic COC of 111 ug/L. At a wastewater treatment plant influent volume of 1,000,000 kilograms per year PTAP, the high-end scenario of E-FAST predicted that the acute COC for freshwater fish of 409 ug/L would be exceeded less than one day per year, the endangered species COC of 41 ug/L would be exceeded 22 days per year, and the chronic COC of 111 ug/L would be exceeded 3 days per year. The COCs that were predicted to be exceeded for one day orPage 41 of 43 more per year based on the high-end scenario fo r a wastewater treatmen t plant influent volume of 1,000,000 kilograms per year were also used as inputs to estimate the number of days per year of exceedance based on the average scenario. At a wastewater treatment pl ant influent volume of 1,000,000 kilograms per year PTAP, based on the av erage scenario the endangered species COC was predicted to be exceeded 2 days per year and the chronic COC was predicted to be exceeded less than one day per year. At a wastewater treatment pl ant influent volume of 100,000 kilograms per year PTAP, the high-end scenario of E-FAST predicted no exceedances of acute, endangered species, or chronic COCs for freshwater fish.

For freshwater invertebrate s, the ecotoxicology endpoint s estimated from ECOSAR corresponded to an acute COC of 304 ug/L (LC 50 /2) , an endangered species COC of 30.4 ug/L (LC 50 /20), and a chronic COC of 115 ug/L. At a wastewater treatment plant influent volume of 1,000,000 kilograms per year PTAP, the high-end scen ario of E-FAST predicted that the acute COC of 304 ug/L would be exceeded less than one day a year, the endangered species COC of 30.4 ug/L would be exceeded 34 days per year and the chronic COC of 115 ug/L would be exceeded 3 days per year. The COCs that were pr edicted to be exceeded for one day or more per year based on the high-end scenario for a wa stewater treatment plant influent volume of 1,000,000 kilograms per year were also used as input s to estimate the number of days per year of exceedance based on the average scenario. For th e average scenario of E-FAST, the endangered species COC was predicted to be exceeded 4 days per year and the chronic COC was predicted to be exceeded less than one da y per year. At a wastewater treatment plant influent volume of 100,000 kilograms per year PTAP, the high-end scen ario of E-FAST pred icted no exceedances of acute, endangered species, or chronic COCs for freshwater invertebrates.

For freshwater fish, the ecotoxicology endpoint s estimated from Web-ICE corresponded to an acute COC of 425 ug/L (LC 50 /2) and an endangered species COC of 42.5 ug/L (LC 50 /20). At a wastewater treatment plant influent volume of 1,000,000 kilograms per year PTAP, the high-end scenario of E-FAST predicted that the acute COC for freshwater fish of 425 ug/L would be exceeded less than one day per year and the endangered species COC of 42.5 ug/L would be exceeded 20 days per year. The COCs that were predicted to be exceeded one day or more per year based on the high-end scenario for a wa stewater treatment plant influent volume of 1,000,000 kilograms per year were also used as input s to estimate the number of days per year of exceedance based on the average scenario. For th e average scenario of E-FAST, the endangered species COC was predicted to be exceeded 2 days per year. At a wastewater treatment plant influent volume of 100,000 kilograms per year PTAP, the high-end scenario of E-FAST predicted no exceedances of acute, endangered sp ecies, or chronic COCs for freshwater fish.

For freshwater invertebrate s, the ecotoxicology endpoint s estimated from Web-ICE corresponded to an acute COC of 180 ug/L (LC 50 /2) and an endangered species COC of 18 ug/L (LC 50 /20). At a wastewater treatment plant in fluent volume of 1,000,000 kilograms per year PTAP, the high-end scenario of E-FAST pred icted that the acute COC for freshwater invertebrates of 180 ug/L would be exceeded 1 da y per year and the endangered species COC of 18 ug/L would be exceeded 65 days per year. The CO Cs that were predicted to be exceeded one or more days per year based on the high-end scen ario for a wastewater treatment plant influent volume of 1,000,000 kilograms per year were also us ed as inputs to estimat e the number of daysPage 42 of 43 per year of exceedance based on the average scenar io. For the average scen ario of E-FAST, the endangered species COC was predicted to be exceeded 7 days per year. At a wastewater treatment plant influent volume of 100,000 kilogr ams per year PTAP, the high-end scenario of E-FAST predicted 1 day of exceedance per ye ar for the endangered species COC and no exceedances for the acute and chronic COCs.

Activated Sludge

No data are available regarding concentrations of PTAP that may potentia lly inhibit respiration of activated sludge microorganisms, which are the most sensitive microorganisms present in wastewater treatment systems. Results from ready biodegradability studies i ndicate that PTAP is not readily biodegradable; these results indicate that PTAP may potentially inhibit activated sludge microorganisms at fairly low concentr ations. Consequently, an Activated Sludge Respiration Inhibition (ASRI) st udy is anticipated to be required for use in determining concentrations at which PTAP would be expect ed to inhibit respira tion of activated sludge microorganisms.

Data on degradation and transport during wastewater treatment are anticipa ted to be needed to determine the extent of removal of PTAP prior to being released to wa ter bodies downstream of WWTPs. Since PTAP failed the ready biodegr adability test (MRID 46624701), results from a simulation test would be anticipated to be needed to determine the extent of biodegradation of PTAP during wastewater treatment. The log Kow of PTAP of 4.03 indicate s that this chemical has the potential to be removed by sorption to activated sludge during wastewater treatment. An Activated Sludge Sorption Isotherm test is anticipated to be requi red to determine the extent to which PTAP would be expected to be rem oved by sorption during wa stewater treatment.Page 43 of 43 

# Appendix E Comments Received Concerning the Preliminary Work Plan

The Agency received two comments on the initial docket, described below. In the PWP, the Agency solicited comments on specific topics : environmental justice, water body impairment, trade irritants, and structure ac tivity relationships. No comments or information were received during the public comment pe riod concerning these issues.

Comment: The Physicians Committee for Responsib le Medicine (PCRM) suggests the registrant use (a) Organisation for Economic Cooperation a nd Development (OECD) Test Guideline (TG) 223 (Avian Acute Oral Toxicity Test), rather than the EP A Guideline 850.2100 and (b) OECD TG 443 (Extended One-Generation Reproductive Toxi city Study) instead of the multi-generation EPA guideline 870.3800.

Response: The Agency agrees th at (a) results from tests c onducted according to OECD 223 18 or OCSPP Guideline 850.2100 can be submitted for consid eration to address the Avian Acute Oral Toxicity Test requirement 19 and (b) results from tests conducted according to OECD 443 20 or OCSPP Guideline 870.3800 can be submitted for c onsideration to address the Reproductive Toxicity Study requirement 21

. Comment: The FIFRA Endangered Species Task Force (FESTF) submitted a comment noting that it has data that will assist the Agency in conducting an endangered species risk assessment for 4-t-amylphenol, and requesting that any techni cal registrant for 4-t- amylphenol who is not a member of the FESTF (or a company having met its data compensation oblig ations) be asked to provide a formal offer-to-pay to FESTF for reliance on their data.

Response: The Agency thanks FESTF for its comment and will consider this information as it conducts the registration review and make s its registration review decisions.

18 http://www.oecd-ilibrary.org/environment/test-no-22 3-avian-acute-oral-toxicity-test_9789264090897-en
19 OECD TG 233 using the "LD 50 - slope test" or "limit dose test" can be us ed instead of OCPSS 85 0.2100 for certain species and conditions ( e.g ., causes no delayed effects, causes no regurgitation). Details on the species and conditions under which TG 233 would not fulfill the data requirement are described at http://www.epa.gov/pesticides/science/efed/policy_guidan ce/team_authors/terrestrial_biology_tech_team/review_av ian_acute_oral_oecd_tg223.htm
20 http://www.oecd-ilibrary.org/environment/test-no-44 3-extended-one-generation-reproductive-toxicitystudy_9789264122550-en
21 The Agency will accept a multi-generation or an extended one-generation reproductive and fertility effects study.