Docke t Number EPA -HQ-OPP-2012-0682
www.regu l ations.gov



## 4-tertiary-Amylphenoi and Salts Preliminary Work Plan

Registration Review: Initial Docket Case Number 3016

September 2012

Approved by:**~ ~**  

### J 

### an Harrigan-F affe lly**Director** 

### Antimicrobia ls Di vis ion

Date: 

# 1/ovt/ ;kl I.Z

Page 1 of43Page 2 of 43 

### Table of Contents
1 Introduction

................................ ................................ ................................ ............................. 4

1.1 Statutory and Regulatory Authority

................................ ................................ ................. 4

1.2 Case Overview

................................ ................................ ................................ ................. 6

1.3 Chemical Identification and Properties

................................ ................................ ............ 6

1.4 Use/Usage Description

................................ ................................ ................................ ..... 7

1.4.1 Registrations

................................ ................................ ................................ ............. 7

1.4.2 Summary of Registered Uses

................................ ................................ .................... 7

1.4.3 Usage Information

................................ ................................ ................................ .... 8

1.5 Regula tory History

................................ ................................ ................................ ........... 8

1.5.1 Recent/Pending Regulatory Actions

................................ ................................ ......... 8

1.5.2 Tolerance Information

................................ ................................ .............................. 9

1.6 In cidents

................................ ................................ ................................ ........................... 9

1.6.1 Human Health

................................ ................................ ................................ ........... 9

1.6.2 Ecological

................................ ................................ ................................ ................. 9

2 Anticipated Data Needs

................................ ................................ ................................ .......... 9

3 Human Health Risk Assessment

................................ ................................ ........................... 12

3.1 Existing Toxicological Endpoints

................................ ................................ .................. 12

3.2 Dietary Exposure

................................ ................................ ................................ ............ 13

3.2.1 Food

................................ ................................ ................................ ........................ 13

3.2.2 Drinking Water

................................ ................................ ................................ ....... 14

3.3 Occupational and Residential Exposures

................................ ................................ ....... 14

3.3.1 Occupational Handler Exposure

................................ ................................ ............. 14

3.3.2 Residential Handler Exposures

................................ ................................ ............... 15

3.3.3 Residential Post

- Application Exposures

................................ ................................ . 15

3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 16

3.4.1 Aggregate Exposures

................................ ................................ .............................. 16

3.4.2 Cumulative Exposures

................................ ................................ ............................ 16

4 Environmental Risk Assessment

................................ ................................ ........................... 16

4.1 Environmental Conceptual Model Exposure Pathways

................................ ................. 16

4.2 Ecological Effects Assessment

................................ ................................ ....................... 18

4.2.1 Mechanism of Action

................................ ................................ .............................. 18

4.2.2 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 19

4.3 Exposure Analysis Plan

................................ ................................ ................................ .. 20Page 3 of 43 4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............ 20

4.3.2 Screening Level Down

- the

- Drain Analysis

................................ ............................ 21

4.4 Effects Analysis Plan

................................ ................................ ................................ ..... 21

5 Endo crine Disruptor Screening Program (EDSP)

................................ ................................ . 22

6 Guidance for Commenters

................................ ................................ ................................ .... 2 3

6.1 Preliminary Work Plan

................................ ................................ ................................ ... 23

6.1.1 Trade Irritants

................................ ................................ ................................ .......... 23

6.1.2 Water Quality

................................ ................................ ................................ .......... 23

6.1.3 Environmental Justice

................................ ................................ ............................. 23

6.1.4 Structure Activity Relationships

................................ ................................ ............. 24

6.1.5 Additional Information

................................ ................................ ........................... 25

7 Next Steps

................................ ................................ ................................ ............................. 25

8 References

................................ ................................ ................................ ............................. 26

Appendix A T oxicology Profile

................................ ................................ ............................... 28 Appendix B Environmental Fate

................................ ................................ ............................. 32 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 34 Appendix D Screening Level Down

- the

- Drain Analysis

................................ ........................ 41

List of Tables Table 1

- Summary of Anticipated Risk Assessm ents and Data Needs

................................ ......... 5 Table 2

- Anticipated Registration Review Schedule

................................ ................................ ..... 5 Table 3

- Chemical Identification of p

- tertiary

- Amyl Phenol (PTAP)

................................ ........... 6 Table 4

- Physical

- Chemical and Fate Properties for PTAP and salts

................................ ............ 6 Table 5

- Summary of PTAP Registered Uses

................................ ................................ ................ 7 Table 6

– Studies Anticipated as Needed for the Registration Review of PTAP

......................... 10 Table 7

– Existing Toxicological Endpoints

................................ ................................ ................. 12 Table 8

– Occupational Handler Exposure Sc enarios for PTAP

................................ .................. 14 Table 9

– Residential Handler Exposure Scenarios for PTAP

................................ ..................... 15 Table 10

– Residential Post

- Application 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 14

- Acute Toxicit y Studies for PTAP

................................ ................................ ................ 28 Table 15

– Aquatic Organism PTAP Toxicology

................................ ................................ ......... 35 Table 16

– Examples of PTAP Affecting the Endocrine System in Fish

................................ ..... 37

List of Figures Figure 1

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

................................ .......... 18Page 4 of 43 

## 1 Introduction

1.1 Statutory and Regulatory Authority
The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distributed or sold in the Unit ed States 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 risks to human health or the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects to hum an 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 m arketplace can be used safely. Information on this program is provided at http://www.epa.gov/oppsrrd1/registration_review/

. The Agency is implementing the registration review program pursuant t o Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration. The regulations governing registration review begin at 40 CF R 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 registration review decision. After reviewing and responding to comments and data received in the docket during this initial comment period, the Agency will develop and commit to a F inal W ork P lan (FWP) and anticipated schedule for the 4

- tertiary

- Amylphenol and Salts Case.

Documents associated with this registration review can be viewed at http://www.regulations.gov in docket EPA

- HQ

- OPP

- 2012

- 0682. Below is a summary of t he issues relevant to this registration review case.Page 5 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 more detail about anticipated data needs)

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

Tolerance Review No N/A None 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 Registration Review Schedule

Anticipated Activity Target Date Completion Date Phase 1: Opening the Docket Open Docket and 60

- Day Comment Period for Preli minary Work Plan 2012

- 09 2012

- 09

- 26 Close Public Comment Period 2012

- 11 Phase 2: Case Development Issue Final Work Plan 2013

- 03 Issue Data Call

- In (DCI) 2014

- 03 Receive Data to be Considered in Risk Assessment 2016

- 03 Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 2017

- 09 Close Public Comment Period 2017

- 1 0 Phase 3: Registration Review Decision and Implementation Open 60

- Day Public Comment Period for Pro posed Decision 2018

- 03 Close Public Comment Period 2018

- 0 5 Issue Final Decision 2018

- 09 Begin Post

- Decision Followup 2018 Total (years) 6Page 6 of 43 

## 1.2 Case Overview

The docket for the 4

- tertiary

- Amylphenol and Salts Case (Case 3016) has been established at http://www.regulations.gov in docket number EPA

- HQ

- OPP

- 2012

- 0682.



## 1.3 Chemical Identification and Properties

Table 3 presents the three active ingredients to be assessed in C ase 3016 : 4

- tertiary

- amylphenol (PC Code 064101) ; p

- tertiary

- amylphenol, potassium salt (PTAP

- K, PC Code 064111) ; and p

tertiary

- amylp henol, sodium salt (PTAP

- Na, PC Code 064112). Except where otherwise noted, the three active ingredients in this case will 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 (PTAP

- Na)
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

The PTAP product chemistry information relevant to risk assessment is summarized in Table 4

.

Table 4

- Physical

- Chemical and Fate 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

.

830.1800 Enforcement analytical method GC MS GC MS GC MS

830.6302 Color White crystals White White
830.6303 Physical State Solid; Flakes Solid Solid
830.6304 Odor Slight phenolic odor Slight phenolic odor Slight phenolic odor

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 3,811 mg/L (EPI 4,595 mg/L (EPIPage 7 of 43 (Measured) Suite) 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 a t 25 o C (Calculated) 5.4 x 10 - 14 atm

m 3 /mole at 25 o C (EPI Suite) 4.1 x 10 - 14 atm

m 3 /mole at 25 o C (EPI suite)



## 1.4 Use/Usage Description

1.4.1 Registrations

There are 36 EPA

- registered products that contain PTAP as an active ingredient (a.i .). The products include 34 that contain 4

- tertiary

- amylphenol , one product that contains the potassium salt of PTAP (PTAP

- K), and one product that contains the sodium salt of PTAP (PTAP

- Na). The percent a.i. ranges from 0.00275 percent to 10 percent and t he formulations include ready to use solutions, liquid concentrates, pressurized liquids in aerosol cans, and wipes. All of these products contain other phenol active ingredients such as o

- phenyl phenol ( o PP) or o

- benzyl

- p

chlorophenol ( o BCP). There is one manufacturing use product ( EPA Registration Number 39967

- 82) that contains 98.5 percent 4

- tertiary

- amylphenol.



### 1.4.2 Summary of Registered Uses

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

.

Table 5

- Summary of PTAP Registered Uses

Use Application Method Application Rate Agricultural Premises and Equipment

– Indirect Food Contact

Non

- porous surfaces in: Animal and poultry farms, egg handling areas, aquaculture greenhouses and mushroom farms 1 Fogger, Thermal Unknown 2
Fogger, Total Release 0.5 mg/m 3

Mop, Soak or Wipe 76 to 598 ppm

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

Non

- porous surfaces

- Floors, walls, finished woodwork, chairs, countertops, sinks, garbage cans, cabinets. Fogger, Total Release 0.2 to 1.4 mg/m

Mop, Spray, Wipe 28 to 598 ppm Food Handling/Storage Establishments Premises and Equipment

– Indirect Food Contact

Non

- porous surfaces Fogger Unknown 2Page 8 of 43 Mop, Spray, Wipe 78 to 450 ppm

Residential and Public Access Premises

Non

- porous surfaces 3 Fogger, Thermal Unknown 2
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 2
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 Labels specify that use is not permitted in milking stalls, milking parlors or milk houses.

2 L abels 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 ).

3 Labels specify that fogger use is not permitted in a room 5ftx5ft or smaller.



### 1.4.3 Usage Information

According to the Kline Biocides Report for 2004/2005 (Kline, 2005), PTAP makes up less than 1
pe rcent of the estimated U.S. consumption of specialty biocides in household disinfectant and sanitizer products. Production volume data in the EPA Section Seven Tracking System (SSTS) for the years 2004 through 2008 indicate that no more than 100,000 kilogr ams of PTAP are sold per year in the United States 1

.


## 1.5 Regulatory History
The first product containing PTAP as an active ingredient was registered in the United States in 1962. The first product containing PTAP

- K as an active ingredient was registered in th e United States in 1967. The first product containing PTAP

- Na as an active ingredient was registered in the United States in 1986. The Agency completed a Reregistration Eligibility Decision (RED) for PTAP in 2005. The p ost

- RED Data Call

- In (DCI) has not be en issued.



### 1.5.1 Recent/Pending Regulatory Actions
There are no recent regulatory actions for PTAP

. EPA anticipates issuing the post

- RED DCI

soon.

1 Data for the years 2009 through 2011 were not used in this estimate since data collection is still in progress.Page 9 of 43 

### 1.5.2 Tolerance Information

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 a limit of 80 ppm. The need for additional tolerances or tolerance exemptions will be determin ed during the risk assessment stage of this registration review.



## 1.6 Incidents

1.6.1 Human Health

No PTAP human poisoning incidents have been reported in OPP’s Incident Data System (IDS).



### 1.6.2 Ecological

No PTAP incidents ecological incidents have been reported in the Agency’s Ecological Incident Information System (EISS).



## 2 Anticipated Data Needs

Table 6 presents a summary of the data anticipated as being needed to support this registration review.Docket Number EPA

- HQ

- OPP

- 2012

- 0682 www.regulations.gov

Page 10 of 43 Table 6

– Studies Anticipated as Needed for the Registration Review of PTAP

GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Risk Assessment(s) Data Will Support Use Site(s) Triggering Anticipated Data Requirement Applicable Exposure Scenario

Studies Anticipated to be Required through the Registration Review DCI

835.1110 Activated Sludge Sorption Isotherm TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain

. 835.3220 Porous Pot Test TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain

.

835.3280 Simulation Tests to Assess the Biodegradability of Chemicals Discharged to Wastewater TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain

.

835.3240 Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units TGAI 24 Ecological Hard Surface Disinfection Down the drain; h ard surface disinfectants are often rinsed down the drain

.

850.10 35 Acute marine/estuarine invertebrate toxicity (shrimp) TGAI 12 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain

. 850.1500 Fish life

- cycle TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain

. 850.1025 or 850.1055 Acute estuarine/marine invertebrate toxicity (mollusk) TGAI 12 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain

. 850.1350 Chronic marine/estuarine invertebrate toxicity (shrimp) TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain

. 850.2100 Avian acute oral toxicity test TGAI 12 Ecological Hard Surface Disinfection Birds i ngesti ng aquatic animals that have absorbed or ingested PTAP

850.4400 Aquatic plant toxicity test using Lemna gibba TGAI 12 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain

.

OECD 209 or 850.3300 Activated Sludge Respiration Inhibition or Modified Activated Sludge Respiration Inhibition TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard surface disinfectants are often rinsed down the drain. PTAP may potentially inhibit respiration of activated sludge microorganisms, the most sensitive organisms present in wastewater treatment systems.

870.3465 9 0

- day inhalation toxicity study TGAI 24 Occupational and Residential Air Sanitization, HVAC Treatments, Hard Surface Disinfection All scenarios that involve inhalation
exposures.

870.3800 Two

- gen reproductive toxicity TGAI 24 Dietary

, Food Contact Dietary exposures from indirect and directPage 11 of 43 GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Risk Assessment(s) Data Will Support Use Site(s) Triggering Anticipated Data Requirement Applicable Exposure Scenario

study Ecological Surfaces food contact uses.

875.1200 Indoor Exposure, Dermal TGAI 24 Occupational and Residential Hard Surface Disinfection 1. Trigger pump sprayer, low pressure handwand , high pressure handwand, mop, and wipe 1 2. Hand held fogger

875.1400 Indoor Exposure, Inhalation TGAI 24 Occupational and Residential Hard Surface Disinfection 1. Trigger pump sprayer, low pressure handwand, high pressure handwand, mop, and wipe 1 2. Hand held fogger

875.1600 Data Reporting/Calculations TGAI 24 Occupational and Residential Hard Surface Disinfection 1. Trigger pump sprayer, low pressure handwand, high pressure handwand, mop, and wipe 1 2. Hand held fogger 875.1700 Product Use Information TGAI 12 All All All scenarios.

875.2300 Indoor Surface Residue Dissipation 3 TGAI 24 Residential Surface disinfection of household floors and carpets Dermal and incidental exposures to PTAP are expected for toddlers who sit or play on household floors or carpets after they are disinfected with PTAP products.

875.2500 Post Application Exposure, Inhalation TGAI 24 Residential Air Sanitization, HVAC Treatments Inhalation exposure following the use of air deodorizers or HVAC treatments.

875.2900 Data Reporting/Calculations TGAI 24 Residential Air Sanitization, HVAC Treatments Inhalation exposure following the use of air deodorizers or HVAC treatments.

875.3700b Developmental Toxicity in Rabbits TGAI 24 Dietary Food Contact Surfaces Dietary exposures from indirect and direct food contact uses. Studies Expected to be Required through the Anticipated Post

- RED DCI 870.3100 90

- day Oral Subchronic in Rats (including neurotoxicity and endocrine endpoints) TGAI 24 Dietary Food Contact Surfaces Dietary exposures from indirect and direct food contact uses.

875.2800 Descriptions of Human Activity TGAI 24 All All All scenarios.

Special Study Dietary

- Residues in Food from Treating Countertops with 4

- t Amylphenol (FDA Wipe Study Methodology) TGAI 24 Dietary Food Contact Surfaces Dietary exposures from indirect and direct food contact uses.

1 It may be possible to use proprietary surrogate exposure data if data compensation issues are appropriately and adequately addressed

. 3 If surface residue data are not available, then the standard assumption of 100 percent transferable surface residue will be used which might overestimate the risk.Docket Number EPA

- HQ

- OPP

- 2012

- 0682 www.regulations.gov

Page 12 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 Existin g Toxicological Endpoints
EPA anticipates the need to revise the existing toxicological endpoints as part of this registration review. Table 7 presents the endpoints used in EPA’s most recent human health risk assessment in support of the 2005 RED. As previously stated, toxicological studies were identified as data gaps in the RED and identified in the registration review as anticipated data needs based on
current ly registered uses. All available information including existing toxicology studies, valid scientific literature

, and the studies that are expected to be required for regis tration review will be considered in establishing the endpoints to be used in the registration review 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 N o O bserved A dverse E ffect L evel (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 variatio n) 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 and intermediate

term) (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 = 2 5 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 13 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 can cer data available for PTAP



## 3.2 Dietary Exposure
The Agency anticipates the need to revise the dietary (food) assessment conducted in support of the 2005 RED

. Uses of PTAP that may result in dietary exposures include 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 performed for each population subgroup for which an endpoint exists . A risk estimate that is less than 100% of the acute or chronic PAD is not of

concern. Acute dietary risk for PTAP will be assessed by comparing dietary exposure esti mates 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 revis e the acute and chronic dietary food assessment conducted in support of the 2005 RED. In the RED, EPA considered exposures to residues on various hard nonporous surfaces such as countertops, sinks and stoves and did not identify any dietary risks of

concer n

. A t that time, EPA assumed a residue transfer factor of 10%, provided that registrants submit confirmatory residue data

. In the absence of these confirmatory data ( the Nature of the Residue on Surfaces and Migration S tud ies expected to be required throug h the post

- RED DCI )

, EPA will need to estimate risk utilizing a transfer rate of 100%

. EPA will estimate dietary exposures using the highest treatment concentration for any product containing PTAP approved for nonporous food contact surfaces.

The acute and chronic assessment s will estimate dietary exposure for all population subgroup s.
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.Page 14 of 43 

### 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 drinking water is not expected to occur

.


## 3.3 Occupational and Residential Exposures
The Agency anticipates the need to revise the occupational and residential assessment s 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 u pdated values. Uses of PTAP that may result in occupational handler and residential handler/post

application exposure are presented in Table 8

, Table 9 , and Table 10

.



### 3.3.1 Occupational Handler Exposure

EPA anticipates the need to revise the occupational handler assessment conducted in support of the 2005 RED. Occupational handler dermal and inhalation exposures to PTAP were assessed in the RED for applications using low pressure handwands, high pressure handwands, aerosol cans, trigger sprayers, mops and wipes. These exposures were assessed using unit exposure data from the Pesticide Handler Exposure Database ( PHED ) and Chemical Manufacturer’s Association ( CMA ) data. In all cases, the respective dermal an d inhalation MOE s 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 were a ssessed for the application 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 assessed in the RED will need to be revised during regi stration review upon receipt of the unit exposure data that is anticipated to be required to supplement or replace the unit exposure data that were used in the RED. It will also be necessary to reassess the fogger handler exposures for fogging applications that are made using hand held foggers and it will be necessary to reassess post application exposures once the application 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 TermPage 15 of 43 

### 3.3.2 Residential Handler Exposures
EPA anticipates the need to revise the residential handler assessment conducted in support of the 2005 RED. Residential handler dermal and inhalation 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 application of PTAP products used as a hard surface disinfectant (e.g., walls, flo ors, tables, fixtures), to textiles (e.g., clothing, diapers, mattresses, bedding) and to carpets. PTAP products are widely used disinfectants and have a large number of use patterns. As such, the Agency has selected representative scenarios for each use s ite 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 i n Table 9

.

Table 9

– Residential Handler Exposure Scenarios for PTAP

Scenario Exposure Route(s) Duration
Residential Exposures Applying disinfectant to hard surfaces 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 residential post

- application assessment conducted in support of the 2005 RED. Residential post

- application exposures could result when bystanders (adults and children) come in co ntact with PTAP in areas where pesticide end

- use products have recently been applied (e.g., treated hard surfaces/floors), or when children incidentally ingest the pesticide residues through mouthing the treated end products/treated articles (i.e., hand

- to

- mouth or object

- to

- mouth contact).

Residential post

- application exposures to residues arising from the 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 disinfection of floors but they were calculated using an assumption of solution coverage (1000 square feet per gallon) that possibly underestimates exposure and will have to be reassessed using updated values. The MOE s were of concern for the clothing and diaper use. The dermal MOEs for the treated clothing ranged from <1 when 100 percent residue transfer was assumed to 17 when 5 percent transfer was assumed. Based on these concerns, the RED specified that the diaper u se was ineligible for reregistration and that label statements be added requiring other treated textile articles be washed after treatment. The MOEs for air sanitization were not of concern. The quantitative exposure/risk assessment to be developed for re sidential handlers will be based on the following scenarios presented in Table 10

.Page 16 of 43 Table 10

– Residential Post

- Application Exposure Scenarios f or 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 Term



## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

EPA anticipates the need to revise the aggregate assessment conducted in support of the 2005 RED. Upon a reevaluation and selection of toxicological endpoints, combined with the human health exposure assessments expected as a part of this registration revi ew case, aggregate exposures will need to be assessed. This assessment 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 cumulat ive risk approach based on a common mechanism 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, therefore, EPA has not assumed that PTAP has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumula tive effects of such chemicals, see http://www.epa.gov/pesticides/cumulative/

. 

## 4 Environmental Risk Assessment

The Agency has not conducted a risk assessment that supports a complete endangered specie s determination for PTAP. The ecological risk assessment 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 de signated critical habitats. When an assessment concludes that a pesticide’s use 'may affect' 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 antimicrobials that can be used as disinfectants or sanitizers on hard inanimate surfaces in a variety of settings. Antimicrobials that are used to disinfect or sanitize surfaces are often rinsed down the drain with potable water in order to remove residues and therefore have the potential to reach aquatic organisms, if they are notPage 17 of 43 removed by wastewater treatment plants. Although the half

- life for PTAP is reported to be relatively short, ranging from 1 to 5 days in air, water, and soil, this half

- life is not short enough that PTAP would be expected to be appreciably degraded prior to entering Waste Water Treatment Plants ( WWTPs ) . Data on the half

- life of PTAP in environmental media do not provide specific informa tion on the potential for PTAP to be removed during the wastewater treatment process in which conditions are present that tend to promote removal of chemical substances from WWTPs, particularly via processes such as biodegradation and sorption (MRID 43733201)

. Because pesticide residues have the potential to reach the habitat 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 exposur es will be from any residues 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.Page 18 of 43 Figure 1

- Conceptual Model f or 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 direct and indirect effects to biological receptors. Ac ute 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 A gency does not have ecological effects data for PTAP . Data discussed here

- in were found in the peer

- reviewed literature as well as OPPT’s High Production Volume (HPV) Challenge ( http://www.epa.gov/HPV/ ).



### 4.2.1 Mechanism of Action

PTAP and its salts are broadly categorized within the alkylphenols chemical category. For ecotoxicological purposes the alkylphenols are classified as polar narcotics. Aquatic toxicities for the alkylphenols appear to be related to their degree of lipophilicity and increases relative 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 bioc oncentration factors range from 177

- 230, which is less than the level of concern (1,000) indicating significant degradation and/or depuration (removal) is occurring.Page 19 of 43 Using alkylphenols with comparable lipophilicity, it is possible to use ECOSAR data to su pport available experimental data in this case (EPA HPV, 2006).

Additionally since PTAP is considered an ecoestrogen there is concern about the possibility of endocrine disruption in fish. PTAP’s estrogenic properties were documented 2 in several studies

on carp ( Cyprinus carpio ).



### 4.2.2 Measures of Effect (Ecotoxicology Endpoints)
Current selected ecotoxicological endpoints are summarized in Table 11

. All available information including existing toxicology studies, valid scientific literature, and the studies that are expected to be required for registration review will be considered in establishing the endpoints to be used in the registration review risk assessment. A more detailed description of the ecotoxicity studies are provided in Appendix C

.

Table 11

– Existing Effects Endpoints for Risk Assessm ent 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

Generic fish Chronic ChV = 111 ppb Supplemental information, use will underestimate chronic risks, because there are endocrine disruption concerns a full life

cycle study is anticipated to be required rather than an early life

- stage study ( ChV values are early life

- stage) , a n acute test conducted on the same test species would allow for the calculation of an acute

- to

chronic ratio ECOSAR v 1.11

Freshwater inver tebrates Waterflea ( Daphnia spp. ) Acute 48

- hr EC 50 = 169 ppb* Supplemental information, preferred sensitive species estimated using Web

- ICE and lowest acute fathead minnow

, uncertainty is expected to be low, no additional studies are anticipated to be
requ ired 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 ECOSAR v 1.11

2 Gimeno, S., Komen, H., Venderbosch, P.W., and Bowner, T. (1997) Disruption of sexual dif ferentiation 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 Bowner, T. (1998b): Demasculinisation of sexually mature male common carp, Cyprinus carpio , exposed to 4

- tert

- amylphenol during spermatogenesis. Aquatic ToxicologyPage 20 of 43 anticipated to be required at this time

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 E C 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 E C 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 required

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 hypothesis, the potential for adverse effects on the environment will be estimated. For down

- the

- drain (DtD) risk estimates, an approach that estimates the number of days a concentration

- of

- concern (COC) is exceeded, also referred to as a probabilistic dilution model (PDM) approach is used to assess risk to aquatic organisms

. A screening DtD assessment using thi s 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. The results of the screenPage 21 of 43 are provided in Appendix D. Based on the results of the screen, where at even low end estimates of release there is potential for endangered species 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 refined 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 (Exposure and Fate Assessment Screening Tool) was used to screen for the potential for aquatic organisms downst ream of domestic wastewater treatment plants to be exposed to PTAP. Inputs used in this screening level DtD module run included concentrations of concern (COCs) for aquatic organisms, zero percent removal during
wastewater treatment 3 , and two wastewater tr eatment plant influent volume scenarios. The results of the DtD module are expressed as number of days of exceedance of COCs for aquatic organisms. A detailed description is provided in Appendix D

.

Table 12

– S ummary of S creening Level 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 kilograms/year Exceeded <1 day per year E xceeded 22 days per year E xceeded 3 days per year
100,000 kilograms/year N o exceedances N o exceedances N o exceedances

Influent Volume Freshwater fish acute ( COC = 4 25 ug/L ) Endangered Freshwater fish ( COC = 4 2.5 ug/L ) 1,000,000 kilograms/year Exceeded <1 day per year E xceeded 2 0 days per year
100,000 kilograms/year N o exceedances N o exceedances

Influent Volume Freshwater invertebrates acute ( COC = 304 ug/L ) Endangered Freshwater invertebrates ( COC = 30.4 ug/L ) Freshwater invertebrates chronic (COC = 11 5 ug/L)
1,000,000 kilograms/year Exceeded < 1 day per year Exceeded 34 days per year Exceeded 3 days per year
100,000 kilograms/year N o exceedances N o exceedances N o exceedances

Influent Volume Freshwater invertebrates acute ( COC = 180 ug/L ) Endangered Freshwater invertebrates ( COC = 18 ug/L ) 1,000,000 kilograms/year Exceeded 1 day per year Exceeded 65 days per year
100,000 kilograms/year N o exceedances Exceeded 1 day per year



## 4.4 Effects Analysis Plan
Additional open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) database 4 , which employs a literature search engine for locating chemical toxicity data for

3 In the absence of data c on cerning removal of PTAP during wastewater treatment , no removal of PTAP during wastewater treatment was assumed.
4 http://cfpub.epa.gov/ecotox/Page 22 of 43 aquatic life, terrestrial plants, and wildlife. The ECOTOX database will be searched when the risk assessment for PTAP is prepared. E ndpoints more sensitive than those already selected will be reviewed.

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


## 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. F or ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision for PTAP, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), PTAP is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA h as developed the EDSP to determine whether 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 other such endocrine effects as t he Administrator may designate.” The EDSP employs a two

- tiered approach to making the 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 estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if an y, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredi ents. PTAP is not among the group of 58 pesticide active ingredients on the initial 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 EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.Page 23 of 43 

## 6 Guidance for Commenters

6.1 Preliminary Work Plan
The public is invited to comment on EPA’s Preliminary Work Plan and rationale. The Agency will carefully consider all comments as well as any additional information or data provided in a timely manner prior to issuing a final work plan for the 4

- tertiary

- Amylphenol and Salts registration review case.



### 6.1.1 Trade Irritants
Through the registration review process, the Agency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The Agency will work to harmonize tolerances and international maximum residue limits (MRLs) and may modify tolerance levels to do so, when possible. Stakeholders are asked to comm ent on any trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the nature of the concern.



### 6.1.2 Water Quality
Unidentified phenolics (which may contain PTAP) have been identified as a cause of impairment for a single water body (Oil Drain Canal, Utah) listed as impaired under section 303(d) of the Clean Water Act, based on information provided at EPA’s website 5 . In addition, no Total Maximum Daily Loads (TMDL) has been developed for PTAP based on information provided at the website 6 . More information on impaired water bodies and TMDLs can be found at EPA’s website 7

. The Agency invites submission of water quality data for this pesticide. To t he extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 8 in or der to ensure they can be used quantitatively or qualitatively in pesticide risk assessments.



### 6.1.3 Environmental Justice
EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all people, regardless of race, color, nationa l origin, or income, in the development, implementation, and enforcement of environmental laws, regulations, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who , as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to PTAP compared to the general population. Please comment if you are aware of any sub

- populations that may have atypical, unusually high
exp osure compared to the general population.

5 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885
6 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_
group _name=PESTICIDES
7 http://www.epa.gov/owow/tmdl/
8 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htmPage 24 of 43 

### 6.1.4 Structure Activity Relationships
EPA must rely upon information of appropriate quality and reliability for each decision made by the Agency. In the Office of Pesticide Programs (OPP), the evaluation process for a pesticide chemical traditionally begins with the applicant’s submission of a set of studies conducted with the specific pesticide chemical of interest. The use of the results of such testing (measured data) is a logical, scientifically rigorous process that identifies the physical, chemical, and environmental fate properties of th e pesticide, as well as the dose and endpoints at which an adverse effect can occur in various animal species.

Today, there is significant interest in alternative techniques, i.e., techniques other than data generation that could significantly inform the Agency’s decision

- making process. Recently, OPP has made increasing use of structure activity relationship (SAR) as part of its regulatory decision

- making process. In the SAR process, a chemical's molecular structure is compared to that of other chemicals for which data are available. These structural similarities are then used to make predictive judgments about a chemical’s physical, chemical, and biological properties. Thus, the chemical’s physical, chemical, and biological properties are a function of (o r directly related to) the chemical’s molecular structure. Quantitative SAR is referred to as QSAR. To develop a QSAR, a selected set of measured data on a single physical, chemical, or biological property is used to derive a model (an equation) to predict the value of that property.

Since SAR assessments and QSAR modeling are another set of tools that are available to Agency scientists, OPP has begun a process shift that envisions shifting from the current study

- by

- study approach to an approach in which t he use of predicted data, generated using validated models, is considered along with information from open literature and studies specifically generated under Part 161 requirements. All relevant information would be considered as part of a weight

- of

- the

ev idence evaluation.

At this time, EPA believes that for certain endpoints, especially physical/chemical and fate properties, that SAR and QSAR might be effectively utilized to fulfill these data requirements for many antimicrobial pesticide chemicals. When considering biological properties, at this time, EPA believes that SAR and QSAR can be most effectively utilized in the evaluation of chemicals that exhibit lower toxicity for human health and/or ecotoxicity parameters. This is appropriate because the ris k assessment for lower toxicity chemicals can be stream

- lined, i.e., a screening

- level assessment procedure rather than multiple tiers of assessments with progressively more data requirements.

If stakeholders believe that submission of predicted data can fulfill one of the data needs for the 4

- tertiary

- Amylphenol and Salts Case, then the Agency invites submission of this information. The submitter would be expected to supply a rationale describing the utility of the information and provide documentation on the scientific validity of the information. The determination that the predicted data fulfills the data requirement would be at the sole discretion of the Agency. Pre

- submission consultation with the Agency is encouraged.Page 25 of 43 

### 6.1.5 Additional Information

Stakehol ders are also specifically asked to provide available information and data that will assist the Agency in refining its risk assessments, including any species

- specific ecological effects determinations. The Agency is interested in receiving the following i nformation:

1. Confirmation on the following label information: A. Sites of application B. Formulations C. Application methods and equipment D. Maximum application rates E. Frequency of application, application intervals and maximum number of applications F. Geographic limitations on use 2. Use or potential use distribution 3. Use history 4. Usage/use information for non

- agricultural uses (e.g., materials preservation) 5. Typical application interval 6. State or local use restrictions 7. Ecological incidents (non

- target p lant damage and avian, fish, reptilian, amphibian and mammalian mortalities) not already reported to the Agency 8. Monitoring data



## 7 Next Steps

After the 60

- day comment period closes in November 2012, the Agency will review and respond to any comments receive d in a timely manner, and then issue a Final Work Plan for the 4

- tertiary

- Amylphenol and Salts case.Page 26 of 43 

## 8 References

Ellis DD et al; Arch Environ Contam Toxicol 11: 373

– 82, 1982 Gimeno, S., Gerritsen, A., Bowmer, T., and Komen, H. (1996) Feminization of male carp. Nature 384:221

- 222. 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 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 Schmi eder, 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 Additives 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 C hemicals Associated with Estrogenic Activity, Journal of Biological 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 acti on from chemical structure: acute 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 est rogen 4

- 1

- pentylophenol on medaka ( Oryzias latipes ). Environ Toxicol Chem 22:1487

- 1496. Smeets, J.M.W., van Holsteijn, I., Giesy, J., Seinen, W., and van den Berg, M. (1999) Estrogenic potencies of several environmental pollutants, as determined by vitell ogenin induction in a carp hepatocyte assay. Toxicological 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 Schmieder, P. (2005) Rainbow trout estrogen (ER) binding and ER

- mediated vitellogenin production in a trout liver slice assay. [Measurements made at the EPA/ORD/NHEERL/Midcontinent Ecology Division (MED) Duluth, MN]Page 27 of 43 Tollefsen et al; Estrogenicity of Alkylphenols and Alkylated Non

- Phenolics in a Rainbow Trout ( Oncorhynchus mykiss ) Primary Hepatocyte Culture. Ecotoxicology and Environmental Safety 71, pp 370

- 383, 2008 U.S. Environmental Prot ection Agency (EPA). 2002. ECOTOX User Guide: ECOTOXicology Database System. Version 3.0. Available: http://www.epa.gov/ecotox/ U.S. Environmental Protection Agency. High Production Volume Information System (HPVIS). http://www.epa.gov/hpvis/ Yamasaki et al; Immature Rat Uterotrophic Assay of 18 Chemicals and Hershberger Assay of 30 Chemicals. Toxicology 183, pp 93

- 115, 2003. Yokota, H., Abe, T., Nakai, M., Murakami, H., Eto, C., and Yakabe, Y. (2005) Effects of 4

- te rt

pemtyulphenol on the gene expression of P450 11B

- hydroxylase in the gonad of medaka. Aquatic Toxicology 71:121

- 132.Page 28 of 43 

# Appendix A T oxicology Profile
Acute Toxicity for Product Labeling

As listed in Table 13 , PTAP is a primary dermal irritant (Category I) and is in Category III for acute oral toxicity based on guideline studies. It is likely an eye irritant (Category I), and is believed to be Cat egory III for acute dermal toxicity according to data from the open literature. However, acceptable guideline acute studies are not available for dermal, inhalation, primary eye irritation or dermal sensitization, and the literature data protocols were ina dequate. 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 fo r males and females III

870.1200/ Acute dermal toxicity N/A
No studies were submitted and studies in the literature do not meet applicable guidelines. These 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 No 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 subchronic or al rodent toxicity test is expected to be required for the indirect food uses of PTAP and this study was 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 administered 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 sub stance 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 irritation, such as erythema and desquamation which progressed to eschar formation with subsequent eschar exfoliation. The incidence and severity of the dermal irritation were incr eased in the 25 mg/kg/day group where the eschar formationPage 29 of 43 progressed to cover 50

- 75% of the application site 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 group 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 includ ed minimal to marked acanthosis, minimal to mild chronic or acute dermatitis, inflammatory exudate on the epidermal surface and occasional ulcers. The incidence and severity of the dermal changes were dose dependent. The dermal NOAEL is 2.5 mg/kg/day. The LOAEL is 10 mg/kg/day based on histopathological changes, dermal irritation characterized by erythema, desquamation, eschar formation and subsequent eschar exfoliation.

No significant changes in body weight or body weight gain were observed at any dose le vel. No significant changes in food consumption were observed. 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 treatment

- related ocu lar effects were noted in test animals. Hematological parameters showed no significant 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 treatment with the test substance. 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 for the non

- food uses of PTAP. An additional developmental study in another species (i.e., rabbits) is anticipated as need ed for registration review of indirect or direct food uses.

Prenatal Developmental Toxicity Study in Rats (MRID 41920002) Nipacide Amylphenol was administered by gavage to pregnant Sprague

- Dawley rats (25/dose) from gestation days (GD) 6 to GD 15 at dose levels of 0, 50, 200, and 500 mg/kg/day. Animals were sacrificed on GD 20, and dams and litters were examined for signs of toxicity. Maternal toxicity, observed at 200 and 500 mg/kg/day, was manifested as increased 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 and 500 mg/kg/day groups, respectively. Si milarly, mean food consumption was decreased 9

- 58% respectively during gestation at 200 and 500 mg/kg/day. No adverse maternal effects 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 si gns, decreases in body weight and body weight 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/litter) and an increased incide nce of bent ribs (p<0.05). No adverse developmental effects 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 30 of 43 

## Reproduc tive 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 concerns for PTAP that need to be evaluated in a reproductive study. A two generatio n reproduction study is therefore anticipated to be needed for registration review. 

## Chronic Toxicity

The data base for chronic toxicity is adequate for the indirect food uses of PTAP. Tier II c hronic toxicity studies are typically required for direct die tary 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

c arcinogenic ity 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 b ased on EPA's 1991 mutagenicity guidelines and indicates that PTAP is not mutagenic or genotoxic. In a submitted bacterial study (MRID 41438401) and in a study identified in the literature (Zeiger et al. 1988), PTAP was not mutagenic to the bacteria in the presence or absence of mammalian metabolic activation. An assay using cultured mouse lymphoma cells also proved negative (MRID 41572701). Finally, a mouse micronucleus test using male and female CD

- 1 mice also was negative (MRID 41710801). 

## Other Toxicolog ical Effects

There are studies in the literature that indicate PTAP has other toxicological 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 was 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 m easuring 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 (negative control) and in the presence of 17β

- estradiol (po sitive control) is compared with the number of cells achieved with a range of concentrations of the test chemical. For PTAP, a concentration of 1 0 p M was the lowest concentration needed for maximal cell yield. For the positive control 17β

- estradiol, the lo west 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 17β

- estradiol. A value of 100 indicates that the compound tested is a full agonist of the estradiol; a valu e of 0 indicates that the compound lacks estrogenicity at the doses tested. Intermediate values suggest that the compound is a partial agonist of 17β

- estradiol. For PTAP,Page 31 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 bindi ng of chemical to rainbow trout ER; PTAP showed positive results. Feminization of young male common carp was observed when treated with PTAP (Gimeno S, Komen H, and Gerritsen AGM, Bowmer T. 1998).Page 32 of 43 

# Appendix B Environmental Fate
Environmental Fate Properties

Except as noted, the environmental fate properties of PTAP were based on the predictions of EPI

- WEB 4.0 along with the High Production Volume documents from the Office of Toxic Substances. Biodegradation of PTAP is the apparent route of dissipation, which will fo rm CO 2 and tightly sorbed residues.

Parent substance, PTAP

PTAP, with a pKa of 10.43, ionizes (loses hydrogen) at a higher pH value than phenol, which has a pKa value of 10. The pKa is the pH in water 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 surface 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 will not volatilize significantly from water. However, it will have the tendency to volatilize from solid surfaces into 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 hy drolysis (no hydrolysable functional groups) and essentially stable to direct photodegradation because of limited light absorption (>290 nm). However, indirect photodegradation in air is more rapid. The reported half

- life due to indirect photodegradation i n air (oxidation with photosensitizers such as nitrate) 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 tend 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 sludge 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, w hile 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 33 of 43 works in Illinois, PTAP was detected at only one site (final ef fluent from a trickling filter plant partially inoperative in Roselle, IL) although concentrations 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 34 of 43 

# Appendix C Ecotoxicology Profile
Toxicity to Terrestrial Receptors

Birds

For indoor uses, an acute oral toxicity study using the technical grade of the active ingredient (TGAI) is anticipated to be needed for use in establishing the toxicity of PTAP and its salts to birds. The 2005 RED indicated this data gap but the DCI has no t 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 the Agency's files for PTAP and its salts. The tests were conducted in 1974 usi ng the bobwhite quail (MRID 00049836) and mallard duck (MRIDs 00049838 and 00096236). The tests were conducted using antiquated procedures. The results showed moderate toxicity, which highlights the importance of obtaining a study that satisfies the curren t guideline requirements (850.2100).

A single acute oral is anticipated to be required to support hazard labeling. Furthermore, since PTAP is expected to reach surface water, these data are anticipated as needed for use in a risk assessment for examining risks to birds 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 registration of PTAP. The first study (MRID # 240 116619) was conducted in 1974 and tested both rainbow trout and bluegill 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 curren t guideline s, and cannot be used in a risk
assessment.

In the 2005 RED, results from freshwater fish acute toxicity studies with fathead minnow were obtained from peer

- reviewed literature. The fathead 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 similar to OPPTS guidelines and is more likely to be used in a risk assessment than the subsequent study (Russon et al ., 1997) w hich did not provide any information on how the study was conducted. 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 preferred warmwat er bluegill and that of the coldwater species, rainbow trout.

Where results with only nonpreferred species are available, species uncertainty factors may be applied or models may be used to estimate toxicity values for the preferred sensitive indicator
sp ecies. The Web

- based Interspecies Correlation Estimation (Web

- ICE) application estimates 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 bl uegill sunfish (1,560 μg/L;Page 35 of 43 95% C.I. 1,068

– 2,280 μg/L) and the rainbow trout (1,160 μg/L; 95% C.I. 849

– 1,588 μg/L). Web

- ICE includes polar narcosis compounds within its model data for development of correlation estimates. For the fathead minnow the tox icity value for PTAP falls within the midrange of the fathead minnow toxicity model data.

The HPV Information System (HPVIS) 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 version 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 chronic 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 Estimation (Web

- ICE) application estimates acute toxicity to a desired aquatic 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 substances are part of the model 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 data set

, the 95% lower confidence limit of 849 μg/L for rainbow trout will be used to assess acute risks to freshwater fish species.

Table 14

– Aquatic Organism PTAP Toxicology

Test Organisms Exposure Scenario and Comments T est 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 ) F reshwater flow

through;

- 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 Toxicity (log value)

μg/L (3.39) 1160.75 μg/L (3.06) 2500Page 36 of 43 Select Confidence Interval: Lower Limit Upper Limit
848.67 μg/L 1587.59 μg/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 Toxicity (log value)

μg/L (3.39) 1560.46 μg/L (3.19)

Select Confidence Interval: Lower Limit Upper Limit
1068.19 μg/L 2279.58 μg/L

Model Information Intercept: 0.022235 Slope: 0.933218 Degrees of Freedom (N

- 2): 66 R 2 : 0.790938
p - value: 0.000000 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) 95%

2500

95%Page 37 of 43 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 that was identified in the 2005 RED indicates that PTAP is an endocrine disruptor (see the following Table). For known reproductive toxicants, fish full life cycle testing is required rather than early life stages. There are no early life stage or fish life cycle data submitted in support of PTAP. There is a chronic estimate for PTAP from ECOSAR

, but it is an estimate based on early life stage data, 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 ECOS AR estimated chronic value provides supplemental information, but it is not adequate to conduct a risk assessment for PTAP, and will underestimate chronic risks.

Table 15

– Examples of PTAP Affecting 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.

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.Page 38 of 43 Organism/ Age Results Comments Reference

Cultured hepatocytes from genetically

uniform, 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 ef

fects - 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 b inding - 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 spermatoge nesis, 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 invertebrates using ECOSAR. Estimat ed values were calculated using ECOSAR v.0.99e. As with the chronic fish data, the chronic 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:

 Acute Toxicity to Aq uatic 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 Aquatic Invertebrates: 48 hour LC 50 = 608 μg/L ( Daphnia sp. )Page 39 of 43  Chronic Aquatic Invertebrate Toxicity: ChV = 115 μg/L ( Daphnia sp. )

ECOSAR v.1.11 estimates will be used in the ecological risk assessment unless acute and chronic affects data for PTAP are submitted to the agency. Because of these available estimates, acute and chronic invertebrate data will not be called in.

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.

Web

- ICE version 3.1 Calculato r - Aquatic Species (Freshwater Invertebrates)
Surrogate Species: Fathead minnow ( Pimephales promelas ) Predicted Species: Daphnid ( Daphnia magna ) Surrogate Acute Toxicity (log value) Predicted Acute Toxicity (log value)

μg/L (3.39) 357.39 μg/L (2.55)

Select Confidence Interval: Lower Limit Upper Limit
169.15 μg/L 755.09 μg/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 40 of 43 Estuarine/Marine Fish

Web

- ICE version 3.1 Calculator

- Aquatic Species ( Estuarine/Marine Fish )
Surrogate Species: Fathead minnow ( Pimephales promelas ) Predicted Species: Sheepshead minnow ( Cyprinodon variegatus ) Surrogate Acute Toxicity (log value) Predicted Acute Toxicity (log value)
μg/L (3.39) 2258.55 μg/L (3.35)

Select Confidence Interval: Lower Limit Upper Limit 1010.64 μg/L 5047.35 μg/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 literature. The peer reviewed study (McLeese, 1981) measured the acute toxicity to shrimp was LC 50 =1,700 μg/L. This indicates that PTAP is moderately toxic to shrimp. The study does not meet current guideline requirements and cannot be used in a risk assessment. An acute freshwater in vertebrates toxicity study is anticipated to be required for registration review.

2500

95%Page 41 of 43 

# Appendix D Screening Level Down

- the

Drain Analysis

The Down

- the

- Drain (DtD) module of E

- FAST (Exposure and Fate Assessment Screening Tool), version 2 was used to screen for the potential for aquatic organisms downstream of domestic wastewater treatment plants to be exposed to PTAP. The Down

- the

- Drain module uses daily per capita release of household wastewaters, stream dilution factors, and wastewater treatment plant removal effi ciency to provide both high

- end and median (average) time

- averaged surface water concentrations of chemicals discharged by domestic wastewater treatment plants. The high

- end scenario uses surface water concentrations downstream of domestic wastewater trea tment 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 t he wastewater treatment plant flow. Inputs used to run the DtD module included concentrations of concern (COCs) for aquatic organisms, percent removal during wastewater treatment, and hypothetical wastewater treatment plant influent volumes. The results o f 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 f

or non

- listed species were based on No Observed 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 PTAP during wastewater treatment was assumed. The Down

- the

- Drain module was first run using a high

- end sce nario 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 ecotoxicology endpoints for freshwater fish and invertebrates that were estimated using two different tools: ECOSAR, version 1.11, and Web

ICE, version 3.1. For freshwater fish, ECOSAR estimated an acute toxicity endpoint of 0.817 ppm (LC 50 = 817 ug /L) and a chronic toxicity endpoint of 0.111 ppm (111 ug/L). For freshwater invertebrates, ECOSAR estimated an acute ecotoxicity endpoint of 0.608 ppm (LC 50 = 608 ug/L) and a chronic toxicity endpoint of 0.115 ppm (115 ug/L). Web

- ICE estimated an acute

e cotoxicity 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 endpoints estimated from ECO SAR 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 pre dicted 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 t hat were predicted to be exceeded for one day orPage 42 of 43 more per year based on the high

- end scenario for a wastewater treatment 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 ba sed on the average scenario. At a wastewater treatment plant influent volume of 1,000,000 kilograms per year PTAP, based on the average 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 plant 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 fre shwater invertebrates, the ecotoxicology endpoints 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 o f 1,000,000 kilograms per year PTAP, the high

- end scenario 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 predicted to be exceeded for one day or more per year based on the high

- end scenario for a wastewater treatment plant influent volume of 1,000,000 kilograms per year were also used as inputs to es timate the number of days per year of exceedance based on the average scenario. For the 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 day 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 species, or chronic COCs for freshwater invertebrates.

For freshwater fish, the eco toxicology endpoints 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 mor e per year based on the high

- end scenario for a wastewater treatment 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. For the average scenar io 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 specie s, or chronic COCs for freshwater fish.

For freshwater invertebrates, the ecotoxicology endpoints 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 influent volume of 1,000,000 kilograms per year PTAP, the high

- end scenario of E

- FAST predicted that the acute COC for freshwater invertebrates of 180 ug/L would be exceeded 1 day per year and the endangered species COC of 18 ug/L would be exceeded 65 days per year. The COCs that were predicted to be exceeded one or more days per year based on the high

- end scenario for a wastewater treatment plant influent volume of 1,000,000 kilograms per year were also used as inputs to estimate the number of daysPage 43 of 43 per yea r of exceedance based on the average scenario. For the average scenario 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 kilograms per year PTAP, the high

- end s cenario of E

- FAST predicted 1 day of exceedance per year 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 potentially inhibit respiration of a ctivated sludge microorganisms, which are the most sensitive microorganisms present in wastewater treatment systems. Results from ready biodegradability studies indicate that PTAP is not readily biodegradable; these results indicate that PTAP may potential ly inhibit activated sludge microorganisms at fairly low concentrations. Consequently, an Activated Sludge Respiration Inhibition (ASRI) study is anticipated to be required for use in determining concentrations at which PTAP would be expected to inhibit re spiration of activated sludge microorganisms.

Data on degradation and transport during wastewater treatment are anticipated to be needed to determine the extent of removal of PTAP prior to being released to water bodies downstream of WWTPs. Since PTAP failed the ready biodegradability 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 indicates 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 required to determine the extent to which PTAP would be expected to be removed by sorption during wastewater treatment.