Docket Number EPA-HQ-OPP-2012-0682 

www.regulations.gov 

4-tertiary-Amylphenoi and Salts Preliminary Work Plan 

Registration Review: Initial Docket 

Case Number 3016 

September 2012 

Approved by: ~ ~ 

J an Harrigan-Faffelly 

Director 

Antimicrobials Division 

Date: 1/ovt/;kl I.Z 

Page 1 of43 
Page 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 Regulatory History ........................................................................................................... 8

1.5.1 Recent/Pending Regulatory Actions......................................................................... 8

1.5.2 Tolerance Information .............................................................................................. 9

1.6 Incidents........................................................................................................................... 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.................................................................................................. 20
Page 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 Endocrine Disruptor Screening Program (EDSP)................................................................. 22

6 Guidance for Commenters.................................................................................................... 23

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 Toxicology 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 Assessments 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 Scenarios 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 Toxicity 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.......................................... 18
Page 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 United 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 human 

health or the environment. Changes in science, public policy, and pesticide use practices will 

occur over time. Through the registration review program, the Agency periodically reevaluates 

pesticides to make sure that as change occurs, products in the marketplace 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 to Section 3(g) of the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered 

pesticide every 15 years to determine whether it continues to meet the FIFRA standard for 

registration. The regulations governing registration review begin at 40 CFR 155.40. The Agency 

will consider benefits information and data as required by FIFRA. The public phase of 

registration review begins when the initial docket is opened for each case. The docket is the 

Agency’s opportunity to state what it knows about the pesticide and what additional risk analyses 

and data or information it believes are needed to make a 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 Final Work Plan (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 the 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 Preliminary 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 2017-10

Phase 3: Registration Review Decision and Implementation 

Open 60-Day Public Comment Period for Proposed Decision 2018-03

Close Public Comment Period 2018-05

Issue Final Decision 2018-09

Begin Post-Decision Followup 2018

Total (years) 6
Page 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 Case 3016: 4-tertiary-amylphenol 

(PC Code 064101); p-tertiary-amylphenol, potassium salt (PTAP-K, PC Code 064111); and ptertiary-amylphenol, 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 C11H16O C11H15KO C11H15NaO

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/cm3 at 20 °C N/A N/A 

830.7370 Dissociation Constant pKa = 10.43 NA NA 

830.7550 Partition coefficient (noctanol/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 (EPI 
Page 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-m3

/mole at 

25oC (Calculated) 

5.4 x 10-14 atmm3

/mole at 25oC (EPI 

Suite) 

4.1 x 10-14 atmm3

/mole at 25oC (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 the 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 (oPP) or o-benzyl-pchlorophenol (oBCP). 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, soaking, 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 farms1

Fogger, Thermal Unknown2

Fogger, Total 

Release 0.5 mg/m3

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 Unknown2
Page 8 of 43

Mop, Spray, Wipe 78 to 450 ppm 

Residential and Public Access Premises

Non-porous surfaces3 Fogger, Thermal Unknown2

Fogger, Total 

Release 

0.2 to 0.5 

mg/m3

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 Unknown2

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 Labels specify a fogging solution concentration (i.e., 5000 ppm) and an application time (i.e., fog for three minutes 

per 2000 ft3). The labels do not indicate how much fogging solution should be applied per unit volume (i.e., three 

ounces per 1000 ft3). 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 

percent 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 kilograms of PTAP are sold 

per year in the United States1.

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 the 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 post-RED Data Call-In (DCI) has not been 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 determined 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; hard surface disinfectants 

are often rinsed down the drain.

850.1035 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 ingesting 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 90-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 direct 
Page 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 wipe1

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 wipe1

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 wipe1

2. Hand held fogger

875.1700 Product Use Information TGAI 12 All All All scenarios. 

875.2300 Indoor Surface Residue 

Dissipation3 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 Existing 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 

currently registered uses. 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 

detailed description of the toxicity studies is provided in Appendix A .

Table 7 – Existing Toxicological Endpoints 

Exposure 

Scenario

Dose Used in Risk 

Assessment 

(mg/kg/day) 

Target Margin of Exposure 

(MOE), UF, Special FQPA 

SF, for Risk Assessment

Study and Toxicological Effects

Acute Dietary 

Females 13+ b.w. 

= 60kg

No Observed 

Adverse Effect 

Level (NOAEL) = 

200 mg/kg/day 

UF = 3000 (10x inter-species 

extrapolation, 10x intra-species 

variation)

FQPA SF= 10

DB UF = 3

Acute PAD =0.067 mg/kg/day 

Developmental toxicity study in the rat

NOAEL of 200 mg/kg/day, based on 

skeletal effects and decreased fetal body 

weight at 500 mg/kg/day 

Chronic Dietary 

All populations

b.w. = 70 kg

NOAEL = 50 

mg/kg/day 

UF = 3000 (10x inter-species 

extrapolation, 10x intra-species 

variation)

FQPA SF= 10

DB UF = 3

Chronic PAD =0.017 mg/kg/day 

Developmental toxicity study in the rat

NOAEL of 50 mg/kg/day, based on clinical 

signs, decreased body weight and body 

weight gain, and decreased food 

consumption in maternal animals at 200 

mg/kg/day 

Incidental Oral 

(short and 

intermediate 

term)

NOAEL =50 

mg/kg/day 

MOE = 3000 (10x interspecies 

extrapolation, 10x intraspecies 

variation, 10x FQPA , 3x 

database UF) 

Developmental toxicity study in the rat 

NOAEL of 50 mg/kg/day, based on clinical 

signs, decreased body weight and body 

weight gain, and decreased food 

consumption in maternal animals at 200 

mg/kg/day 

Dermal

(short and 

intermediateterm)

(occupational and 

residential)

NOAEL = 25 

mg/kg/day (HDT) 

MOE (occupational) = 100

MOE (residential) =1000 (10x 

interspecies extrapolation, 10x 

intraspecies variation, 10x 

FQPA)

Subchronic dermal toxicity in the rat

No systemic effects identified up to and 

including the high dose of 25 mg/kg/day

Dermal

(long-term)

(occupational and 

residential)

NOAEL = 25 

mg/kg/day (HDT) 

MOE (occupational) = 300

MOE (residential) =3000 (10x 

interspecies extrapolation, 10x 

intraspecies variation, 10x 

FQPA, 3X for subchronic to 

chronic duration)

Subchronic dermal toxicity in the rat

No systemic effects identified up to and

including the high dose of 25 mg/kg/day
Page 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 cancer 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 estimates 

expressed in mg/kg/day to the acute Population Adjusted Dose (aPAD) and chronic Population 

Adjusted Dose (cPAD).

3.2.1 Food 

EPA anticipates the need to revise the acute and chronic dietary food assessment conducted in 

support of the 2005 RED. In the RED, EPA considered exposures to residues on various hard 

nonporous surfaces such as countertops, sinks and stoves and did not identify any dietary risks of 

concern. At that time, EPA assumed a residue 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 Studies expected to be required through 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 assessments will estimate dietary exposure for all population subgroups.

PTAP has a tolerance exemption in 40 CFR 180.940(c) as a food-contact sanitizer for use in 

food-processing equipment and utensils at a use dilution not to exceed 80 ppm. 
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 assessments

conducted in support of the 2005 RED since Margins of Exposure (MOE)s were calculated using 

assumptions that possibly underestimates exposure and will need to be reassessed using updated 

values. Uses of PTAP that may result in occupational handler and residential handler/postapplication exposure are presented in Table 8, Table 9, and Table 10.

3.3.1 Occupational Handler Exposure

EPA anticipates the need to revise the 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 and inhalation MOEs were not of concern. 

Occupational handler exposures were assessed for the pouring of liquid concentrate into the 

fogger, but exposures while operating the fogger were not assessed. Occupational post 

application inhalation exposures were assessed 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 

registration 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 

Term 
Page 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, floors, 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 site that are 

believed to be representative of the PTAP uses, based on end-use product application methods 

and use amounts. The quantitative exposure/risk assessment to be developed for residential 

handlers will be based on the following scenarios presented in Table 9.

Table 9 – Residential Handler Exposure Scenarios for PTAP

Scenario Exposure 

Route(s) Duration

Residential Exposures

Applying disinfectant to hard 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 contact 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 MOEs 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 use 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 residential handlers will be based on the following scenarios 

presented in Table 10.
Page 16 of 43

Table 10 – Residential Post-Application Exposure Scenarios for PTAP

Scenario Exposure 

Route(s) Duration

Residential Exposures

Post application exposure to floors and carpets cleaned with preserved 

household cleaning solutions. 

Dermal Incidental 

Oral 

Short and Intermediate 

Term 

Post application exposure to aerosols and vapors released from air 

deodorizing treatments Inhalation Short and Intermediate 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 review 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 

cumulative 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 cumulative 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 species 

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 designated 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 not 
Page 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 information 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 exposures 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 for Ecological Exposure and Effects of PTAP and Its Major Reaction 

Products/Degradates to Aquatic and Terrestrial Organisms

4.2 Ecological Effects Assessment

Ecological effects data are used as measures of direct and indirect effects to biological receptors. 

Acute and chronic toxicity data from studies submitted by pesticide registrants along with the 

available open literature will be used to evaluate the potential direct and indirect effects of PTAP 

and its degradates to aquatic and terrestrial receptors. The Agency does not have ecological 

effects data for PTAP. Data discussed here-in 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 Kow values. PTAP has a log Kow value of 4.03 and therefore surpasses the Agency's 

threshold of concern (Kow value of 3.0) and indicates a potential for bioaccumulation in fatty 

tissues. However, the bioconcentration factors range from 177-230, which is less than the level 

of concern (1,000) indicating 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 support 

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 documented2 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 Assessment of PTAP

Receptor Group Surrogate 

Species

Risk 

Scenario

Toxicity 

Endpoint 

as a.e.

Comment Reference

Freshwater fish

Rainbow trout

(Oncorhyncus 

mykiss)

Acute 96-hr LC50

= 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 LC50

= 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 lifecycle study is anticipated to be required

rather than an early life-stage study (ChV

values are early life-stage), an acute test 

conducted on the same test species would

allow for the calculation of an acute-tochronic ratio

ECOSAR v 

1.11

Freshwater 

invertebrates

Waterflea 

(Daphnia spp.)

Acute 48-hr EC50

= 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 

required at this time

Web-ICE v. 

3.1, see 

Appendix C 

Acute LC50 = 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 

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
Page 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 LC50

= 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 dataavailable See above

Estuarine/Marine 

invertebrates

Shrimp

(Crangon 

septemspinosa)

Acute

96-hr LC50

= 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 EC50 = 

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 EC50 

= 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

LD50

>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 this approach was conducted to evaluate if PTAP uses resulting in DtD releases could 

potentially be identified as minimal use and unlikely to result in effects. The results of the screen 
Page 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 downstream 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 treatment3

, and two wastewater treatment 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 – Summary of Screening 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 Exceeded 22 days per year Exceeded 3 days per year

100,000 

kilograms/year No exceedances No exceedances No exceedances

Influent Volume Freshwater fish acute (COC 

= 425 ug/L)

Endangered Freshwater fish 

(COC = 42.5 ug/L)

1,000,000 

kilograms/year Exceeded <1 day per year Exceeded 20 days per year

100,000 

kilograms/year No exceedances No exceedances

Influent Volume Freshwater invertebrates

acute (COC = 304 ug/L)

Endangered Freshwater 

invertebrates (COC = 30.4

ug/L)

Freshwater invertebrates 

chronic (COC = 115 ug/L)

1,000,000 

kilograms/year Exceeded <1 day per year Exceeded 34 days per year Exceeded 3 days per year

100,000 

kilograms/year No exceedances No exceedances No exceedances

Influent Volume Freshwater invertebrates

acute (COC = 180 ug/L)

Endangered Freshwater 

invertebrates (COC = 18 ug/L)

1,000,000 

kilograms/year Exceeded 1 day per year Exceeded 65 days per year

100,000 

kilograms/year No exceedances Exceeded 1 day per year

4.4 Effects Analysis Plan

Additional open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) 

database4, which employs a literature search engine for locating chemical toxicity data for 

 3 In the absence of data concerning 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. Endpoints more sensitive than those already selected will 

be reviewed.

Data from an ECOTOX run for PTAP and its degradates will be evaluated for possible 

quantitative and/or qualitative 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. For 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 has 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 the 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 any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the 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 ingredients. 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 comment 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 website5. In addition, no Total 

Maximum Daily Loads (TMDL) has been developed for PTAP based on information provided at 

the website6. More information on impaired water bodies and TMDLs can be found at EPA’s 

website7. The Agency invites submission of water quality data for this pesticide. To the 

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 Process8 in order 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, national 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 

exposure 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.htm
Page 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 the 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 (or 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 the 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-theevidence 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 risk 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 

Stakeholders 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 information: 

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 plant 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 received 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 Schmieder, P. (2003) Induction of an estrogen-responsive 

reporter gene in rainbow trout hepatoma cells (RTH-149) at 11 or 18C. Environ Toxicol. 

Chem. 22:866-871.

McLeese, D.W. (1981) Lethality and accumulation of alkylphenols in aquatic fauna. 

Chemosphere 10(7): 723-730. 

Miller et al; Estogenic Activity of Phenolic 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 Chemicals 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 action 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 estrogen 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 vitellogenin 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 Protection 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-tertpemtyulphenol on the gene expression of P450 11B-hydroxylase in the gonad of medaka. 

Aquatic Toxicology 71:121-132.
Page 28 of 43

Appendix A Toxicology 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 Category 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 inadequate. These studies 

were identified as data gaps in the RED. 

Table 13 - Acute Toxicity Studies for PTAP

Guideline No./ Study 

Type MRID No. Results Toxicity Category

870.1100/ 

Acute oral toxicity 46616601 LD50 >2000 mg/kg for males and females III

870.1200/ 

Acute dermal toxicity N/A

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 oral 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 substance was dissolved in a 50% v/v solution of ethanol in distilled water; all 

doses were administered at a constant volume of 6.0 ml/kg. No treatment-related deaths or 

clinical signs were observed. 

Dermal irritation was not observed in controls or at 2.5 mg/kg/day. At 10 and 25 mg/kg/day, 

both sexes exhibited dose-related dermal irritation, such as erythema and desquamation which 

progressed to eschar formation with subsequent eschar exfoliation. The incidence and severity of 

the dermal irritation were increased in the 25 mg/kg/day group where the eschar formation 
Page 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 included 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 level. 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 ocular 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 needed 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. Similarly, 

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 

signs, 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 incidence 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

Reproductive Toxicity

There is no reproductive toxicity study available and such a study is normally required to support 

indirect or direct food uses. In addition, there are other toxicological concerns for PTAP that 

need to be evaluated in a reproductive study. A two generation 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 chronic 

toxicity 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. 

Carcinogenicity 

The data base for carcinogenicity is adequate for the indirect food uses of PTAP. Tier II 

carcinogenicity studies are typically required for direct dietary uses or long-term, high-level uses 

(e.g., metal working fluids) and are not expected to be needed for the registered uses of PTAP. 

Mutagenicity 

The data base for mutagenicity is considered adequate based on EPA's 1991 mutagenicity 

guidelines and indicates that PTAP is not 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 Toxicological 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 measuring 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 (positive 

control) is compared with the number of cells achieved with a range of concentrations of the test 

chemical. For PTAP, a concentration of 10 pM was the lowest concentration needed for maximal 

cell yield. For the positive control 17β-estradiol, the lowest concentration needed was 30 pM. 

The relative proliferative effect (RPE) is calculated as 100 x (PE-1) of the test compound divided 

by (PE-1) of 17β-estradiol. A value of 100 indicates that the compound tested is a full agonist of 

the estradiol; a value 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 binding 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 form CO2

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 oC), a water solubility of 168 mg/l, and a 

Henry’s Law Constant of 2.57 x 10-6 atm m3/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 hydrolysis (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 in 

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, while 86% of 

sodium benzoate mineralized to CO2. In a monitoring study of organic constituents of 

mutagenically active secondary effluents from 10 industrial plants and publicly owned treatment 
Page 33 of 43

works in Illinois, PTAP was detected at only one site (final effluent 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 CO2, which occurred in sewage sludge. However, 

the phenolic nature of the compound indicates that CO2 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 not yet gone out. The preferred test 

species is either mallard duck (a waterfowl) or northern bobwhite quail (an upland game bird). 

Two avian acute toxicity studies were found in the Agency's files for PTAP and its salts. The 

tests were conducted in 1974 using 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 current 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 # 240116619) 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 current guidelines, 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) which 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 warmwater 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 

species. 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 bluegill 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 toxicity 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 LC50 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 

LC50 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

Test 

Substance

(% Purity)

Toxicity Endpoint

(95% C.I.)

Study 

Classification/

Toxicity 

Classification

Reference

Rainbow trout Freshwater PTAP Unacceptable MRID 240116619

Bluegill sunfish Freshwater PTAP Unacceptable MRID 240116619

Zebrafish Freshwater PTAP Unacceptable MRID 44474208

Fathead minnow

(Pimephales 

promelas)

Freshwater flowthrough; -necrosis 

observed in 

surviving fish

PTAP 96-hr LC50 = 2,500

(1,870 – 3,340) moderately toxic

Holcombe, G W et 

al. 1984

Rainbow trout Freshwater -- 96-hr LC50 = 849* highly toxic Web-ICE v.3.1 (see 

calculations below)

Fathead minnow

(P. promelas) freshwater PTAP 96-hr LC50 = 16,000 (NR) slightly toxic Russon, C L et al. 1997 

Shrimp (Crangon 

septemspinosa) estuarine PTAP 96-hr LC50 = 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) 2500 1160.75 μg/L (3.06)
Page 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

R2: 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 (Sxx): 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

R2: 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 (Sxx): 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 ECOSAR 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 EC50 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 geneticallyuniform, all male, F1-

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; IC50 = 

7.6x10-7 M

- identified as causing endocrine disruption 

effects

- relative potency is 

0.036 approx. 75% of 

maximum E2

Hornung et al. 2003

Partial life cycle carp (C. 

carpio)

- Estrogenic LOEC = -6.2 log M

- identified as causing endocrine disruption 

effects

- oviduct development 

in male

Gimeno et al. 1996

Partial life cycle Medaka 

(Oryzias latipes)

- Estrogenic LOEC = -5.8 log M

- identified as causing endocrine disruption 

effects

- sex reversal; 

- Inhibition of P450 

11B hydroxylase 

mRNA levels

Yokota et al. 2005

Full life cycle Medaka 

(O. latipes)

- Estrogenic LOEC = -6.5; - cytoxicity = -

5.2 F0 and -5.8 F1

- identified as causing endocrine disruption 

effects

- Vtg induction at -6.5 

log M

Seki et al. 2003

Rainbow trout cytosol 

ER competitive binding

- Estrogenic LOEC = -5 log M; IC50 = 

2.2x10-4 M; 

- RBA 0.004 %

- identified as causing endocrine disruption 

effects 

Tapper et al. 2005

Male rainbow trout liver 

slice/Vtg gene 

expression

- elevated levels of vitellogenin, inhibition 

of spermatogenesis, disappearance of 

speratozoa and spermatogenic cysts, 

reduced diameter of seminiferous lobules, 

reduced spermatocrit values and early 

appearance of ovo-testes 

LOAEL= 32 ppb

- identified as causing endocrine disruption 

effects and

no mortality or growth effects

- 3 month test duration

- nominal 

concentrations of 32, 

100, 320 and 1000 

ppb were tested

Gimeno et al. 1998b

Freshwater Invertebrates

No freshwater invertebrate toxicity studies were submitted in support of PTAP or identified from 

peer-reviewed literature in the 2005 RED. As with fish, the HPVIS contains estimated 

ecotoxicity values for PTAP to aquatic invertebrates using ECOSAR. Estimated 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 Aquatic Invertebrates: 48 hour LC50=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 LC50 = 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 EC50 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 Calculator - 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

R2: 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 (Sxx): 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

R2: 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 (Sxx): 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 LC50 =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 invertebrates toxicity study is anticipated to be 

required for registration review.

2500

95%
Page 41 of 43

Appendix D Screening Level Down-theDrain 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 efficiency 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 treatment plants 

based on the 10th percentile stream dilution factor (SDF); the average scenario uses surface water 

concentrations based on the 50th percentile SDF. SDF is defined as the ratio of the stream flow 

downstream of a wastewater treatment plant to the 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 of the DtD module are expressed as number of days of exceedance 

of COCs for aquatic organisms. COCs for acute effects were determined by dividing LC50 values 

from acute toxicity tests on aquatic vertebrates and invertebrates by 2. COCs for chronic effects 

for 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 LC50 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 scenario to determine whether the 

model predicted exceedances of concentrations of concern. If the high-end scenario predicted 

exceedances of the concentration of concern, the model was also run using the average scenario. 

The Down-the-Drain module was run using ecotoxicology endpoints for freshwater fish and 

invertebrates that were estimated using two different tools: ECOSAR, version 1.11, and WebICE, version 3.1. For freshwater fish, ECOSAR estimated an acute toxicity endpoint of 0.817 

ppm (LC50 = 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 (LC50 = 608 ug/L) 

and a chronic toxicity endpoint of 0.115 ppm (115 ug/L). Web-ICE estimated an acute 

ecotoxicity endpoint of 849 ug/L (LC50 = 849 ug/L) for freshwater fish and 357 ug/L (LC50 = 

357 ug/L) for freshwater invertebrates. Web-ICE does not estimate chronic ecotoxicity 

endpoints.

For freshwater fish, the ecotoxicology endpoints estimated from ECOSAR corresponded to an 

acute COC of 409 ug/L (LC50/2), an endangered species COC of 41 ug/L (LC50/20), and a 

chronic COC of 111 ug/L. At a wastewater treatment plant influent volume of 1,000,000 

kilograms per year PTAP, the high-end scenario of E-FAST predicted that the acute COC for 

freshwater fish of 409 ug/L would be exceeded less than one day per year, the endangered 

species COC of 41 ug/L would be exceeded 22 days per year, and the chronic COC of 111 ug/L 

would be exceeded 3 days per year. The COCs that were predicted to be exceeded for one day or 
Page 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 based 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 freshwater invertebrates, the ecotoxicology endpoints estimated from ECOSAR 

corresponded to an acute COC of 304 ug/L (LC50/2) , an endangered species COC of 30.4 ug/L 

(LC50/20), and a chronic COC of 115 ug/L. At a wastewater treatment plant influent volume of 

1,000,000 kilograms per year PTAP, the high-end 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 estimate 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 ecotoxicology endpoints estimated from Web-ICE corresponded to an 

acute COC of 425 ug/L (LC50/2) and an endangered species COC of 42.5 ug/L (LC50/20). At a 

wastewater treatment plant influent volume of 1,000,000 kilograms per year PTAP, the high-end 

scenario of E-FAST predicted that the acute COC for freshwater fish of 425 ug/L would be 

exceeded less than one day per year and the endangered species COC of 42.5 ug/L would be 

exceeded 20 days per year. The COCs that were predicted to be exceeded one day or more per 

year based on the high-end scenario for a 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 scenario of E-FAST, the endangered 

species COC was predicted to be exceeded 2 days per year. At a wastewater treatment plant 

influent volume of 100,000 kilograms per year PTAP, the high-end scenario of E-FAST 

predicted no exceedances of acute, endangered species, 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 (LC50/2) and an endangered species COC of 18 ug/L 

(LC50/20). 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 days 
Page 43 of 43

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 7 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 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 activated 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 potentially 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 respiration 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.