Docket Number EPA-HQ-OPP-20 12-0682 

www.regulations.gov 

4-tertiary-Amylphenol and Salts Final Work Plan 

Registration Review: 

Case Number 3016 

March 2013 

Approved by: 

Date: 

Susan Lewis 

Acting Director 

Antimicrobials Division 

Page 1 of43 
Page 2 of 43

4-tertiary-Amylphenol and Salts Registration Review Team

Human Health & Environmental Effects

Srinivas Gowda 

Timothy Dole 

Zoë Layton 

Jonathan Chen 

James Breithaupt 

Pat Jennings 

Risk Management

Seiichi Murasaki 

Lance Wormell 

Office of General Counsel

Philip Ross 

 
Page 3 of 43

Table of Contents 

1 Introduction ............................................................................................................................. 4

1.1 Statutory and Regulatory Authority ................................................................................. 4

1.2 Updates to the Work Plan ................................................................................................. 5

1.3 Case Overview ................................................................................................................. 7

1.4 Chemical Identification and Properties ............................................................................ 7

1.5 Use/Usage Description ..................................................................................................... 8

1.5.1 Summary of Registered Uses .................................................................................... 8

1.5.2 Usage Information .................................................................................................... 9

1.6 Incidents ........................................................................................................................... 9

1.6.1 Human Health ........................................................................................................... 9

1.6.2 Ecological ............................................................................................................... 10

2 Anticipated Data Needs ........................................................................................................ 10

3 Human Health Risk Assessment ........................................................................................... 13

3.1 Existing Toxicological Endpoints .................................................................................. 13

3.2 Dietary Exposure ............................................................................................................ 14

3.2.1 Food ........................................................................................................................ 14

3.2.2 Drinking Water ....................................................................................................... 14

3.3 Occupational and Residential Exposures ....................................................................... 15

3.3.1 Occupational Handler Exposure ............................................................................. 15

3.3.2 Residential Handler Exposures ............................................................................... 15

3.3.3 Residential Post-Application Exposures ................................................................. 16

3.4 Aggregate and Cumulative Exposure ............................................................................. 17

3.4.1 Aggregate Exposures .............................................................................................. 17

3.4.2 Cumulative Exposures ............................................................................................ 17

4 Environmental Risk Assessment........................................................................................... 17

4.1 Environmental Conceptual Model Exposure Pathways ................................................. 17

4.2 Ecological Effects Assessment ....................................................................................... 18

4.2.1 Mechanism of Action .............................................................................................. 19

4.2.2 Measures of Effect (Ecotoxicology Endpoints) ...................................................... 19

4.3 Exposure Analysis Plan .................................................................................................. 21

4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates ............................................ 21

4.3.2 Screening Level Down-the-Drain Analysis ............................................................ 21

4.4 Effects Analysis Plan ..................................................................................................... 22

5 Endocrine Disruptor Screening Program (EDSP) ................................................................. 22

6 Next Steps ............................................................................................................................. 23

7 References ............................................................................................................................. 24

Appendix A Toxicology Profile ............................................................................................... 26

Appendix B Environmental Fate ............................................................................................. 30

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

Appendix D Screening Level Down-the-Drain Analysis ........................................................ 40

Appendix E Comments Received Concerning the Preliminary Work Plan ............................ 43

List of Tables 

Table 1 – Summary of Anticipated Risk Assessments and Data Needs ......................................... 6
Page 4 of 43

Table 2 – Anticipated Registration Review Schedule .................................................................... 6

Table 3 – Chemical Identification of p-tertiary-Amyl Phenol (PTAP) .......................................... 7

Table 4 – Physical-Chemical and Fate Properties for PTAP and salts ........................................... 7

Table 5 – Summary of PTAP Registered Uses ............................................................................... 8

Table 6 – Studies Anticipated as Needed for the Registration Review of PTAP ......................... 11

Table 7 – Existing Toxicological Endpoints ................................................................................. 13

Table 8 – Occupational Handler Exposure Scenarios for PTAP .................................................. 15

Table 9 – Residential Handler Exposure Scenarios for PTAP ..................................................... 16

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 13 – Acute Toxicity Studies for PTAP ............................................................................... 26

Table 14 – Aquatic Organism PTAP Toxicology ......................................................................... 33

Table 15 – Examples of PTAP Affecting the Endocrine System in Fish ..................................... 35

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

1 Introduction 

This document is the Environmental Protection Agency’s (EPA or “the Agency”) Final Work 

Plan (FWP) for the registration review of the 4-tertiary-Amylphenol and Salts Case. The FWP 

document explains what EPA's Office of Pesticide Programs knows about the chemicals, 

highlighting anticipated data and assessment needs, identifying the types of information that 

would be especially useful to the Agency in conducting the review, and providing an anticipated 

timeline for completing their review. This work plan also addresses public comments received 

concerning the Preliminary Work Plan (PWP), which was posted in the 4-tertiary-Amylphenol 

and Salts registration review docket (EPA-HQ-OPP-2012-0682). Further, this document makes 

final the work plan for the 4-tertiary-Amylphenol and Salts registration review process. 

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 
Page 5 of 43

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. The 4-

tertiary-Amylphenol and Salts Preliminary Work Plan (PWP) was published on September 26, 

2012 and the 60-day comment period ended on November 26, 2012. 

Documents associated with this registration 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. 

1.2 Updates to the Work Plan 

Since the publication of the PWP, the agency has made the following updates: 

• Deleted anticipated data requirements no longer required to support registration review 

since these are to be addressed in the submission of the remaining anticipated exposure 

data requirements: 

o 875.1600: Data Reporting and Calculations 

o 875.2900: Data Reporting and Calculations 

• Added the following anticipated data requirement 

o 850.1075 Fish Acute Toxicity Test. Results from this study are needed to 

calculate an acute-to-chronic ratio for freshwater fish. 

• Clarified throughout the document that additional tolerances may need to be established 

as determined during the planned risk assessments. 

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

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

• Updated Table 6 to clarify that (a) results from tests conducted according to OECD 2231

or OCSPP Guideline 850.2100 can be submitted for consideration to address the Avian 

Acute Oral Toxicity Test requirement and (b) results from tests conducted according to 

OECD 4432

 or OCSPP Guideline 870.3800 can be submitted for consideration to address 

the Reproductive Toxicity Study requirement. These updates were made in response to 

comments received during the public comment period (see Appendix E ). 

• Corrected formatting and typographical errors 

The Agency received two comments on the initial docket. The comments received did not affect 

the data needs (except as noted in the next two sentences), work plan and timeline described in 

the PWP. One comment requested that the Agency consider the possibility that two data 

requirements could possibly be addressed by testing results obtained from use of OECD 

guidelines. The Agency considered this possible approach and agrees that the OECD methods 

referenced in the comment could be considered for use in the subject testing. A summary of the 

comments received and the Agency’s responses are presented in Appendix E . 

 

1

 http://www.oecd-ilibrary.org/environment/test-no-223-avian-acute-oral-toxicity-test_9789264090897-en 2

 http://www.oecd-ilibrary.org/environment/test-no-443-extended-one-generation-reproductive-toxicitystudy_9789264122550-en 
Page 6 of 43

Table 1 – Summary of Anticipated Risk Assessments and Data Needs 

Risk Assessment 

Assessment 

Necessary to 

Support 

Registration 

Review 

Date of 

Most 

Recent 

Assessment 

Type of 

Assessment 

Required 

(New/Updated) 

Data Anticipated as Needed 

(See Table 6 for details) 

Dietary (food) Yes 5/26/2005 Updated 

Surface / Dietary Residue 

Reproductive Toxicity 

Developmental Toxicity 

Dietary (drinking water) No (see 3.2.2) 5/26/2005 None None 

Occupational Handler Yes 5/26/2005 Updated Indoor Exposure 

Inhalation Toxicity 

Residential Handler Yes 5/26/2005 Updated Indoor Exposure 

Inhalation Toxicity 

Residental Post Application - 

Incidental Oral and Dermal Yes 5/26/2005 Updated Surface Residue 

Residental Post Application - 

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

Aggregate Yes 5/26/2005 Updated 

Surface Residue 

Reproductive Toxicity 

Developmental Toxicity 

Cumulative No (see 3.4.2) N/A None None 

Tolerance Review Yes N/A New None 

Ecological Yes N/A New 

Invertebrates, aquatic plants, and 

avian Toxicity 

Fish life-cycle 

Reproductive Toxicity 

Environmental Fate 

N/A = Not applicable 

Table 2 – Anticipated 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 2012-11-26 

Phase 2: Case Development 

Issue Final Work Plan 2013-03 2013-03-13 

Issue Data Call-In (DCI) 2014-03 

Receive Data to be Considered in Risk Assessment 2016-03 

Open 30-Day Public Comment Period for 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 

*The anticipated schedule will be revised as necessary (e.g., need arising under the Endocrine Disruptor Screening Program with respect to the 

active ingredients in this case). 
Page 7 of 43

1.3 Case Overview 

The docket for the 4-tertiary-Amylphenol and Salts Case (Case 3016) has been established at 

http://www.regulations.gov in docket number EPA-HQ-OPP-2012-0682. 

1.4 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 (PTAPNa) 

Classification Alkyl Phenol Alkyl Phenol Alkyl Phenol 

PC Code 064101 064111 064112 

CAS No. 80-46-6 53404-18-5 31366-95-7 

Molecular Formula C11H16O C11H15KO C11H15NaO 

Molecular Weight 164.25 g/mol 202.3345 g/mol 186.23 g/mol 

First registered in US 1962 1967 1986 

Reregistration Eligibility Decision (RED) 

issued3 2005 2005 2005 

Registered Products (as of 02/12/2013) 31 1 1 

Tolerances4 40 CFR 180.940(c) None None 

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. 

830.1650 Description of Formulation 

Process 

Confidential Business 

Information (CBI) CBI CBI 

830.1800 Enforcement analytical 

method GC MS GC MS GC MS 

830.6302 Color White crystals White White 

830.6303 Physical State Solid; Flakes Solid Solid 

830.6304 Odor Slight phenolic odor Slight phenolic odor Slight phenolic odor 

 

3

 EPA anticipates issuing the post-RED DCI soon. 

4

 PTAP (expressed as Phenol, 4-(1,1-dimethylpropyl)-) has a tolerance exemption in 40 CFR 180.940(c) as a foodcontact sanitizer for use in food-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. 
Page 8 of 43

OPPTS 

Guideline 

No. 

Physical and Chemical 

Properties 4-tertiary-amylphenol PTAP-K PTAP-Na 

830.6313 

Stability to sunlight, normal 

and elevated temperature, 

metals/metal ions 

Stable under normal 

temperatures and 

pressures. 

Stable under normal 

temperatures and 

pressures. 

Stable under normal 

temperatures and 

pressures. 

830.7000 pH 6.5 - 7 (0.1% aq.sol.) N/A N/A 

830.7050 UV/Visible Absorption Limited absorbance above 

290 nm 

Limited absorbance 

above 290 nm 

Limited absorbance 

above 290 nm 

830.7200 Melting point 91-94°C; 95° C 206 °C (EPI Suite) 205.87 °C (EPI Suite) 

830.7220 Boiling point 262.5 °C at 760 mmHg 262.5°C at 760 

mmHg 

262.5°C at 760 

mmHg 

830.7300 Density 0.96 g/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 

(Measured) 

3,811 mg/L (EPI 

Suite) 

4,595 mg/L (EPI 

Suite) 

830.7860 Solubility in organic solvents 

Soluble in alcohol, ether, 

benzene, chloroform, 

DMSO, Acetone 

N/A N/A 

830.7950 Vapor pressure 2.0 x 10-3 mm Hg at 25° C 

(Measured) 

7.7 x10-10 at 25° C 

(EPI suite) 

7.7 x10-10 at 25° C 

(EPI suite) 

 N/A Henry's Law Constant 2.6 x 10-6 atm-m3

/mole at 

25o

C (Calculated) 

5.4 x 10-14 atmm3

/mole at 25oC (EPI 

Suite) 

4.1 x 10-14 atmm3

/mole at 25oC (EPI 

suite) 

1.5 Use/Usage Description 

1.5.1 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 farms5

Fogger, Thermal Unknown6 

Fogger, Total 

Release 0.5 mg/m3

 

Mop, Soak or 

Wipe 76 to 598 ppm 

 

5

 Labels specify that use is not permitted in milking stalls, milking parlors or milk houses. 

6

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

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

ounces per 1000 ft3

). 
Page 9 of 43

Use Application 

Method 

Application 

Rate 

Shoe Baths 78 to 156 ppm 

Commercial, Industrial, Institutional, Premises and Equipment 

Non-porous surfaces - Floors, walls, finished woodwork, chairs, countertops, 

sinks, garbage cans, cabinets. 

Fogger, Total 

Release 

0.2 to 1.4 

mg/m3

Mop, Spray, Wipe 28 to 598 ppm 

Food Handling/Storage Establishments Premises and Equipment – Indirect Food Contact 

Non-porous surfaces Fogger Unknown6

 

Mop, Spray, Wipe 78 to 450 ppm 

Residential and Public Access Premises 

Non-porous surfaces37 Fogger, Thermal Unknown6

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 Unknown6

Spray, Mop, Wipe 28 to 781 ppm 

Fiberglass bath and therapy Units Circulate then 

Drain 195 ppm 

Barber and Beauty Shop Instruments Immersion 35 to 580 ppm 

Dental Handpieces Immersion 580 ppm 

Medical Instruments Immersion 598-1197 ppm 

1.5.2 Usage Information 

According to the Kline Biocides Report for 2004/2005 (Kline, 2005), PTAP makes up less than 1 

percent of the estimated U.S. consumption of 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 States8. 

1.6 Incidents 

1.6.1 Human Health 

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

for the time period spanning 2005 to 2012. 

 

7

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

8

 Data for the years 2009 through 2011 were not used in this estimate since data collection is still in progress. 
Page 10 of 43

1.6.2 Ecological 

No PTAP incidents ecological incidents have been reported in the Agency’s Ecological Incident 

Information System (EISS) for the time period spanning 2005 to 2012. 

2 Anticipated Data Needs 

Table 6 presents a summary of the data anticipated as being needed to support this registration 

review. 
Docket Number EPA-HQ-OPP-2012-0682 

www.regulations.gov 

Page 11 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 S

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 su

often rinsed down the dr

835.3220 Porous Pot Test TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

835.3280 

Simulation Tests to Assess the Biodegradability of Chemicals Discharged to Wastewater 

TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

835.3240 

Simulation Test – Aerobic Sewage Treatment: A. Activated Sludge Units 

TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

850.1035 Acute marine/estuarine invertebrate toxicity (shrimp)9 TGAI 12 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

850.1075 Fish acute toxicity (freshwater) 10 TGAI 12 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

850.1500 Fish life-cycle (freshwater)10 TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

850.1025 or 850.1055 

Acute estuarine/marine invertebrate toxicity (mollusk) TGAI 12 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

850.1350 Chronic marine/estuarine invertebrate toxicity (shrimp)9 TGAI 24 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

850.210011 Avian acute oral toxicity test TGAI 12 Ecological Hard Surface Disinfection Birds ingesting aquatic a

or ingested PTAP 

850.4400 Aquatic plant toxicity test using Lemna gibba TGAI 12 Ecological Hard Surface Disinfection Down the drain; hard su

often rinsed down the dr

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 su

often rinsed down the dr

9 Results using the same species as that used in the chronic study are anticipated to be required to calculate an acute-to-chronic ratio. 10 An acceptable acute 96-h LC50 value for the same species tested for the full life cycle test is expected to be required to calculate an acu11 OECD TG 233 using the "LD50- slope test" or "limit dose test" can be submitted for consideration instead of OCPSS 850.2100 for cert

(e.g., causes no delayed effects, causes no regurgitation). Details on the species and conditions under which TG 233 would not fulfill the described at http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/terrestrial_biology_tech_team/review_avian_acu
Page 12 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 S

870.3465 90-day inhalation toxicity study TGAI 24 

Occupational and Residential 

Air Sanitization, HVAC Treatments, Hard Surface Disinfection 

All scenarios that involv

870.380012 Reproduction and Fertility Effects study TGAI 24 Dietary, Ecological Food Contact Surfaces Dietary exposures from 

contact uses. 

875.1200 Indoor Exposure, Dermal TGAI 24 

Occupational and Residential 

Hard Surface Disinfection 

(1) Trigger pump sprayehigh pressure handwand

Hand held fogger 

875.1400 Indoor Exposure, Inhalation TGAI 24 

Occupational and Residential 

Hard Surface Disinfection 

(1) Trigger pump sprayehigh pressure handwand

Hand held fogger 

875.1700 Product Use Information TGAI 12 All All All scenarios. 875.2300 Indoor Surface Residue Dissipation14 TGAI 24 Residential Surface disinfection of household floors and carpets Dermal and incidental ex

expected for toddlers whfloors or carpets after thPTAP products. 

875.2500 Post Application Exposure, Inhalation TGAI 24 Residential Air Sanitization, HVAC Treatments Inhalation exposure follo

deodorizers or HVAC tr

875.3700 Developmental Toxicity in Rabbits TGAI 24 Dietary Food Contact Surfaces Dietary exposures from 

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 

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 

contact uses. 

12 Results from a multi-generation (EPA guideline 870.3800) or an extended one-generation reproductive and fertility effects study using 

(http://www.oecd-ilibrary.org/environment/test-no-443-extended-one-generation-reproductive-toxicity-study_9789264185371-en) may b

consideration in response to this requirement. 

13 It may be possible to use proprietary surrogate exposure data if data compensation issues are appropriately and adequately addressed. 14 In the absence of surface residue data, EPA will need to estimate risk utilizing a transfer fate of 100%. 
Docket Number EPA-HQ-OPP-2012-0682 

www.regulations.gov 

Page 13 of 43

3 Human Health Risk Assessment 

The Agency anticipates the need to conduct a human health risk assessment for PTAP. The 

Agency expects to require additional data for use in conducting the registration review. 

3.1 Existing Toxicological Endpoints 

EPA anticipates the need to revise the existing 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 14 of 43

Exposure 

Scenario

Dose Used in Risk 

Assessment 

(mg/kg/day) 

Target Margin of Exposure 

(MOE), UF, Special FQPA 

SF, for Risk Assessment

Study and Toxicological Effects 

Inhalation 

All time periods 

(occupational and 

residential) 

NOAEL = 50 

mg/kg/day 

MOE (occupational) = 300 

MOE (residential) = 3000 

(10x interspecies extrapolation, 

10x intraspecies variation, 10x 

route extrapolation, 3x database 

uncertainty) 

Developmental toxicity study in the rat 

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

signs, decreased body weight and body 

weight gain, and decreased food 

consumption in maternal animals at 200 

mg/kg/day 

Cancer No cancer data available for PTAP 

3.2 Dietary Exposure 

The Agency anticipates the need to revise 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%. 

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

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

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

3.2.2 Drinking Water 

EPA does not anticipate the need to revise the drinking water assessment conducted in support of 

the 2005 RED because dietary exposure from drinking water is not expected to occur based on 

PTAP’s sorption to soils and sediments and lack of persistence (see Appendix B ) and a range 

finding assessment of down the drain exposures (see Appendix D ). 
Page 15 of 43

3.3 Occupational and Residential Exposures 

The Agency anticipates the need to revise the occupational and residential assessments 

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

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

values. Uses of PTAP that may result in 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 

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, 
Page 16 of 43

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 dermal exposures can occur when adults 

and children come in contact with PTAP in areas where PTAP has been applied to floors and 

carpets. Incidental oral exposures to children can also occur from hand to mouth contact with 

treated floors and carpets. Inhalation exposures can occur following the application of PTAP. 

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. 

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 
Page 17 of 43

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 

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). 
Page 18 of 43

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. 

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 

Stressor

Source

Receptors 

and Exposure 

Routes

Attribute

Change(s)

Individual organisms

Reduced survival

Reduced growth

Reduced reproduction

Food chain

Reduction in algae

Reduction in prey

Modification of PCEs related 

to prey availability

Habitat integrity

Reduction in primary productivity

Reduced cover

Community change

Modification of PCEs related to 

habitat

Aquatic Animals

Invertebrates

Vertebrates

Exposure

Media

Ingestion Ingestion

Uptake/gills 

or integument

Aquatic Plants

Non-vascular

Vascular

Uptake or sorption by 

cells, roots, leaves, 

Piscivorous*

Invertebrates

Vertebrates

Phytoplanktivore/ 

Herbivore

Invertebrates

Vertebrates

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

Ingestion

Waste Water Treatment Plant (WWTP)

Key

Most likely

exposure pathway 

contributing to risk

Low likelihood of 

contributing to risk

In-Service Use of Disinfectants or 

Sanitizers on Hard Inanimate Surfaces

WWTP 

microorganisms

Uptake or 

sorption

Population

Respiration 

inhibition

Waste Water Disposal Down-the-Drain

Surface Water

Sediment
Page 19 of 43

as OPPT’s High Production Volume (HPV) Challenge (http://www.epa.gov/HPV/) or estimated 

using modeling as described below and in Appendix C . 

4.2.1 Mechanism of Action 

PTAP and its salts are broadly categorized 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. 

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 documented15 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 

 

15 Gimeno, S., Komen, H., Venderbosch, P.W., and Bowner, T. (1997) Disruption of sexual differentiation in 

genetic male carp (Cyprinus carpio) exposed to an alkyphenol during different life stages. Environ. Sci. Technol. 

31(10): 2884-2890. 

Gimeno, S., Komen, H., Gerritsen, A.G., and Bowner, T. (1998a): Feminisation of young males of the common 

carp, Cyprinus carpio, exposed to 4-tert-pentyphenol during sexual differentiation. Aquatic Toxicology 

(Amsterdam) 43: 77-92. 

Gimeno, S., Komen, H., Jobling, S., Sumpter, J., and 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

Receptor 

Group 

Surrogate 

Species 

Risk 

Scenario 

Toxicity 

Endpoint 

as a.e. 

Comment Reference 

Generic fish Chronic ChV = 111 

ppb 

Supplemental information, use will 

underestimate chronic risks, because there are 

endocrine disruption concerns a full life-cycle 

study is anticipated to be required rather than 

an early life-stage study (ChV values are early 

life-stage), an acute test conducted on the same 

test species would allow for the calculation of 

an acute-to-chronic 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 

anticipated to be required at this time 

ECOSAR v 

1.11 

Chronic ChV = 115 

ppb 

Supplemental information, use will 

underestimate chronic risk but ChV value for 

invertebrates includes reproduction and 

uncertainty is expected to be low, ACR will be 

applied to Web-ICE v. 3.1 value, no additional 

studies are anticipated to be required at this 

time 

ECOSAR v 

1.11 

Estuarine / 

Marine fish 

Sheepshead 

minnow Acute 

96-hr 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 data available 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 
Page 21 of 43

Receptor 

Group 

Surrogate 

Species 

Risk 

Scenario 

Toxicity 

Endpoint 

as a.e. 

Comment Reference 

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 

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 treatment16, 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 kg/year Exceeded <1 day per year Exceeded 22 days per year Exceeded 3 days per year 

100,000 kg/year No exceedances No exceedances No exceedances 

Influent Volume Freshwater fish acute 

(COC = 425 ug/L) 

Endangered Freshwater fish 

(COC = 42.5 ug/L) 

1,000,000 kg/year Exceeded <1 day per year Exceeded 20 days per year 

100,000 kg/year No 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 kg/year Exceeded <1 day per year Exceeded 34 days per year Exceeded 3 days per year 

 

16 In the absence of data concerning removal of PTAP during wastewater treatment, no removal of PTAP during 

wastewater treatment was assumed. 
Page 22 of 43

100,000 kg/year No exceedances No exceedances No exceedances 

Influent Volume Freshwater invertebrates 

acute (COC = 180 ug/L) 

Endangered Freshwater 

invertebrates (COC = 18 ug/L) 

1,000,000 kg/year Exceeded 1 day per year Exceeded 65 days per year 

100,000 kg/year No exceedances Exceeded 1 day per year 

4.4 Effects Analysis Plan 

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

database17, which employs a literature search engine for locating chemical toxicity data for 

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, 

 

17 http://cfpub.epa.gov/ecotox/ 
Page 23 of 43

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/. 

6 Next Steps 

A DCI will be developed regarding the data needs listed under the “Anticipated Data Needs” 

section of this document. The Agency expects to issue the DCI in March 2014. The Agency will 

conduct human health and environmental fate and ecological hazard assessments for all uses. 

 
Page 24 of 43

7 References 

Ellis DD et al; Arch Environ Contam Toxicol 11: 373 – 82, 1982 

Gimeno, S., Gerritsen, A., Bowmer, T., and 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 25 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 26 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 27 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 28 of 43

Reproductive Toxicity 

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

indirect or direct food uses. In addition, there are other toxicological 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 29 of 43

an RPE of 105 was estimated. Both Routledge and Sumpter, 1997 and Miller et al., 2001, 

demonstrated estrogenic activity of PTAP gene activation in hER in yeast reporter system. 

Hornung et al., 2008 studied the gene activation in rainbow trout ER in a reporter cell line; PTAP 

showed positive results. Tollefsen et al., 2008 studied the binding of chemical to rainbow trout 

ER; PTAP showed positive results. Feminization of young male common carp was observed 

when treated with PTAP (Gimeno S, Komen H, and Gerritsen AGM, Bowmer T. 1998). 

 
Page 30 of 43

Appendix B Environmental Fate 

Environmental Fate Properties 

Except as noted, the 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 31 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 32 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. However, as explained below, the agency intends to use values estimated from 

surrogate species and does not anticipate the need to require additional studies for these specific 

fish species. 

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 
Page 33 of 43

acute toxicity to a desired aquatic species, for which data are missing, from data for a different 

species. Web-ICE version 3.1 was used to estimate the toxicity to bluegill sunfish (1,560 μg/L; 

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) 
Page 34 of 43

μg/L (3.39) 1160.75 μg/L (3.06) 

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 

2500

95%

2500

95%
Page 35 of 43

Average value of surrogate (log value): 1843.51 (3.26) 

Minimum value of surrogate (log value): 1.18 (0.075366) 

Maximum value of surrogate (log value): 10600000.00 (7.02) 

Mean Square Error (MSE): 0.475436 

Sum of Squares (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. Since estimated chronic values based on early life stages are not adequate as substitutes 

for full life cycle values, the agency anticipates the need to require a fish life-cycle study. 

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. 
Page 36 of 43

Organism/ 

Age 

Results Comments Reference 

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. 

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: 
Page 37 of 43

 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.) 

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

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. 

The most conservative 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, 

the agency does not anticipate the need to require acute and chronic invertebrate data. 

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 38 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 

2500

95%
Page 39 of 43

moderately toxic to shrimp. The study does not meet current guideline requirements and cannot 

be used in a risk assessment. An acute freshwater invertebrates toxicity study is anticipated to be 

required for registration review. 

 
Page 40 of 43

Appendix D Screening Level Down-theDrain Analysis 

The Down-the-Drain (DtD) module of E-FAST (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 41 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 42 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. 

 
Page 43 of 43

Appendix E Comments Received 

Concerning the Preliminary Work Plan 

The Agency received two comments on the initial docket, described below. In the PWP, the 

Agency solicited comments on specific topics: environmental justice, water body impairment, 

trade irritants, and structure activity relationships. No comments or information were received 

during the public comment period concerning these issues. 

Comment: The Physicians Committee for Responsible Medicine (PCRM) suggests the registrant 

use (a) Organisation for Economic Cooperation and Development (OECD) Test Guideline (TG) 

223 (Avian Acute Oral Toxicity Test), rather than the EPA Guideline 850.2100 and (b) OECD 

TG 443 (Extended One-Generation Reproductive Toxicity Study) instead of the multi-generation 

EPA guideline 870.3800. 

Response: The Agency agrees that (a) results from tests conducted according to OECD 22318 or 

OCSPP Guideline 850.2100 can be submitted for consideration to address the Avian Acute Oral 

Toxicity Test requirement19 and (b) results from tests conducted according to OECD 44320 or 

OCSPP Guideline 870.3800 can be submitted for consideration to address the Reproductive 

Toxicity Study requirement21. 

Comment: The FIFRA Endangered Species Task Force (FESTF) submitted a comment noting 

that it has data that will assist the Agency in conducting an endangered species risk assessment 

for 4-t-amylphenol, and requesting that any technical registrant for 4-t-amylphenol who is not a 

member of the FESTF (or a company having met its data compensation obligations) be asked to 

provide a formal offer-to-pay to FESTF for reliance on their data. 

Response: The Agency thanks FESTF for its comment and will consider this information as it 

conducts the registration review and makes its registration review decisions. 

 

18 http://www.oecd-ilibrary.org/environment/test-no-223-avian-acute-oral-toxicity-test_9789264090897-en 19 OECD TG 233 using the "LD50- slope test" or "limit dose test" can be used instead of OCPSS 850.2100 for certain 

species and conditions (e.g., causes no delayed effects, causes no regurgitation). Details on the species and 

conditions under which TG 233 would not fulfill the data requirement are described at 

http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/terrestrial_biology_tech_team/review_av

ian_acute_oral_oecd_tg223.htm 

20 http://www.oecd-ilibrary.org/environment/test-no-443-extended-one-generation-reproductive-toxicitystudy_9789264122550-en 

21 The Agency will accept a multi-generation or an extended one-generation reproductive and fertility effects study.