Docket Number EPA-HQ-OPP-2014-0406

www.regulations.gov

1,3-Propanediamine, N-(3-aminopropyl)-N-dodecyl- Registration Review Team

Human Health & Environmental Effects

Jenny Tao

Nate Mottl

Don Wilbur

Patricia Jennings

James Breithaupt

William Erickson

Srinivas Gowda

Risk Management

Tina Pham

Rose Kyprianou

Emilia Oiguenblik

Velma Noble

Office of General Counsel

Philip Ross

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TERMS, ABBREVIATIONS AND SYMBOLS

A.I. or a.i. active ingredient

ASRI activated sludge respiration inhibition

atm-m3

/mole atmospheric pressure-cubic meter per mole

°C degrees Celsius

CAS Chemical Abstracts Service 

CFR Code of Federal Regulations 

CHO Chinese hamster ovary

DCI data call-in

EC50 median (or 50 percent) effect concentration

ECOTOX ECOTOXicology

EDSP Endocrine Disruptor Screening Program 

EEC estimated environmental concentration

E-FAST Exposure and Fate Assessment Screening Tool

EPA Environmental Protection Agency

FDA Food and Drug Administration 

FFDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act 

FWP Final Work Plan

g/ml grams per milliliter

g/mol grams per mole

GLN guideline number

IDS Incident Data System 

Koc organic carbon normalized soil-water partition coefficient

Kd soil-water partition coefficient

Kow octanol-water partition coefficient

LC50 median (or 50 percent) lethal concentration

LD50 median (or 50 percent) lethal dose

LOAEL lowest-observed-adverse-effect-level

Log Kow logarithm of the octanol-water partition coefficient

LTD lowest tested dose

μg microgram

ml/g milliliter per gram

mg/kg milligram per kilogram

mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury

MOE margin of exposure 

MRID Master Record Identification Number

N/A not applicable 

nm nanometers

NOAEC no-observed-adverse-effect-concentration

NOAEL no-observed-adverse-effect-level

OCSPP Office of Chemical Safety and Pollution Prevention

OECD Organization for Economic Co-operation and Development

OPP Office of Pesticide Programs

ORE occupational and residential exposure

PAD population adjusted dose

PC Code Pesticide Chemical Code

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pH power of hydrogen or power of the concentration of the hydrogen ion

pKa power of the acid dissociation constant or negative base-10 logarithm of the acid 

dissociation constant of a solution

ppm parts per million

PWP Preliminary Work Plan

RED Reregistration Eligibility Decision

TEP typical end-use product

TGAI technical grade active ingredient

TMDL total maximum daily loads

UF uncertainty factor

UV/VIS ultraviolet/visible light absorption

WWTP wastewater treatment plant

1,3-PAD 1,3-propanediamine, N-(3-aminopropyl)-N-dodecylPage 4 of 53
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Table of Contents

1 Introduction............................................................................................................................. 7

1.1 Statutory and Regulatory Authority ................................................................................. 7

1.2 Updates to the Workplan.................................................................................................. 7

1.3 Case Overview ................................................................................................................. 8

1.4 Chemical Identification and Properties............................................................................ 9

1.5 Use/Usage Description................................................................................................... 11

1.5.1 Registrations ........................................................................................................... 11

1.5.2 Summary of Registered Uses.................................................................................. 11

1.5.3 Usage Information .................................................................................................. 12

1.6 Regulatory History ......................................................................................................... 12

1.6.1 Tolerance Information ............................................................................................ 12

1.7 Incidents......................................................................................................................... 12

1.7.1 Human Health ......................................................................................................... 12

1.7.2 Ecological ............................................................................................................... 12

2 Anticipated Data Needs ........................................................................................................ 12

3 Human Health Risk Assessment........................................................................................... 15

3.1 Existing Toxicological Endpoints.................................................................................. 15

3.2 Dietary Exposure............................................................................................................ 15

3.2.1 Food ........................................................................................................................ 16

3.2.2 Drinking Water ....................................................................................................... 16

3.3 Occupational and Residential Exposures....................................................................... 16

3.3.1 Occupational Handler Exposure ............................................................................. 16

3.3.2 Occupational Post-application ..................................................................................... 17

3.3.3 Residential Handler Exposures.................................................................................... 17

3.3.4 Residential Post-Application Exposures...................................................................... 17

3.4 Aggregate and Cumulative Exposure............................................................................. 18

3.4.1 Aggregate Exposures.............................................................................................. 18

3.4.2 Cumulative Exposures............................................................................................ 18

4 Environmental Risk Assessment........................................................................................... 18

4.1 Environmental Fate Assessment .................................................................................... 19

4.1.1 Water Quality.......................................................................................................... 19

4.2 Environmental Exposure Pathways................................................................................ 19

4.2.1 Ecological Effects Assessment ............................................................................... 19

4.2.2 Mechanism of Action.............................................................................................. 20

4.3 Exposure Analysis Plan.................................................................................................. 20

4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates ............................................ 20

4.3.2 Screening Level Down-the-Drain Analysis............................................................ 20

4.4 Effects Analysis Plan ..................................................................................................... 21

5 Endocrine Disruptor Screening Program (EDSP)................................................................. 21

6 Optional Label Changes........................................................................................................ 22

7 Next Steps............................................................................................................................. 22

8 References............................................................................................................................. 23

Appendix A Toxicology Profile............................................................................................... 25

Appendix B Environmental Fate ............................................................................................. 44

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Appendix C Ecotoxicology Profile.......................................................................................... 48

Appendix D Screening Level Down-the-Drain Analysis ........................................................ 51

Appendix E Product Chemistry............................................................................................... 52

List of Tables

Table 1 – Summary of Anticipated Risk Assessments and Data Needs for Registration Review: 

1,3-PAD .......................................................................................................................................... 8

Table 2 – Anticipated Registration Review Schedule .................................................................... 9

Table 3 – Chemical Identification of 1,3-Propanediamine,N-(3-aminopropyl)-N-dodecyl-........ 10

Table 4 – Physical-Chemical and Environmental Fate Properties for 1,3-Propanediamine, N-(3-

aminopropyl)-N-dodecyl- ............................................................................................................. 10

Table 5 – Summary of 1,3-PAD Registered Uses ........................................................................ 11

Table 6 – Studies Anticipated as Needed for the Registration Review of 1,3-PAD .................... 13

Table 7 – Existing Toxicological Endpoints for 1,3-PAD............................................................ 15

Table 8 – Occupational Handler Exposure Scenarios for 1,3-PAD.............................................. 17

Table 9 – Residential Post-Application Exposure Scenarios for 1,3-PAD................................... 17

Table 10 – Ecological Effects Endpoints...................................................................................... 20

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1 Introduction

This document is the United States Environmental Protection Agency’s (USEPA, EPA or “the 

Agency”) Final Work Plan (FWP) for 1,3-Propanediamine, N-(3-aminopropyl)-N-dodecyl-,

herein referred to as 1,3-PAD. The FWP document explains what EPA's Office of Pesticide 

Programs (OPP) knows about 1,3-PAD, 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 1,3-PAD’s review.

The registration review process was designed to include a public participation component to 

solicit input from interested stakeholders. The Agency intends, by sharing this information in the 

docket, to inform the public of what it knows about 1,3-PAD and what types of new data or other 

information would be helpful for the Agency to receive as it moves toward a decision on 1,3-

PAD.

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 USEPA 

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://www2.epa.gov/pesticide-reevaluation.

The Agency is implementing the registration review program pursuant to Section 3(g) of the 

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

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

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

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

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

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

and data or information it believes are needed to make a registration review decision. 

1.2 Updates to the Workplan

Since the publication of the Preliminary Work Plan (PWP), the Agency has made the following 

updates:

• Updated Section 1.3, Case Overview.

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• Updated Table 1 and Sections 1.5.1, 1.6, 3.2, and 3.4 based on label changes submitted 

since the publication of the PWP, specifying non-food use only. Dietary (food) and 

Tolerance Review assessments are no longer anticipated for registration review. 

• Updated the timeline in Table 2, Anticipated Registration Review Schedule.

• Revised Table 6, Studies Anticipated as Needed for the Registration Review of 1,3-PAD

to include guideline 835.1110. This data gap was identified in Appendix B of the PWP 

but not captured in Table 6.

• Updated Section 6, Optional Label Changes.

• Deleted the “Guidance for Commenters” section.

• Updated Section 7, Next Steps.

• Updated Appendix A, including the Agency’s final review of chronic toxicity and 

carcinogenicity and Toxicology References.

No public comments were received on the initial docket and no modifications were made to the

anticipated data needs or registration review schedule of the 1,3-PAD PWP. This document 

makes final the work plan for the 1,3-PAD registration review process.

1.3 Case Overview

The PWP for 1,3-PAD was published on September 24, 2014, and the 60-day comment period 

ended on November 24, 2014. No public comments were received concerning the PWP. 

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

in docket EPA-HQ-OPP-2014-0406. 

Tables 1 and 2 below summarize the issues relevant to this registration review case and the 

anticipated registration review schedule.

Table 1 – Summary of Anticipated Risk Assessments and Data Needs for Registration 

Review: 1,3-PAD 

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) No 

(See Section 3.2) N/A None None

Dietary (drinking water) Yes1 N/A New None1

Occupational Handler Yes 11/7/2007 New

90-Day Inhalation Toxicity

Prenatal Developmental Toxicity

Dermal Indoor Exposure

Inhalation Indoor Exposure

Product Use

Occupational PostApplicationNo

(See Section 3.3.2) N/A None None

Residential Handler No

(See Section 3.3.3) N/A None None

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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)

Residential Post 

Application - Incidental 

Oral and Dermal 

Yes 8/3/2005 Updated 

Prenatal Developmental Toxicity

Indoor Residue

Product Use

Description of Human Activity

Residential Post 

Application - Inhalation 

No

(See Section 3.3.4) N/A None None

Aggregate Yes N/A New None1

Cumulative No

(See Section 3.4.2) N/A None None

Tolerance Review No N/A None None

Ecological Yes N/A New

Down-the-Drain

Ecotoxicology

Environmental Fate

(See Table 6)

1 No residue chemistry data are required at this time. However, additional residue chemistry data may be necessary, if the toxicological point of 

departure for either the acute or chronic scenario changes during the registration review process. 

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 2014-09 2014-09-24

Close Public Comment Period 2014-11 2014-11-24

Phase 2: Case Development 

Issue Final Work Plan 2015-03 2015-03

Issue Data Call-In (DCI) 2016-03

Receive Data to be Considered in Risk Assessment 2018-03

Open 30-Day Public Comment Period for Preliminary Risk Assessment(s) 2019-09

Close Public Comment Period 2019-10

Phase 3: Registration Review Decision and Implementation 

Open 60-Day Public Comment Period for Proposed Decision 2020-03

Close Public Comment Period 2020-05

Issue Final Decision 2020-09

Begin Post-Decision Follow-up 2020

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).

1.4 Chemical Identification and Properties

Table 3 presents the active ingredient to be assessed in case 5109: 1,3-Propanediamine,N-(3-

aminopropyl)-N-dodecyl- (PC Code 067300). 

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Table 3 – Chemical Identification of 1,3-Propanediamine,N-(3-aminopropyl)-N-dodecylChemical Name 1,3-Propanediamine,N-(3-aminopropyl)-N-dodecylChemical Classification Alkyl Amino Propane

PC Code 067300

CAS Number 2372-82-9

Molecular Formula C18H41N3

Molecular Weight (grams/mole) 299.543

Molecular Structure

The 1,3-Propanediamine,N-(3-aminopropyl)-N-dodecyl- product chemistry information relevant 

to risk assessment is summarized in Table 4, and the details of the product chemistry (Source: 

MRID Nos. 46332202, 45115304, 45115305, 45115307, 45115308, 45115309, 46309706, and 

Lonza MSDS) are discussed in Appendix E.

Table 4 – Physical-Chemical and Environmental Fate Properties for 1,3-Propanediamine,

N-(3-aminopropyl)-N-dodecylGuideline No. Parameter 1,3-Propanediamine,N-(3-aminopropyl)-NdodecylPhysical/Chemical Properties

830.7000 pH 10.6 (1% aqueous solution)

830.7050 UV/Visible Absorption 203.6 nm; 201.6 nm; 218.4 nm; in methanol, acidic 

methanol and alkaline methanol solutions.

830.7200 Melting point (oC) Setting point ≥10oC

830.7220 Boiling point (oC) The boiling point could not be determined due to 

decomposition of the test substance at approx. 280oC

830.7300 Density 0.87 g/ml at 20oC

830.7370 Dissociation constant (pKa) pKa values: 9.3 ± 0.104 and 7.15 ±0.054 at 20oC

830.7550 Octanol-water partition coefficient at 25 o

C

(Log Kow)

1,3-PAD is a polar chemical substance and therefore 

log Kow is not required. 

830.7840 Solubility in water (mg/L) Completely and infinitely soluble in water

830.7860 Solubility in organic solvents Completely miscible at 20oC in Acetone, Ethyl 

acetate, and Methanol.

830.7950 Vapor pressure (mmHg) 3.3 x 10-6 at 25oC

None (calculated)

Henry’s law (atm m3 mol-1)

[VP (mm Hg) * molecular weight 

(grams/mol)]/[760 * solubility (mg/l)]

1.3 x 10-10

atm-m3/mol = atmosphere cubic meter per mole; oC = degrees Celsius; mg/L = milligrams per liter; mmHg = 

millimeters of mercury

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1.5 Use/Usage Description

1.5.1 Registrations

There are four registered 1,3-PAD products. Since the publication of the PWP, a voluntary 

cancellation request has been submitted for one product (EPA Reg. No 6836-284). All remaining 

products are currently registered for non-food uses. There are no inert uses and no pending 

registrations.

1.5.2 Summary of Registered Uses

Table 5 presents a summary of the registered uses of 1,3-PAD that will be assessed in this 

registration review case. 1,3-PAD can be applied by the following application methods: mop, 

foaming generator, mechanical sprayer, and metering pump. 

Table 5 – Summary of 1,3-PAD Registered Uses

Use Application Method Application Rate

Agricultural Premises and Equipment 

Dairy

Farm Premises

Poultry Premises

Animal Housing Facilities

Mop 3.6 ppm

Foaming Generator 3.2 ppm

Mechanical Sprayer 3.6 ppm

Commercial, Industrial, Institutional, Premises and Equipment

Restaurants

Mop 3.6 ppm

Foaming Generator 3.2 ppm

Mechanical Sprayer 3.6 ppm

Food Handling/Storage Establishments Premises and Equipment 

Beverage and Food Processing Plants

Mop 3.6 ppm

Foaming Generator 3.2 ppm

Mechanical Sprayer 3.6 ppm

Residential and Public Access Premises

Schools

Mop 3.6 ppm

Foaming Generator 3.2 ppm

Mechanical Sprayer 3.6 ppm

Bars and Cafeterias

Mop 3.6 ppm

Foaming Generator 3.2 ppm

Mechanical Sprayer 3.6 ppm

Athletic Facilities

Mop 3.6 ppm

Foaming Generator 3.2 ppm

Mechanical Sprayer 3.6 ppm

Medical/Dental/Veterinary Premises and Equipment

Pet Shops Mop 3.6 ppm

Foaming Generator 3.2 ppm

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Use Application Method Application Rate

Mechanical Sprayer 3.6 ppm

Preservatives

Metalworking Fluids (Enclosed) Metering Pump 2500 ppm

Oil Field Flood Water Systems Metering Pump 20 ppm

1.5.3 Usage Information

No usage information is available in the Kline Biocides Report for 1,3-PAD.

1.6 Regulatory History

A Reregistration Eligibility Decision (RED) was not completed for 1,3-PAD because it was 

registered after November 1, 1984. In 2015, labels were amended to specify that products must 

only be used in non-food-use areas.

1.6.1 Tolerance Information

For the active ingredient 1,3-PAD, EPA has not established tolerances or exemptions from 

tolerances in/on raw agricultural commodities or processed food and feed products under the 

Federal Food, Drug and Cosmetic Act (FFDCA) Section 408. The US Food and Drug 

Administration (US FDA) has not established any food contact notifications or food additive 

regulations under FFDCA Section 409 for 1,3-PAD.

The Agency does not anticipate reviewing the potential need for tolerances/exemptions during 

the registration review process for the currently registered non-food uses.

1.7 Incidents

1.7.1 Human Health 

No 1,3-PAD human poisoning incidents have been reported in OPP’s Incident Data System 

(IDS) for the time period spanning 2005 to 2013 based on the search conducted on August 25, 

2014.

1.7.2 Ecological

There are no ecological incidents in IDS as of March 5, 2014.

2 Anticipated Data Needs

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

review.

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Table 6 – Studies Anticipated as Needed for the Registration Review of 1,3-PAD

GLN Study Name Test 

Substance

Time Frame 

(Measured in 

months from 

DCI Receipt)

Risk Assessment(s) Data 

Will Support

Use Site(s) Triggering 

Anticipated Data 

Requirement

Applicable Exposure 

Scenario

835.1110 Activated sludge sorption 

isotherm (ASSI) TGAI 12 Environmental exposure All Ecological and drinking water exposure

835.1230 Leaching-adsorption-desorption TGAI 12 Environmental exposure All Ecological and drinking 

water exposure

835.3110

835.3220

835.3240

835.3280

Ready biodegradability or one of 

three biodegradation in activated 

sludge simulation tests1,2

TGAI 12 Environmental exposure All Ecological and drinking 

water exposure

835.4100 Aerobic soil metabolism TGAI 24 Environmental exposure All Ecological and drinking 

water exposure

835.4300 Aerobic aquatic metabolism TGAI 24 Environmental exposure All Ecological and drinking 

water exposure

835.4400 Anaerobic aquatic metabolism TGAI 24 Environmental exposure All Ecological and drinking 

water exposure

850.1025

or

850.1055

Oyster, shell deposition

or

Bivalve embryo larval toxicity

TGAI 12 Saltwater organisms All Down-the-drain

850.1035 Mysid, acute toxicity TGAI 12 Saltwater organisms All Down-the-drain

850.1075 Estuarine/marine fish, acute 

toxicity TGAI 12-18 Saltwater fish All Down-the-drain

850.1300 Aquatic invertebrate, life cycle TGAI 12 Aquatic organisms All Down-the-drain

850.1400 Fish, early life stage4 TGAI 12 Aquatic organisms All Down-the-drain

850.3300 or 

OECD 209

Activated sludge respiration 

inhibition (ASRI) 2 TGAI 12 Toxicity to WWTP organisms All Ecological and drinking water exposure

850.4400 Aquatic plant toxicity, Lemna sp.3 TGAI 12 Aquatic organisms All Down-the-drain

850.4500 Algal toxicity Tier II, green algae TGAI 12 Aquatic plants All Down-the-drain

850.4500 Algal toxicity Tier II, freshwater 

and saltwater diatoms3 TGAI 12 Aquatic plants All Down-the-drain

850.4550 Cyanobacteria 3 Tier II TGAI 12 Aquatic plants All Down-the-drain

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GLN Study Name Test 

Substance

Time Frame 

(Measured in 

months from 

DCI Receipt)

Risk Assessment(s) Data 

Will Support

Use Site(s) Triggering 

Anticipated Data 

Requirement

Applicable Exposure 

Scenario

870.3465 90-Day Inhalation Toxicity TGAI 12 Occupational handlers Hard surface disinfectant 

and sanitizer

Mopping; sprayer; 

foaming

870.3700 Prenatal Developmental Toxicity 

Study in non-rodents TGAI 12 Occupational handlers; residential post-application All Human health exposure

875.1200 Dermal Indoor Exposure TEP 12-24 Occupational Handler All (except metalworking 

and oil fields)

Mopping; sprayer; 

foaming

875.1400 Inhalation Indoor Exposure TEP 24 Occupational Handler All (except metalworking 

and oil fields)

Mopping; sprayer; 

foaming

875.1700 Product Use TEP 12 Occupational Handler All Mopping; sprayer; 

foaming

875.2300 Indoor Residue TEP 24 Residential Post Application 

- Incidental Oral and Dermal

Disinfectant Use on 

Floors

Dermal and Incidental 

Ingestion Post

Application exposure 

875.2700 Product Use TEP 12 Residential Post Application 

- Incidental Oral and Dermal All

Dermal and Incidental 

Ingestion Post

Application exposure

875.2800 Description of Human Activity TEP 12-14 Residential Post Application 

- Incidental Oral and Dermal

Disinfectant Use on 

Floors

Dermal and Incidental 

Ingestion; Postapplication exposure

1 The need for these biodegradation studies will be based on results of an Activated Sludge Respiration Inhibition test. 2 The results of the Activated Sludge Respiration Inhibition Test (ASRI) will determine which of the four biodegradation tests would be anticipated to be 

required. 

• If the ASRI test EC50 is less than or equal to 20 mg/L, then either the (i) Biodegradation in Activated Sludge Study, GLN 835.3280 or (ii) Simulation 

Test - Aerobic Sewage Treatment: A. Activated Sludge Units, GLN 835.3240, or (iii) the Porous Pot Test, GLN 835.3220 would be required. If the 

ASRI test EC50 is greater than 20 mg/L, then the registrant would be required to conduct either: (i) Ready Biodegradability or (ii) a) Biodegradation in 

Activated Sludge or b) Simulation Test - Aerobic Sewage Treatment: A. Activated Sludge Units or c) the Porous Pot Test. 

• If the Ready Biodegradability study is conducted and passes, then no further testing would be required. If, however, the antimicrobial fails the Ready 

Biodegradability study, then either the a) Biodegradation in Activated Sludge or b) Simulation Test - Aerobic Sewage Treatment: A. Activated Sludge 

Units, or c) the Porous Pot study would be required. 3 Data for freshwater and marine diatoms and cyanobacteria would be needed only if the EC50 for the green algae is less than 1 ppm. 4 Either freshwater or estuarine/marine, depending on which was most acutely sensitive.

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3 Human Health Risk Assessment

The Agency anticipates the need to conduct a human health risk assessment for 1,3-PAD. 

Additionally, the Agency anticipates the need to require additional data for the currently 

registered uses, such as a 90-day inhalation toxicity study and a developmental toxicity study in 

non-rodents, and all applicable exposure studies when conducting the registration review (as 

noted in Table 6).

3.1 Existing Toxicological Endpoints

The Agency anticipates the need to revise the existing toxicological endpoints, shown in Table 7,

as part of this registration review. All available information, including existing toxicology 

studies and valid scientific literature, will be considered in establishing the endpoints to be used 

in the registration review risk assessment. Additional studies, such as a 90-day inhalation toxicity 

study and developmental toxicity study in non-rodents are anticipated to be required for risk 

assessment based on the adverse effects observed in the oral studies and the currently registered

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

Table 7 – Existing Toxicological Endpoints for 1,3-PAD

Exposure Scenario

Dose Used 

in Risk Assessment 

(mg a.i./kg/day)

Target Margin of Exposure (MOE) Study and Toxicological 

Effects

Occupational/Residential (Non-Dietary) Risk Assessments

Incidental Oral

Short-Term 

(1-30days) and 

Intermediate-Term

(30 days-6 months)

NOAELmaternal = 7.6 MOE = 100 (10X interspecies, 10X 

intraspecies)

Developmental/Rat

(MRID 45151903)

LOAEL= 22.7 mg a.i./kg/day,

based on clinical signs,

decreased mean body weight

gain and mean food

consumption

Dermal

All routes

LOAEL=1.5 (LDT) MOE = 300 (10X interspecies, 10X 

intraspecies, 3X for using a LOAEL 

value)

90 Day Subchronic Dermal/

Rat (45151902)

NOAEL: not established

LOAEL=1.5 mg a.i./kg/day 

(LDT), based on dermal erythema 

and edema observed in male and 

female rats. Sternal bone marrow 

hyperplasia in female rats

3.2 Dietary Exposure

The Agency has not previously conducted a dietary (food and drinking water) exposure and risk 

assessment for 1,3-PAD. A dietary (food) exposure assessment is not required for 1,3-PAD at 

this time because the registered uses are for non-food-use areas and are not expected to result in 

direct or indirect dietary (food) exposure.

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With respect to drinking water exposure, several approved uses (disinfectants and sanitizers, 

metalworking fluids, oil recovery water systems, and storage ponds for oilfield uses) may result 

in 1,3-PAD being discharged into waste water and subsequently running off into surface water.

3.2.1 Food

The Agency does not anticipate the need to conduct dietary exposure (food) assessments as part 

of the registration review process, and residue chemistry data are not required at this time. 

3.2.2 Drinking Water

A drinking water assessment has not been conducted for 1,3-PAD in the past. However, for 

several approved uses (disinfectants and sanitizers, metalworking fluids, oil recovery water 

systems, and storage ponds for oilfield uses) the Agency cannot rule out the potential for 1,3-

PAD to enter drinking water. There are uncertainties with respect to the residues of concern in 

drinking water, the magnitude of these potential residues, their mammalian toxicities, how 

persistent they will be, and if they are likely to pass through a wastewater treatment plant 

(WWTP). Therefore, the Agency anticipates needing certain environmental fate data listed in 

Section 4 of this FWP. These data will be useful to determine whether, and to what extent, 

residues of 1,3-PAD pass through a WWTP. The Agency anticipates using these data and/or 

other sources of information during the risk assessment stage of registration review to determine 

the potential for discharged residues of 1,3-PAD to result in human dietary exposure via drinking 

water, which may trigger a drinking water assessment. No residue chemistry data are expected to 

be needed at this time to characterize residues of 1,3-PAD in drinking water. However, additional 

residue chemistry data may be necessary, if the toxicological point of departure for either the 

acute or chronic scenario changes during the registration review process.

3.3 Occupational and Residential Exposures

The Agency anticipates the need to develop a new occupational and residential exposure (ORE) 

assessment during the registration review process. The ORE assessment will need to be revised 

to account for new ORE methodologies and to utilize the exposure data that are anticipated to be 

required for registration review. 

3.3.1 Occupational Handler Exposure

Occupational handler exposures for the mopping, low pressure spray and wipe scenarios were 

assessed for registration in 2005 (US EPA, 2005). The resulting margins of exposure (MOE)s in 

the 2005 occupational assessment ranged from 308-815 for low pressure spray and mop, which 

are greater than the target dermal MOE of 300. The resulting MOEs for the wiping scenario were 

less than the target dermal MOE of 300. However, the wiping use is not currently found on the 

existing registered labels. The Agency anticipates the need to reassess the current occupational 

application scenarios (mopping, foaming generator, and mechanical sprayer) and anticipates the 

need for new dermal and inhalation exposure studies. 

Occupational handler exposures for enclosed metalworking fluids and oil field flood water 

systems were assessed in 2007 (U.S. EPA 2007). EPA expects dermal and inhalation exposures 

to be minimal based on engineering controls and existing labeling. Due to the fact that 1,3-PAD 

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is used in closed systems for metalworking fluids and oil field uses and has a low vapor pressure 

(10-6), inhalation exposures are not expected. Thus, EPA anticipates that there are no dermal and 

inhalation risks for 1,3-PAD from these uses; and therefore these exposures will not be evaluated

for these two uses. 

The occupational handler scenarios as listed in Table 8 will need to be assessed during 

registration review. 

Table 8 – Occupational Handler Exposure Scenarios for 1,3-PAD

Scenario Exposure Route(s) Duration

1.Mopping Floors With Disinfectant Cleaners in Industrial,

Commercial and Institutional Facilities Dermal, Inhalation Short and Intermediate Term

2. Mechanical Sprayer Application of Disinfectant Cleaners in 

Industrial, Commercial and Institutional Facilities Dermal, Inhalation Short and Intermediate Term

3. Foaming Generator Sprayer Application in Industrial, 

Commercial and Institutional Facilities Dermal, Inhalation Short and Intermediate Term

3.3.2 Occupational Post-application

No occupational post-application exposures are expected based on engineering controls and 

existing label language.

3.3.3 Residential Handler Exposures

All 1,3-PAD labels indicate products are only for institutional, industrial, and commercial use. 

Therefore, residential handler exposure is not expected.

3.3.4 Residential Post-Application Exposures

EPA anticipates the need to revise the residential post-application assessment conducted in 

support of the 2005 ORE. Residential post-application exposures could result when bystanders 

(adults and children) come in contact with 1,3-PAD in areas where pesticide end-use products 

have recently been applied (e.g., treated hard surfaces/floors), or when children incidentally 

ingest the pesticide residues through hand-to-mouth activities when playing on treated floors.

The MOEs 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 will have to be 

reassessed using updated exposure algorithms. The dermal MOE of 312 for treated floors was 

slightly over the target MOE of 300. 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 Post-Application Exposure Scenarios for 1,3-PAD

Scenario Exposure Route(s) Duration

Residential Exposures

Post application exposure to floors cleaned with disinfectant 

cleaning solutions. Dermal Incidental Oral Short and Intermediate Term 

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3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures 

The Agency anticipates the need to conduct the aggregate assessment. 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 (drinking water) 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 1,3-PAD and any other substances, and 1,3-PAD

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 1,3-PAD 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 previously conducted a risk assessment that supports a complete endangered 

species determination for 1,3-PAD when used in metalworking fluids at 500-2,500 mg/l (ppm) 

and non-marine/non-estuarine oil field water flood systems at 5-20 ppm. The ecological risk 

assessment planned during registration review will allow the Agency to determine potential acute 

and chronic risks to aquatic organisms exposed to 1,3-PAD that may be transported from 

treatment sites into the aquatic environment. Such sites include metalworking fluids that enter 

wastewater treatment plants (WWTPs) and oil field water flood systems that have the potential to 

enter surface water through WWTP effluent or overflow from storage ponds and ground water 

from un-cased wells or from leaching in unlined storage ponds. Sites also include 

sanitizer/disinfectants applied to hard surfaces and subsequently discharged down-the-drain from 

rinsing of mops/cloths used to wipe sanitizer/disinfectant from hard surfaces. The risk 

assessment also will allow the Agency to determine whether each use of 1,3-PAD 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.

Based on the antimicrobial uses of 1,3-PAD with active products in Table 5, the Agency has 

created conceptual models for potential routes of environmental exposure which are included in 

“Conceptual Models for Environmental Exposure Pathways of Antimicrobial Pesticides”, found 

in the docket at www.regulations.gov (EPA-HQ-OPP-2014-0638-001). For particular 1,3-PAD 

uses, the relevant page numbers are 15 (down-the-drain exposure from use of 

sanitizer/disinfectant at beverage and food processing plants, bars, schools, and cafeterias), 18

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(metalworking fluids), and 19-22 (oilfield flood water systems). All relevant routes of 

environmental exposure will be considered in the risk assessment.

4.1 Environmental Fate Assessment

Based on the chemical and physical properties, 1,3-PAD is miscible in water and is unlikely to 

move from soil or water into air based on the vapor pressure of 3.3 x 10-6 mm Hg and the 

Henry’s Law constant of 1.3 x 10-10 atm m3 mol-1 (Table 4). 1,3-PAD is stable to both hydrolysis 

(MRID 45115327) and to photodegradation in water (Table 4), but no data have been submitted 

for biological degradation, sorption, or toxicity to WWTP microorganisms. As a result, the 

Agency cannot determine the potential for 1,3-PAD to reach or persist in the aquatic 

environment, and therefore additional aquatic data will be needed. Additional environmental fate 

information can be found in Appendix B.

4.1.1 Water Quality

1,3-PAD is not identified as a cause of impairment for any water bodies listed as impaired under 

section 303(d) of the Clean Water Act.

1 In addition, no total maximum daily loads (TMDL) have 

been developed for 1,3-PAD.

2 More information on impaired water bodies and TMDLs can be 

found at EPA’s website.

3

4.2 Environmental Exposure Pathways

There are potential pathways by which 1,3-PAD and potential degradates can reach the aquatic 

environment. One pathway is by use of 1,3-PAD in metalworking fluids that enter wastewater 

treatment plants (WWTPs) and subsequently surface water. Other pathways associated with the 

use of 1,3-PAD in oil field water flood systems include: discharge via WWTP effluent to surface 

water; overflow from storage ponds to surface water; and leaching to ground water from uncased 

wells or unlined storage ponds. Another pathway is by use of 1,3-PAD as a hard surface 

sanitizer/disinfectant which is wiped by mop and/or cloth and then rinsed down-the-drain to 

domestic wastewater treatment plants and subsequently to surface water.

4.2.1 Ecological Effects Assessment

Acute and chronic toxicity data from registrant-submitted studies (850 OCSPP Harmonized Test 

Guidelines) are used to evaluate the potential effects of 1,3-PAD to plants and animals. All 

available ecotoxicity endpoints are tabulated in Appendix C. The Agency uses the most sensitive 

of these endpoints for assessing risks. The endpoints selected for 1,3-PAD are provided in Table 

10. 

1 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

2

http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_

group_name=PESTICIDES

3 http://www.epa.gov/owow/tmdl/

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Table 10 – Ecological Effects Endpoints

Receptor Group Test Material Risk Scenario Toxicity Endpoint Reference

Freshwater fish TGAI

Acute LC50 = 0.45 mg ai/L 45115312

Chronic Data gap --

Freshwater invertebrates TGAI

Acute EC50 = 0.073 mg ai/L 45115313

Chronic Data gap --

Estuarine/marine fish TGAI

Acute Data gap --

Chronic Data gap --

Estuarine/marine 

invertebrates TGAI

Acute Data gap --

Chronic Data gap --

Algae TGAI EC50 and NOAEC Data gap --

Aquatic plants, vascular TGAI EC50 and NOAEC Data gap --

Birds TGAI Acute LD50 = 25 mg ai/kg 45115310

4.2.2 Mechanism of Action

The Agency has no information on the mechanism of action for 1,3-PAD for terrestrial and 

aquatic invertebrates.

4.3 Exposure Analysis Plan

4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available OPP models will be used to determine the estimated environmental concentration 

(EECs) in the aquatic environment. The Down-the-Drain module of E-FAST will be used to 

assess potential exposures to aquatic organisms from discharges of sanitizer/disinfectant to 

domestic WWTPs then subsequently to surface water. The General Population and Ecological 

Exposure from industrial releases module of E-FAST will be used to assess potential exposures 

to aquatic organisms from use of 1,3-PAD that is used in metalworking fluids and oil recovery 

water systems and discharged to WWTPs, then subsequently to surface water. For the potential 

surface and ground water exposure from storage ponds for the oilfield uses, the best available 

assessment tools, including models or available monitoring data, will be considered. Resulting

exposure estimates will be compared to the toxicity endpoints to determine if levels of concern 

are exceeded for each receptor group. 

4.3.2 Screening Level Down-the-Drain Analysis

There are two types of down-the-drain releases for 1,3-PAD: those from industrial uses (i.e, 

metalworking fluids and oil recovery water systems) that go to industrial wastewater treatment 

plants and subsequently surface water and those from hard surface sanitizer/disinfectant uses that 

are expected to go primarily to domestic wastewater treatment plants and subsequently to surface 

water. A screening level down-the-drain assessment is used to determine potential upper bound 

exposures and risks to aquatic organisms from uses that are expected to result in discharges to 

domestic wastewater treatment plants and subsequently to surface water. When information on 

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production volume is available, a screening-level down-the-drain analysis can be used to 

demonstrate negligible potential for exposure and risk to aquatic organisms and lead to the 

conclusion that specific environmental fate and ecotoxicity data would not be required.

Production volume data are not the only information needed to determine potential exposures to 

aquatic organisms from industrial uses that can enter surface water via WWTPs. The down-thedrain module of E-FAST is not appropriate for estimating potential exposures to aquatic 

organisms from industrial uses that could result in releases to surface water via WWTPs. To 

estimate potential exposures from industrial uses, one must use the General Population and 

Ecological Exposure from Industrial Releases module of E-FAST. The use of this module 

requires additional input data that are not available and is beyond the scope of this preliminary 

risk assessment. Environmental fate and ecotoxicity data requirements that would be needed to 

perform a risk assessment for industrial uses are expected to be included in the generic data callin (GDCI) based on the absence of this information.

A screening level down-the-drain analysis will not be performed as part of this preliminary risk 

assessment since uses of 1,3-PAD are not limited to those that would result in releases to surface 

water via domestic wastewater treatment plants but also include industrial uses that can reach 

surface water via WWTPs. Consequently, a screening-level down-the-drain assessment would 

not provide information on potential exposure to aquatic organisms from indirect and direct 

releases to surface water as a result of industrial uses.

4.4 Effects Analysis Plan 

The Agency will use acute and chronic toxicity data from studies submitted by the registrant 

(See Table 10). Additional open literature studies will be identified through EPA’s 

ECOTOXicology (ECOTOX) database. The ECOTOX database will be searched during the risk 

assessment phase of 1,3-PAD and the data reviewed following the Agency’s policy for reviewing 

public literature for use in assessing risks from pesticides.

4 Those ecotoxicity values found in the 

public literature to be more sensitive than those currently in Table 10 and those which satisfy an 

existing data gap(s) will be used during the risk assessment phase of 1,3-PAD to update Table 

10. ECOTOX was created and is maintained by the USEPA, Office of Research and 

Development, and the National Health and Environmental Effects Research Laboratory's MidContinent Ecology Division.

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, 

4

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

group/esa_evaluation_open_literature.htm

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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 most recent registration decision, for 1,3-PAD, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. As required by FFDCA section 408(p), 1,3-PAD is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 

2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, 

which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals 

identified for EDSP screening was published on June 14, 20135 and includes some pesticides 

scheduled for registration review and chemicals found in water. Neither of these lists should be 

construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.6

6 Optional Label Changes 

The Agency invites any label amendments that could be considered to eliminate the anticipated 

need for EPA to require certain data, reduce the possibility that EPA’s planned risk assessments 

overestimate risk due to reliance on conservative assumptions, and/or improve label clarity.

Since the publication of the PWP, registrants have submitted amended labels to the Agency to 

clarify that products are intended for nonfood contact use only. As such, the Agency no longer 

anticipates the need to conduct a dietary (food) assessment during registration review. 

A DCI will be developed according to the data needs listed under Table 1 and Section 2, 

“Anticipated Data Needs.” The Agency expects to issue the DCI by March of 2016.

5 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals. 6 http://www.epa.gov/endo/

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8 References 

Lonza. Lonzabac 12 MSDS. 

http://bio.lonza.com/uploads/tx_mwaxmarketingmaterial/Lonza_ProductDataSheets_Lon

zabac_12_PDS.pdf

MRID 45115304. Sloan, R. (1999) Lonzabac 12-Physical and Chemical Properties: Lab Project 

Number: SP-99043-A. Unpublished study prepared by Lonza, Inc. 30 p. {OPPTS 

830.6315, 830.7000, 830.7050, 830.7100, 830.7300} 

MRID 45115305. Sarff, P.; Edgar, L. (1999) Boiling Point Determination of Lonzabac 12: Lab 

Project Number: SP-99005-A: 45066. Unpublished study prepared by ABC Laboratories, 

Inc. 14 p. {OPPTS 830.7220}

MRID 45115307. Sloan, R. (1999) Lonzabac 12-Stability to Normal and Elevated Temperatures, 

Metals and Metal Ions: Lab Project Number: SP-99010-A. Unpublished study prepared 

by Lonza Inc. 24 p. {OPPTS 830.6313} 

MRID 45115308. Lonza, Inc.; Lewis and Harrison, LLC. (2000) Product Chemistry: Discussion 

of Physical and Chemical Properties: Lonzabac 12. Unpublished study. 7 p. {OPPTS 

830.6304, 830.6317, 830.6320}

MRID 45115309. Lonza, Inc.; Lewis and Harrison, LLC. (2000) Product Chemistry: Vapor 

Pressure for Lonzabac 12. Unpublished study. 8 p. {OPPTS 830.7950}

MRID 45115310. Gallagher, S.; Grimes, J.; Beavers, J. (2000) Lonzabac 12: An Acute Oral 

Toxicity Study with the Northern Bobwhite: Final Report: Lab Project Number: 289-114. 

Unpublished study prepared by Wildlife International, Ltd. 54 p. {OPPTS 850.2100} 

MRID 45115312. Drottar, K.; Kendall, T.; Kruegar, H. (2000) Lonzabac 12: 96-Hour FlowThrough Acute Toxicity Test with the Bluegill (Lepomis machrochirus): Lab Project 

Number: 289A-151A. Unpublished study prepared by Wildlife International, Ltd. 57 p. 

{OPPTS 850.1075} 

MRID 45115313. Drottar, K.; Kendall, T.; Kruegar, H. (2000) Lonzabac 12: A 48-Hour FlowThrough Acute Toxicity Test with the Cladoceran (Daphnia magna): Lab Project 

Number: 289A-150. Unpublished study prepared by Wildlife International, Ltd. 59 p. 

{OPPTS 850.1010} 

MRID 45115327. Flack, I. (1996) P4198: Abiotic Degradation: Hydrolysis as a Function of pH: 

Lab Project Number: LZA 102/960267: 2651. Unpublished study prepared by 

Huntingdon Life Sciences Ltd. 20 p.

MRID 45151902. Johnson, W. (2000) Subchronic Dermal Toxicity/Immunotoxicity Study with

Lonzabac 12 in Rats: Lab Project Number: 1076 SN3. Unpublished study prepared by IIT 

Research Institute. 405 p. {OPPTS 870.7800}

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MRID 45151903. Barton, S. (1994) P4150: Developmental Toxicity Study in Rats: Lab Project 

Number: 490730: 2283. Unpublished study prepared by Inveresk Research International. 

81 p. {OPPTS 870.3700}

MRID 46309706. Sarff, P. (1999) Corrosion Characteristics of Lonzabac 12. Project Number: 

45065, SP/99004/A. Unpublished study prepared by ABC Laboratories, Inc. 15 p.

MRID 46332202. Sloan, R. (2000) Procedure for Determining Dodecylamine Content in 

Lonzaback 12. Unpublished study prepared by Lonza, Inc. 5 p.

U.S. Environmental Protection Agency (EPA). 2002. ECOTOX User Guide: ECOTOXicology 

Database System. Version 3.0. Available: http://www.epa.gov/ecotox/

U.S. EPA 2005. Memorandum from S. Mostaghimi to Velma Noble. Subject: Application and 

Post-application Exposure Assessment for Bis-3-aminopropyl dodecylamine. D308675.

U.S. EPA 2005. Memorandum from S. Mostaghimi to Velma Noble. Subject: Application and 

Post-application Exposure Assessment for Bis-3-aminopropyl dodecylamine. D308675.

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Appendix A Toxicology Profile

Acute Toxicity for Product Labeling 

As listed in Table A1, 1,3-PAD was found to be low toxic for both acute oral and dermal toxicity 

(Toxicity Category III) but moderate toxic for acute inhalation toxicity (Toxicity Category II). It 

was shown to be mildly irritating to irritating the eyes (Toxicity Category II-III) but 

corrosive/severely irritating to skin (Toxicity Category I). 1,3-PAD is a dermal sensitizer.

Table A1 – Acute Toxicity Studies for 1,3-PAD

Guideline No./Study Type MRID No. Results Toxicity Category

870.1100

Acute oral toxicity – rat 45115314

LD50 = 933 mg/kg (♂); LD50 = 812 mg/kg 

(♀); 

LD50 = 871 mg/kg (combined) 

III

870.1200

Acute dermal toxicity – rat

45115315 LD50 > 2000 mg/kg III

46603601 LD50 > 200 mg/kg (Limit Test) II

870.1300/ 

Acute inhalation toxicity – rat 

46603603 LC50 > 0.052 mg/L (Limit Test) II

47272201 LC50 > 0.053 mg/L (Limit Test) II

48980409 0.62 mg/L < LC50 < 2.0 mg/L (Limit Test) III

870.2400/ 

Acute eye irritation – rabbit 

48980413 Slightly irritating III

48980414 Irritating II

870.2500/ 

Acute dermal irritation – rabbit

45115316/7; 

45114705 Sever/corrosive skin irritant I

870.2600/ 

Dermal sensitization – guinea 

pig

45115318 Not a skin sensitizer N/A

46603602 A skin sensitizer N/A

48980410 A skin sensitizer N/A

N/A=Not applicable

Subchronic Toxicity 

Adequacy of Database for Subchronic Toxicity: The database for subchronic toxicity is 

considered incomplete. A 90-day oral toxicity study in the rat (MRID 45151901) and a 90-day 

dermal toxicity/immunotoxicity study (MRID 45151902) are available for addressing subchronic 

oral and dermal toxicities. A route-specific 90-day inhalation toxicity study in rats is anticipated 

to be required based on the pulmonary effects observed in the oral studies and the currently 

registered uses such as a hard surface disinfectant/sanitizer with “coarse mechanical sprayer” in 

the registration review risk assessment.

870.3100 90-Day (13-Week) Oral Toxicity – Rat

(1) In a subchronic range-finding toxicity study (MRID 45115319), 1,3-PAD (unknown purity) 

was administered daily to Wistar rats (5/sex group), via oral gavage at dose levels of 10, 60, 360 

and 500 mg/kg-day for a period of 28 days. 

Clinical observations of salivation, respiratory sound, gasping for breath, and slight piloerection 

were noted in rats at 360 and 500 mg/kg-day. Slight piloerection was also noted in individual 

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animals at 10 and 60 mg/kg-day. There were pre-terminal deaths in both sexes of rats at 360 (3 

male, 4 female) and 500 (4 male, 4 female) mg/kg-day. Macroscopic changes (reduced organ 

size of spleen, accessory genital glands and organs, thymus) were noted in rats at ≥360 mg/kgday. Microscopic evidence of submucosal and mucosa gastritis and glandular epithelial 

degeneration were found in rats at 60 mg/kg-day. 

The no observed effect level (NOAEL), determined by the study authors, was 10 mg/kg-day 

based on the absence of macroscopic and microscopic treatment-related findings that were 

reported at higher doses. The lowest observed effect level (LOAEL) is 60 mg/kg/day.

This study is classified as Unacceptable. There is omission of data supporting the preparation, 

stability, homogeneity and concentration of the dosing formulation. There are no guideline 

requirements for this type of study.

(2) In a subchronic toxicity study (MRID 45151901), 1,3-PAD (purity of 29.8% a.i.) suspended 

in purified water was administered to Albino Wistar Crl:(Wi)Br rats (10/sex/dose) by oral 

gavage at dose levels of 0, 5 (1.5 mg a.i.), 10 (3.0 mg a.i.), 30 (8.9 mg a.i.) or 90 (26.8 mg a.i.) 

mg/kg/day for 90 consecutive days. Additional groups of rats (10/sex/dose) were treated at doses

of 0 or 90 (26.8 mg a.i.) mg/kg/day for 90 days and sacrificed after a 28-day recovery period.

Five animals from the 90 (26.8 mg a.i.) mg/kg/day group were sacrificed prematurely due to 

morbidity as a result of dosing complications causing esophageal perforation and pleural gavage. 

Clinical signs of toxicity observed in treated animals included: salivation and hyperactivity in the 

two high-dose groups and reduced righting reflex in the high-dose (90 mg/kg/day) males and in 

all females except the low-dose group.

Decreased mean body weight gains for both males and females in the two high-dose groups were 

observed over Weeks 6-13 and over Weeks 0-13 for the highest-dose group. Mean body weight 

gains were similar to the control group during the recovery period (week 13-17). 

Significantly decreased mean food consumption was reported in the highest-dose males 

throughout the study including the recovery period and in females of the same dose group at 7-13 

weeks only.

Significant differences in hematology parameters were not considered toxicologically or 

biologically relevant since the levels were within normal ranges for Wistar rats. Significant doserelated increases of aspartate aminotransferase (AST) enzymes were reported in both sexes from 

the two high-dose groups at Week 13; alanine aminotransferase (ALT) enzymes were 

significantly increased in the highest-dose males at Week 13. At the end of the recovery period, 

AST values remained statistically elevated, although ALT values normalized. The biological 

importance of these changes is uncertain. 

At terminal necropsy, both sexes surviving until the conclusion of the treatment period exhibited 

macroscopic changes in the small intestine (primary the jejunum) which are correlated with 

histopathological assessments of an increased number of macrophages in the jejunum of the two 

high-dose groups. Macrophages persisted in the recovery animals of the highest-dose group. 

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Nephrotoxicity effects, presented as moderate proximal tubular changes in males and minimal 

changes in females, was observed in the highest-dose group. In the recovery period, minimal 

proximal tubular changes were noted in males and minor basophilic changes in the female. These 

changes were correlated with an increase in the relative organ weight. 

Nasopharyngeal mucosa changes were noted in all treatment groups except for the lowest-dose 

group. These changes persisted into recovery at the highest-dose level. The lungs at the highestdose level also showed changes but didn’t persist into recovery. 

An increased number of macrophages were also noted in the mesenteric lymph nodes of the two 

high-dose group animals of both sexes. These changes persisted into the recovery phase at these 

dose levels.

Based on these findings, the NOAEL 5 (1.5 mg a.i.) mg/kg/day is for systemic toxicity. The 

LOAEL is 10 (3.0 mg a.i) mg/kg/day and is based on the clinical finding of a reduced 

righting reflex. 

This toxicity study is classified as Acceptable and fulfills the guideline requirements of OPPTS 

870.3100 for a subchronic oral toxicity study.

(3) A histopathology review (MRID 45115320) was conducted to verify the reported toxicity of 

1,3-PAD. In a 90-day oral toxicity study (MRID 45151901), 1,3-PAD was administered by oral 

gavage to Albino Wistar Crl:(Wi)Br rats (10/sex/dose) at dose levels of 0, 5 (1.5 mg a.i.), 10 (3.0 

mg a.i.), 30 (8.9 mg a.i.), or 90 (26.8 mg a.i.) mg/kg for 90 consecutive days (Groups I - V, 

respectively), An additional group (10 rats/sex) was treated at doses of 0 or 90 (26.8 mg a.i.) for 

90 days and sacrificed after a 28-day recovery period. Macroscopic and microscopic 

examinations were performed. Histopathological changes were reported in the jejunum, 

mesenteric lymph nodes, skeletal muscle, kidneys, glandular stomach and nasopharyngeal 

mucosa.

The pathological evaluation below has been included in the 90-day oral toxicity study 

(MRID 45151901). 

A re-evaluation of the original tissue samples were conducted by an independent histopathologist 

(slides were obtained from Lonza). Severity of tissue insult was scored on a five point scale. For 

all non-neoplastic lesions in bilateral paired organs, the severity score of the worst affected organ 

was recorded. There were no significant differences between the two assessments and similar 

results were observed in the kidneys, nasopharyngeal mucosa, lungs, liver, small intestine, and 

mesenteric lymph nodes. The conclusions, however, regarding the renal findings were not in 

total agreement with the original assessment. 

Upon re-evaluation of the renal tissues, the review pathologist noted that:

(i) The renal changes were indicative of nephrotoxicity, rather than an exacerbation of a 

spontaneous change, and presented moderate proximal tubular changes characterized by 

multifocal dilation and basophilia with evidence of degeneration, regeneration and hyperplasia in 

Group V males. Proximal tubular changes noted in Group V females were similar, but of lesser 

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severity. Group V recovery males demonstrated interstitial fibrosis while females demonstrated 

only minor basophilic changes. These changes indicated a nephrotoxic effect of the test 

compound. 

(ii) In the re-evaluation the stomach lesions, all changes were considered to be artifacts and not 

treatment related. 

(iii) The respiratory findings were also not completely characterized in the original report. The 

reviewer observed muco-purulent exudate in the respiratory tract indicative of a pneumonitis, 

likely due to the inhalation of the copious nasal mucus exudate. The elevated serum AST levels 

observed were also a possible result of the soft tissue damage of the nasopharynx. 

The pathology reviewer concluded that the NOAEL was 30 (8.9 mg a.i.) mg/kg/day (for 

systemic toxicity) and was based on the histopathological re-evaluation. The LOAEL was 90 

(26.8 mg a.i.) mg/kg/day and was based nephrotoxicity.

This study was considered Acceptable and meets the guidelines when use in conjunction with 

the “Final Report: 90 Day Oral Toxicity Study with “P4150" in Rats followed by a 4-Week 

Recovery Period” (MRID 45151901).

870.3250 90-Day Dermal Toxicity – Rat

In a subchronic dermal toxicity/immunotoxicity study (MRID 45151902), 1,3-PAD (purity of 

29.3% a.i.) was administered to Sprague Dawley (Crl:CD_BR) rats (8/sex/group for Cohort I and 

15/sex/group for Cohort II) dermally via a wrapping procedure at dose levels at 0, 5 (1.5 mg a.i.), 

10 (2.9 mg a.i.), and 15 (4.4 mg a.i.) mg/kg-day (dose reduced from 20 [5.9 mg a.i.] mg/kg/day 

during week 1) for a period of 28 days for animals in Cohort I, and 14 weeks for animals in 

Cohort II. 

No treatment-related effects were observed in clinical chemistry, ophthalmology or organ 

weights. No immunosuppression was seen.

Cohort I parameters consisted of observations, immunotoxicity, food consumption and body 

weights and gross and histopathology of animals dying in extremis only. Cohort II measured 

parameters consisted of the above and clinical chemistry, ophthalmology, organ weights, and 

gross and histopathology of 10 surviving animals in the high dose group and the control.

In Cohort I/II, severe dermal irritation was noted in high-dose animals during the first week of 

dosing which resulted in a decrease of the high dose from 20 (5.9 mg a.i.) mg/kg-day to 15 (4.4 

mg a.i.) mg/kg-day. Dermal irritation persisted after the reduction of the dosage level, and began 

to also appear in the low- and mid-dose groups. Females showed greater dermal irritation than 

the males.

In Cohort II, decreases in mean body weight gain (not statistically significant) were noted in the 

mid (12%) and high-dose (14%) males during the study. Additionally, a significant increase in 

food consumption was noted in mid- and high-dose females from week 6 (except for week 10)

through the end of the study. 

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In Cohort II, increases in absolute white blood cells, absolute neutrophils, and absolute and 

relative eosinophil counts, and a decrease in relative lymphocyte count were seen in high-dose 

females and a significant increase in the relative eosinophil count were noted in mid-dose 

female rats. 

Treatment-related microscopic lesions were observed at the application site (skin. all doses), 

axillary lymph nodes, (mid and high dose) and sternal bone marrow (all doses, except low dose 

males).

1. 28 Day Dermal/Immunotoxicity:

The study was unacceptable as a 28 Day Dermal toxicity study and lacking hematology, clinical 

chemistry and gross and microscopic pathology but measuring body weight, food consumption 

and observations. This study was performed mainly to measure immunotoxicity study. Other 

than dermal irritation in point 3 below body weight was decreased by 14% in the high dose 

males. This decrease was not statistically significant.

No immunosuppression was seen. NOAEL >15 (4.4 mg a.i.)/20 (5.9 mg a.i.) mg/kg/day (HDT). 

The LOAEL could not be calculated.

This study is classified as Acceptable and meets the guideline requirements of 870.7800 for an

immunotoxicity study.

2. Subchronic 90 Day study

The LOAEL is 5 (1.5 mg a.i.) mg/kg/day (lowest dose tested [LDT]) was based on sternal bone 

marrow hyperplasia in the female. The NOAEL is <5 (1.5 mg a.i.) mg/kg/day.

This subchronic 90 Day study toxicity study is classified as Acceptable and meets the guideline 

requirements of 870.3250 for a 90 Day Dermal Toxicity Study.

Developmental Toxicity 

Adequacy of Database for Prenatal Developmental Toxicity: The database for prenatal 

developmental toxicity is considered inadequate for the currently registered uses. The 

developmental toxicity assessment for 1,3-PAD is based on developmental studies in the rat 

(MRIDs 45115322 and 45151903). A developmental toxicity study in non-rodent species is 

anticipated to be required, based on the adverse effects observed in the available data and the 

currently registered uses.

870.3700 Prenatal Developmental Toxicity (Gavage) Study – Rat

(1) In a dose range finding developmental toxicity study (MRID 45115322), 1,3-PAD (purity of 

30.2% a.i.) was administered daily to mated Sprague-Dawley CD albino rats (8 females/group), 

via oral gavage at dose levels of 25 (7.5 mg a.i.), 50 (15.0 mg a.i.), 100 (30.2 mg a.i.) and 150 

(45.3 mg a.i.) mg/kg/day for a period of 10 days, over gestational days 6-16. All animals were 

sacrificed at Day 20 of the gestation period. An additional 8 un-mated female rats were similarly 

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dosed with 200 (60.4 mg a.i.) mg/kg/day for 7 consecutive days, after completion of the 

screening study, with the purpose of verifying questionable toxicity findings. The oral route of 

test article administration was chosen as it is a possible route of exposure in humans.

Treatment-related findings included clinical observations of post-dosing salivation, with some 

brown staining, in most females of the two high-dose groups. Salivation was also observed in 

most of the unmated females dosed at 200 (60.4 mg a.i.) mg/kg/day. Mean food consumption 

was marginally lower on the first day of dosing (Day 6 of gestation), compared to predose 

values. Mean food consumption was markedly decreased throughout dosing in females treated at

200 (60.4 mg a.i.) mg/kg/day, compared to predose values. Test substance, 1,3-PAD, had no 

effect on mean body weight or mean weight gain, pregnancy performance or fetal weight.

Based on these findings, the study authors determined that suitable dose levels for a 

teratogenicity study were 25 (7.5 mg a.i.), 75 (22.5 mg a.i.), and 200 (60.4 mg a.i.) mg/kg-day. 

The NOAEL for maternal toxicity is 50 (15.1 mg a.i.) mg/kg/day and the LOAEL is 100 

(30.2 mg a.i.) mg/kg/day based on decreased mean food consumption and salivation. The 

developmental NOAEL is 200 (60.4 mg a.i.) mg/kg/day and the developmental LOAEL is 

>200 (>60.4 mg a.i.) mg/kg/day.

This study is Acceptable, but no guideline are available for this rangefinding study.

(2) In a developmental toxicity study (MRID 45151903), 1,3-PAD (purity of 30.2% a.i.) in 

distilled water was administered orally by gavage to mated female Sprague-Dawley, Charles 

River CD (outbred albino) rats (25/dose) at dose levels (measured) of 0 (distilled water), 25 (7.6 

mg a.i.), 75 (22.7 mg a.i.), or 200 (60.4 mg a.i.) mg/kg/day from Days 6 through 16 of gestation. 

There was clear evidence of maternal effects in the high-dose dams, including clinical signs of 

toxicity (dyspnea, piloerection, salivation associated with brown staining, and indications of 

reduced activity), premature sacrifice of 2 dams, reduced body weight during the dosing period, 

significantly decreased body weight gain during the dosing period, significantly decreased mean 

food consumption during the dosing period, intestinal distension, increased incidence of early 

embryonic deaths, and increased number of total dead implants. Additionally, administration of 

mid-dose resulted in an insignificant reduction in mean body weight gain during the dosing 

period, a significant decrease in mean food consumption during the dosing period, and an 

increased incidence of dyspnea and salivation associated with brown staining. 

No external, visceral or skeletal abnormalities/variations were observed in any of the treatment 

groups.

The NOAEL for maternal toxicity is 25 (7.6 mg a.i. [LDT]) mg/kg/day, and the LOAEL for 

maternal toxicity is 75 (22.7 mg a.i.) mg/kg/day, based on clinical signs of toxicity and 

decreased mean body weight gain and mean food consumption. The developmental 

NOAEL is 200 (60.4 mg a.i.) mg/kg/day, and the developmental LOAEL could not be 

established, based on no developmental toxicity was observed in any of the treatment groups.

This study in the rat is classified as Acceptable and meets the guideline requirement of OPPTS 

870.3700 for a developmental study in rats.

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Reproductive Toxicity

Adequacy of Database for Reproduction and Fertility Effects: The database for reproductive 

toxicity is considered to be adequate for the currently registered uses. Assessment of 

reproduction and fertility effects for 1,3-PAD is based on a two-generation reproduction study in 

rats (MRID 45151904) in the Agency’s hazard database. No additional data are anticipated to be 

required.

870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction study (MRID 45151904), 1,3-PAD (purity of 30.2% a.i.) in 

distilled water was administered orally by gavage to male and female Sprague-Dawley Charles 

River CD (outbred albino) rats at dose levels of 0 (distilled water), 10 (3.0 mg a.i.), 30 (9.1 mg 

a.i.), or 90.0 (27.2 mg a.i.) mg/kg/day. F0 males and females (28 rats/sex/group) were dosed 10 

weeks prior to mating. Treatment continued until termination (after the weaning of F1 litters) and 

included mating, gestation, and lactation periods. F1 animals (24 rats/sex/group) were treated at 

25 days of age until the animals were paired for mating (approximately 11 weeks after weaning). 

Dosing was then resumed until termination (after the weaning of F2 litters), and included mating, 

gestation, and lactation periods. 

Maternal effects in the high-dose dams included clinical signs of toxicity (principally dyspnea, 

piloerection and hunched posture, and post-dosing salivation), death of 8 animals (2 F0 males, 3 

F0 females, 1 F1 male, and 2 F1 females), significantly decreased body weights in F0 and F1

males, decreased body weight gain in F0 and F1 males, decreased body weight gain in F0 and F1

females during pre-mating and gestation periods, and decreased mean food consumption in F0

and F1 males and females. 

The NOAEL for parental toxicity is 30 (9.1 mg a.i.) mg/kg/day, and the LOAEL for 

parental toxicity is 90 (27.2 mg a.i.) mg/kg/day, based on clinical signs of toxicity, mortality, 

decreased mean body weight, decreased mean body weight gain, and decreased mean food 

consumption. 

Mating performance, fertility, duration of gestation, litter size and pup survival were not affected 

by the test substance.

The NOAEL for reproductive toxicity NOAEL is equal to/greater than (≥) 90 (27.2 mg a.i.) 

mg/kg/day (HDT), and the LOAEL for reproductive toxicity is greater than (>) 90 (27.2 mg 

a.i.) (not established).

Two pups showed body tremors and slight decreases in F2 litter and pup weights were observed 

at the high-dose level. 

The offspring toxicity NOAEL is 30 (9.1 mg a.i.) mg/kg/day, and the offspring toxicity 

LOAEL is 90 (27.2 mg a.i.) mg/kg/day, based on decreased litter and pup weights. 

This reproductive toxicity study in the rat is classified Acceptable and satisfies the guideline

requirement of OPPTS 870.3700 for a reproductive/fertility toxicity study in rats.

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Chronic Toxicity/Carcinogenicity 

Adequacy of Database for Chronic Toxicity/Carcinogenicity: The database for chronic toxicity 

and carcinogenicity is considered to be adequate for the currently registered uses. Assessment of 

chronic toxicity and carcinogenicity for 1,3-PAD is based on a combined chronic toxicity and 

carcinogenicity study in rats (MRIDs 48658501/02) in the Agency’s hazard database. No 

additional data are anticipated to be required.

(1) In a combined chronic toxicity/carcinogenicity study (MRID 48658501/02), groups of 10 

male and 10 female CD rats were administered 0, 4, or 8 mg/kg b.w./day of the N-(3-

Aminopropyl) N-Dodecylpropane-1,3-Diamine (89.4% a.i., Batch # 20570-MOl) in feed for 52 

weeks; 20 animals per sex were also administered 20 mg/kg/day of the test compound for 52 

weeks. Hematology, clinical chemistry, organ weights measurements as well as gross and 

histopathology were performed.

Eight high dosed male animals treated with 20 mg/kg b.w./day died prematurely. The body 

weight of the rats treated with 20 mg/kg b.w./day was reduced up to 57% from test week 0 to 25 

for male animals and by up to 25% from test week 0- 51 for the female animals. The body 

weight gain of the rats changed accordingly. The body weight at autopsy was reduced in the 

males and females. The body weight, body weight gain, and body weight at autopsy were not 

influenced in the male and female rats treated with 4 or 8 mg/kg b.w./day.

The food consumption of the animals treated with 20 mg/kg b.w./day was increased by up to 

18% for the male rats in test weeks 39 to 45 and by up to 20% for the females in test weeks 31 to 

51 caused by the severely reduced body weight.

Increased absolute kidney weights were noted in the females and decreased liver weights were 

noted in the males treated with the high dose of test substance. 

The myeloied:erythroid ratio of the male animals treated with 20 mg/kg b.w./day was 

significantly increased (Control 0.993:1, 20 mg/kg 1.847:1). 

The males treated with 8 mg/kg/day and animals of both sexes treated with 20 mg/kg/day 

showed a dose dependent increase of lympho-histiocytic myocarditis. This finding was 

associated with degenerative changes of the myofibers in the heart. The males treated with 8 or 

20 mg/kg/day and the females of the high dose group showed an increase of lympho-histiocytic 

infiltrations in the skeletal muscles. Degeneration of the skeletal muscles was noted in 2 

intermediate dose males. Additionally, the animals treated with 8 or 20 mg /kg b.w./day showed 

a minimal to moderate increase in basophilic tubular cells and lympho-histiocytic infiltration of 

the kidney. 

Suppurative inflammation was observed in the prostate and mesenteric lymph nodes of the 

animals in 20 mg/kg b. w./day dose group compared to the control animals and the other 

treatment groups. Granulomas with central neutrophilic granulocytes were only noted in the 

mesenteric lymph node of male and female rats of the high dose group. The lungs of the male 

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and female animals in the 8 or 20 mg/kg b.w./day dose groups showed an increased incidence of 

foci of foamy macrophages (alveolar histiocytosis) in the alveoles of the lungs.

The NOAEL was 4 mg/kg/day; the LOAEL was 8 mg/kg/day, based on the histopathology 

observed in the heart, lymph node, skeletal muscle, and kidney.

This study is classified as Acceptable/Guideline.

(2) In a combined chronic toxicity/carcinogenicity study (MRID 48658501/02), N-(3-

Aminopropyl) N-Dodecyl-propane-1,3-diamine (89.4% a.i., Batch # 20570-MOl) was 

administered to groups of 50 male and 50 female CD rats in the feed at 0 (Group 1), 4 (Group 2) 

8 (Group 3), or 20/15/12 (Group 4) mg/kg b.w./day for 104 weeks. The 20/15/12 mg/kg

b.w./day was dosed as below.

The initial dose level of 20 mg/kg b.w./day of the high dose group was reduced to 15 mg/kg

b.w./day as of test day 351 (test week 51, both genders) and further reduced to 12 mg/kg 

b.w./day as of test day 386 (test week 56, males) and 407 (test week 59, females). The dosing of 

the high dosed animals was discontinued from test day 431 (test week 62, males) and test day 

568 (test week 82, females) onwards due to a high mortality.

There was no increases of neoplasms in dosed rats. Non-neoplastic histopathological lesions

were seen at 4 mg/kg/day or higher dose levels. Non-neoplastic lesions were noted in the heart,

skeletal muscle, kidney, and lymph node (mesenteric) of male and female rats.

An increased mortality was seen in both males and females at 20/15/12 mg/kg b.w./day, when

compared to the control or the 4 or 8 mg/kg/day animals.

In the high dose animals, males and females showed a body weight change of 69% and 73% (of 

control) for males and females, respectively, for weeks 53. No test compound-related influence 

(<10%) was noted on the body weight gain of the animals treated with 4 or 8 mg/kg b.w./day 

from weeks 0-75; whereas, in the female of the 8 mg/kg b.w./day dose group showed a decrease 

from weeks 0 -103 to 82% of control. 

Hematology changes were seen at 20/15112 mg/kg day when compared to the control and lower

dose animals. Male and female animals showed changes in the clinical biochemistry at 8

mg/kg/day vs. the controls.

The NOAEL was < 4 mg/kg/day (lowest tested dose [LTD]); the LOAEL was 4 mg/kg/day, 

based on the histopathology observed in the heart, lymph node, and skeletal muscle.

This study is classified as Acceptable/Guideline.

Mutagenicity 

Adequacy of Database for Mutagenicity: The database for mutagenicity is considered adequate 

for the currently registered uses based on the EPA's 1991 mutagenicity guidelines. Several 

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mutagenicity studies have been submitted and reviewed by the Office of Pesticide Programs 

(OPP) and found acceptable, except for the in vitro mammalian cytogenetics assay (MRID 

45115323). 1,3-PAD is found to be mutagenic in in vitro mammalian cytogenetics assay. The 

summaries of these studies are provided below. 

Gene Mutation

(1) In a bacterial reverse mutation assay (MRID 45115324), five histidine-dependent strains of 

Salmonella typhimurium (TA98, TA100, TA1535, TA1537, and TA1538) were tested for reverse 

mutations with concentrations of 1,3-PAD ranging from 0.24-150 μg/plate -S9 activation, and 

0.96-600 μg/plate +S9 activation. S. typhimurium was cultured for 2 days with test chemicals and 

then the colonies were counted using an image analyzer. No P4150 treatment resulted in the twofold (strains TA98 and TA100) or three-fold (strains TA1535, TA1537, and TA1538) increase in 

mean revertant numbers that would indicate a positive response.

In this assay, 1,3-PAD did not cause mutagenic activity.

This study is classified as Acceptable and satisfies the guideline requirement of OPPTS

870.5100 for a bacterial reverse mutation assay in S. typhimurium.

(2) The test article, 1,3-PAD (purity of 29.5% a.i.), was evaluated in a mammalian forward 

mutation assay at six dose levels (0.05, 0.1, 0.5, 1.0, 2.5 and 5.0 μg/mL) in Chinese hamster V79 

cells (MRID 45115325). The test doses were based on cytotoxicity results from a preliminary 

range-finding experiment using doses ranging from 0.0016-5.0 mg/mL. In the main and 

confirmatory assays, mutagenicity was tested in the absence and presence of rat liver S9 fraction

(±S9). Two subsequent assays were conducted to assess mutagenicity and cytotoxicity. Relative 

and absolute cloning efficiencies were calculated at the conclusion of the selection period; was 

assessed using a 6-thioguanine selection assay. Criteria for a valid assay were not provided. 

Minimal criteria for a positive response (statistical evaluation of all MF implementing a t-test, p= 

0.05) were listed in the study report. The sensitivity of the system to detect mutations was shown 

by the induction of high MF values by the positive controls, -S9.

The test article did not induce a significant increase in mutation frequency (MF) at any dose or 

condition.

This study is classified as Acceptable and satisfies the guideline requirements of OPPTS 

870.5300 for an In Vitro Mammalian Cell Gene Mutation Test.

Cytogenetics

(1) In an in vitro mammalian cytogenetics assay (MRID 45115323) with 1,3-PAD (purity of 

29.5% a.i.), Chinese hamster V79 cells were tested at concentrations ranging from, 10.0 to 0.1 

μg/ml, ±S9. Toxicity (based on decreases in the mitotic indices) was seen at doses of 10.0 and 

5.0 μg/ml in the absence of S9 and at 10.0 μg/ml in the presence of S9. No increase in the 

percentage of cells with aberrations was observed for any test concentration at any harvest time, 

with or without S9 activation. However, a significant dose-dependent increase of polyploid cells 

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was observed after both 17 as well as 24 hours +S9. This effect was reproduced in the second 

test.

The test material was considered a mutagen, causing the production of polyploid cells after 

both 17 and 24 hours. 

This study is classified as Unacceptable/upgradeable, and does not satisfy the guideline 

requirement [OPPTS 870.5375] for an in vitro mammalian cytogenetics study in mammalian 

cells. Reporting of the data is unclear with respect to the first test and second test and with regard 

to what is actually measured. Statistical methods were not used in the evaluation of the data and 

there are no recommended guidelines as to what criteria are used for a positive study. 

(2) In a mouse bone marrow micronucleus assay (MRID 46342601), 3 Crl:CD-1® (ICR) BR 

mice/sex/dose were exposed once by intraperitoneal injection (i.p.) to 1,3-PAD (purity of 90% 

a.i.) dissolved in water at doses of 8, 16, 31.25, 62.5, 125, 250 or 500 mg/kg. Animals were 

observed for clinical toxicity signs after dosing of test article, 1-hour following, and at least once 

a day for 48 hours after dosing. The maximum tolerated dose was estimated to be 8 mg/kg. No 

differences were observed between sexes and only males, therefore, were used in the main study. 

In the main study, 1,3-PAD (purity of 90% a.i.) in deionized water was administered at 0 

(control), 2, 4, and 8 mg/kg by i/p. to male Crl:CD-1® (ICR)BR mice. Bone marrow was 

harvested at 24 hours, from 6 animals/dose level. After 48 hours 6 animals from the vehicle 

control and 6 animals from the 8.0 mg/kg dose level were sacrificed and the bone marrow 

harvested. The positive control article, cyclophosphamide, dissolved in water, was administered 

once by oral gavage at 80 mg/kg, and the bone marrow harvested after 24 hours. 

Animals dosed at 2 and 4 mg/kg bw and sacrificed after 24 hours, showed signs of hypertension 

of the back, hunched posture, and squinted eyes, one hour post dosing. These clinical toxicity 

observations were not noticed one day after dosing. Animals dosed at 8 mg/kg bw and sacrificed 

after 24 hour and 48 hours showed signs of hyperextension of the back, hunched posture, 

squinted eyes, irregular respiration, and slight hypoactivity one hour after dosing. 

The positive and negative controls showed the appropriate response. 1,3-PAD (purity of 90% 

a.i.) was considered to be negative in the mouse bone marrow micronucleus assay under the 

test conditions of the assay at both time periods. 

This study is classified as Acceptable/Guideline and satisfies the guideline requirement of 

OPPTS 870.5395 for in vivo cytogenetic mutagenicity data, micronucleus test/mouse.

870.7800 Immunotoxicity Study

Adequacy of Database for Immunotoxicity: A subchronic dermal toxicity/immunotoxicity study 

in rats (MRID 45151902) is available in the Agency’s hazard database. The Agency has 

reviewed the study and determined that the immunotoxicity portion of the study was acceptable 

and met the guideline requirements for an immunotoxicity study. The study is summarized under 

the subchronic dermal study above. A summary of the immunotoxicity portion of the study 

(Cohort I) is provided below.

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In a subchronic dermal toxicity/immunotoxicity study (MRID 45151902), 1,3-PAD (purity of 

29.3% a.i.) was administered to Sprague Dawley (Crl:CD_BR) rats (8/sex/group for Cohort I and 

15/sex/group for Cohort II) dermally via a wrapping procedure at dose levels of 0, 5 (1.5 mg 

a.i.), 10 (2.9 mg a.i.), and 20 (5.9 mg a.i.) mg/kg-day (dose reduced to 15 [4.4 mg a.i.] 

mg/kg/day during week 1) for a period of 28 days for animals in Cohort I (28 Day 

Dermal/Immunotoxicity). 

Cohort I parameters consisted of observations, immunotoxicity, food consumption and body 

weights and gross and histopathology of animals dying in extremis only.

Severe dermal irritation was noted in high-dose animals during the first week of dosing which 

resulted in a decrease of the high dose from 20 (5.9 mg a.i.) mg/kg-day to 15 (4.4 mg a.i.) 

mg/kg-day. Dermal irritation persisted after the reduction of the dosage level, and began to also 

appear in the low- and mid-dose groups. Females showed greater dermal irritation than the 

males.

Decreased body weight (14%; not statistically significant) were observed in the high dose males. 

No immunosuppression was observed. 

The immunotoxicity NOAEL was determined to be >15 (4.4 mg a.i.)/20 (5.9 mg a.i.) mg/kg/day 

(highest dose tested [HDT]). The LOAEL could not be calculated.

This study is classified as Acceptable and meets the guideline requirements of 870.7800 for an 

Immunotoxicity Study.

Other Special Studies

There is one metabolism study (MRID 45115326) and one in vitro percutaneous absorption 

study (MRID 46309705) in the Agency’s hazard database. The Agency has reviewed these 

studies and determined they are acceptable. Summaries are provided below.

870.7485 Metabolism and Pharmacokinetics

In a metabolism study (MRID 45115326), radioactive (14C) 1,3-PAD (> 97% a.i. for 

radiolabeled, 99.8% a.i. for non-radiolabeled) suspended in water, was administered orally to 

male and female Sprague Dawley CD® rats at a dose of 3 or 30 mg/kg. The biokinetics, 

metabolism, tissue distribution, and proportion of metabolites were investigated over a 120-hour 

duration. No animals were reported to exhibit any signs of toxicity. There were no dose- or sexrelated differences in 14C-labeled test substance excretion. Approximately 90%-97% of 

radioactive test substance was excreted in the feces of both sexes by the 120th hour. Percent 

radioactivity recovered in the carcasses and gastrointestinal tracts of either treated sex ranged 

from 1.0%-3.0% and 0.4%-1.3%, respectively. Percent radioactivity excreted via urine (2%) and 

expired air (0.1%-0.4%) were minimal regardless of dose or sex. Based upon excretion data, the 

oral administration of single doses of 3 and 30 mg/kg resulted in approximately 0.2% 

gastrointestinal absorption regardless of sex. Low 14C-labeled test substance plasma 

concentrations support this conclusion. Detectable 14C-labeled test substance radioactivity in the 

plasma was generally below the limit of reliable measurement for both the 3 and 30 mg/kg doses. 

Peak concentrations (0.12 μg equiv./mL) were reported at 4 and 12 hours after low and high dose 

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administration, respectively. The half-life plasma concentrations after a 30 mg/kg dose were 

determined to be 28.5 and 46.3 hours for males and females, respectively. Concentration versus 

time curve (AUCt) values were calculated at 4.6 μg equiv./mL hour for males and 5.1 μg 

equiv./mL hour for females. Five male rats were treated (3 mg/kg) and subjected to whole-body 

autoradiography. The highest levels (qualitative data measured visually) of radioactivity were 

distributed throughout the gastrointestinal tract and its contents. Low levels (qualitative data 

measured visually) of the test substance were present in other tissues, providing additional 

evidence for low oral absorption. 

The parent structure was the major compound found in the feces after low (11% females and 

13% males) or high doses (7% females and 10% males). Six minor metabolites were detected in 

the feces after both doses, although all were minor and individually represented 1%-3% of the 

administered doses. One of these metabolites was identified as 1-dodecylamine, the proposed 

biotransformation pathway. Other unidentified metabolites accounted for <3% of the total 

radioactivity administered. A considerable portion of the dose (66%-72%) remained unextracted 

after either of the doses. Further extraction released an additional 17%-20% (low-dose) and 20%-

25% (high-dose); the analysis afterwards was unsuccessful. 

In comparing this study to the guideline requirements for a toxicokinetic study (OPPTS 

870.8500) in rats, the study would not satisfy the requirement that the highest dose did not 

produce any clinical indications of toxicity.

This short-term toxicity study is classified as Acceptable and fulfills the guideline requirements 

of OPPTS 870.7485 for a Metabolism study.

870.7600 Dermal Penetration

In a non-guideline in vitro percutaneous absorption study (MRID 46309705), 1,3-PAD (97.1% 

a.i., Batch No. KV021704), and [14C]-1,3-PAD in the form of a hydrochloride salt (98.3% 

radiochemical purity, specific activity of 25.7 mCi/mmol, lot No. 3494-134), was applied to 

dermatomed human skin samples, in vitro, and adsorption was measured via a flow through 

diffusion cell system after 24 hours of exposure. The test article at 108.12 μg equiv/cm2 in water 

(≈1%) was administered to 11 donor skin samples (200 - 500 μm thick stratum corneum) from 6 

female human donors to an area of 0.64 cm2 at 10 μL/cm2

. The skin samples were obtained from 

4 breasts and 3 abdomens from routine plastic surgery patients between the ages 24 and 66 years. 

The 1% (w/v) [14C]-1,3-PAD/1,3-PAD solution was poorly absorbed with dermal absorption and 

dermal delivery being <0.01% and 0.92% of the applied dose, respectively. The system had 

acceptable recovery with a mean mass balance of 102.14% of the applied dose. 

This study in human skin is classified as Acceptable/Non-guideline. The Agency does not have 

a guideline for such a study. In vitro testing does not account for the influence of systemic 

distribution and excretion kinetics upon dermal absorption of the chemical of concern; therefore, 

in vitro studies alone do not satisfy the guideline requirements of OPPTS 870.7600 for a Dermal 

Penetration study.

The toxicology profile for 1,3-PAD is summarized in Table A2 below.

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Table A2– Toxicology Profile for 1,3-PAD

Guideline No./Study Type/

Substance Purity

MRID No. 

(year) Results

Subchronic Toxicity

Non-guideline

90-Day oral toxicity (range-finding) 

rodents - Rat

purity unknown

45115319 

(1992)

NOAEL = 10 mg/kg/day

LOAEL = 60 mg/kg/day, based on microscopic evidence 

of submucosal and mucosa gastritis and glandular 

epithelial degeneration.

870.3100

90-Day oral toxicity rodents - Rat

purity 29.8%

45151901

(1992)

NOAEL = 5 (1.5 mg a.i.) mg/kg/day

LOAEL = 10 (3.0 mg a.i.) mg/kg/day, based on based on 

the clinical finding of a reduced righting reflex.

Non-guideline

A histopath review of MRID 45151901 

45115320 

(1999)

NOAEL = 30 (8.9 mg a.i.) mg/kg/day

LOAEL = 90 (26.8 mg a.i.) mg/kg/day, based on 

nephrotoxicity

870.3250

90-Day dermal toxicity – Rat 

purity 29.3%

45151902

(2000)

NOAEL < 5 (1.5 mg a.i.) mg/kg/day (LDT)

LOAEL = 5 (1.5 mg a.i.) mg/kg/day, based on sternal 

bone marrow hyperplasia in the female

870.3465

90-Day inhalation toxicity No studies available.

Developmental/Reproductive Toxicity

870.3700

Prenatal developmental (range-finding) 

rodents – Rat

purity 30.2%

45115322 

(1993)

Maternal Toxicity NOAEL = 50 (15.1 mg a.i.) 

mg/kg/day

Maternal Toxicity LOAEL = 100 (30.2 mg a.i.) 

mg/kg/day, based on ↓ mean food consumption and 

salivation.

Developmental Toxicity NOAEL = 200 (60.4 mg a.i.) 

mg/kg/day (HDT)

Developmental Toxicity LOAEL > 200 (60.4 mg a.i.) 

mg/kg/day (not established)

870.3700

Prenatal developmental in rodents – Rat

purity 30.2%

45151903 

(1994)

Maternal Toxicity NOAEL = 25 (7.6 mg a.i.) mg/kg/day 

(LDT)

Maternal Toxicity LOAEL = 75 (22.7 mg a.i.)

mg/kg/day, based on clinical signs of toxicity and ↓ mean 

body weight gain and mean food consumption.

Developmental Toxicity NOAEL = 200 (60.4 mg a.i.) 

mg/kg/day (HDT)

Developmental Toxicity LOAEL > 200 (60.4 mg a.i.) 

mg/kg/day (not established)

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Guideline No./Study Type/

Substance Purity

MRID No. 

(year) Results

870.3800

Reproduction and fertility effects – Rat

purity 30.2%

45151904 

(1995)

Parental/Systemic Toxicity NOAEL = 30 (9.1 mg a.i.)

mg/kg/day

Parental/Systemic Toxicity LOAEL = 90 (27.2 mg a.i.)

mg/kg/day, based on clinical signs of toxicity, mortality, ↓

mean body weight/body weight gain, and ↓ mean food 

consumption.

Reproductive Toxicity NOAEL ≥ 90 (27.2 mg a.i.)

mg/kg/day (HDT)

Reproductive Toxicity LOAEL > 90 (27.2 mg a.i.)

mg/kg/day (not established)

Offspring Toxicity NOAEL = 30 (9.1 mg a.i.) mg/kg/day

Offspring Toxicity LOAEL = 90 (27.2 mg a.i.)

mg/kg/day, based on ↓ litter and pup weights.

Chronic Toxicity/Carcinogenicity

870.4300

Combined Chronic 

Toxicity/Carcinogenicity

Purity 89.4%

48658501/02 

(2010)

Chronic Toxicity NOAEL=4 mg/kg/day

Chronic Toxicity LOAEL =8 mg/kg/day, based on the 

histopathology observed in the heart, lymph node, skeletal 

muscle, and kidney (degenerative changes of the myofibers 

[lympho-histiocytic myocarditis]; degeneration of the 

skeletal muscles [an increase of lympho-histiocytic 

infiltrations]; minimal to moderate increase in basophilic 

tubular cells and lympho-histiocytic infiltration of the 

kidney; suppurative inflammation in mesenteric lymph 

nodes [granulomas with central neutrophilic 

granulocytes]).

There was no increases of neoplasms in dosed rats.

Mutagenicity

870.5100 

Ames Assay

purity 30%

45115324

(1988)

Negative

870.5300 

In vitro Mammalian Cell Gene 

Mutation Test

purity 29.5%

45115325

(1991)

Negative

870.5375 

In vitro Mammalian Chromosomal 

Aberration Assay (CHO)

purity 29.5%

45115323

(1991)

Positive

870.5385 

In vivo Mammalian Bone Marrow 

Micronucleus Assay - Mouse 

purity 90%

46342601 

(2004)

Negative

Immunotoxicity

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Guideline No./Study Type/

Substance Purity

MRID No. 

(year) Results

870.7800 

Immunotoxicity 

purity 29.3%

45151902

(2000)

NOAEL ≥ 15 (4.4 mg a.i.)/20 (5.9 mg a.i.) mg/kg/day 

(HDT)

LOAEL > 15 (4.4 mg a.i.)/20 (5.9 mg a.i.) mg/kg/day (not 

established)

Special Studies

870.7485 

Metabolism and Pharmacokinetics

purity > 97% for radiolabeled and 

99.8% for non-radiolabeled

45115326 

(1996)

Approximately 0.2% GI absorption rate was estimated 

after a single oral dose of 3 and 30 mg/kg of 1,3-PAD. 1,3-

PAD was excreted primarily in the feces (90-97% vs 2% in 

urines) of both sexes by the 120th hour. Detectable 14Clabeled 1,3-PAD radioactivity in the plasma was generally 

below the limit of reliable measurement for both the 3 and 

30 mg/kg doses. Peak concentrations (0.12 μg equiv./mL) 

were reported at 4 and 12 hours for low and high dose 

administration, respectively. The half-life plasma 

concentrations after a 30 mg/kg dose were determined to 

be 28.5 and 46.3 hours for males and females, respectively. 

No differences were observed in the absorption, 

distribution, or excretion patterns in male and female rats 

in any of the dose groups.

The parent structure was the major compound found in the 

feces after low (11% females and 13% males) or high 

doses (7% females and 10% males). One of these 

metabolites was identified as 1-dodecylamine, the 

proposed biotransformation pathway. A considerable 

portion of the dose (66%-72%) remained unextracted after 

either of the doses. Further extraction released an 

additional 17%-20% (low-dose) and 20%-25% (highdose); the analysis afterwards was unsuccessful.

Non-Guideline

In Vitro Percutaneous Absorption

purity 98.3% for radiolabeled and 

97.1% for non-radiolabeled

46309705 

(2003)

The 1% (w/v) [14C]-1,3-PAD/1,3-PAD solution was poorly 

absorbed with dermal absorption and dermal delivery 

being <0.01% and 0.92% of the applied dose, respectively. 

The system had acceptable recovery with a mean mass 

balance of 102.14% of the applied dose.

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Toxicology References

45114705 Moore, G. (2000) Primary Skin Irritation Test with Lonza Formulation LNZ-64 

(in Rabbits): Lab Project Number: 8701: P326 TRS. Unpublished study prepared 

by Product Safety Labs. 25 p. {OPPTS 870.2500}

45115314 Jones, J. (1988) P4150: Acute Oral Toxicity in the Rat: Lab Project Number: 

102/17: 0762. Unpublished study prepared by Safepharm Laboratories Ltd. 21 p. 

{OPPTS 870.1100}

45115315 Jones, J. (1988) P4150: Acute Dermal Toxicity (Limit Test) in the Rat: Lab 

Project Number: 102/48: 0761. Unpublished study prepared by Safepharm 

Laboratories Ltd. 14 p. {OPPTS 870.1200}

45115316 Jones, J. (1988) P4150: Acute Dermal Irritation/Corrosion Test in the Rabbit: Lab 

Project Number: 102/18: 0763. Unpublished study prepared by Safepharm 

Laboratories Ltd. 16 p. {OPPTS 870.2500}

45115317 Allen, D. (1994) P4198: Acute Dermal Irritation Test in the Rabbit: Lab Project 

Number: 102/177: 2438. Unpublished study prepared by Safepharm Laboratories 

Ltd. 16 p. {OPPTS 870.2500}

45115318 Allan, S. (1996) P4150: Skin Sensitization in the Guinea Pig: Lab Project 

Number: LZA 129/953059/SS: 2574. Unpublished study prepared by Huntingdon 

Life Sciences Ltd. 24 p. {OPPTS 870.2600}

45115319 Korn, W. (1992) Final Report: A 4-Week Oral Dose Range Finding Study in Rats 

with 0P4150: Lab Project Number: 20-04-0843-90: 1908. Unpublished study 

prepared by IBR Bioanalytisches Zentrum. 115 p. {OPPTS 870.3100}

45115320 Prentice, D. (1999) 90-Day Oral Toxicity Study with P4150 in Rats Followed by 

a 4-Week Recovery Period (Lonza Report No. 1083): A Histophathological 

Review and Expert Opinion: Lab Project Number: 1083. Unpublished study 

prepared by PCS Consultants Ltd. 44 p. {OPPTS 870.3100}

45115322 Barton, S. (1993) P4150: Dose Range Finding Study in Rats Preliminary to 

Teratogenicity Study: Lab Project Number: 490725: 2161. Unpublished study 

prepared by Inveresk Research International. 45 p. {OPPTS 870.3500}

45115323 Bosse, R. (1991) Final Report: In Vitro Mammalian Cytogenetic Test with P4150: 

Lab Project Number: 95-86-2077/02-90: 1802. Unpublished study prepared by 

IBR Bioanalytisches Zentrum. 25 p. {OPPTS 870.5375}

45115324 Kennelly, J. (1988) Study to Determine the Ability of P4150 to Induce Mutation 

in Five Histidine-Requiring Strains of Salmonella typhimurium: Lab Project 

Number: LOB 11/S: 0765. Unpublished study prepared by Microtest Research 

Limited. 30 p. {OPPTS 870.5265}

Page 41 of 53
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45115325 Bosse, R. (1991) Final Report: In Vitro Mammalian Cell Mutation Test P4150: 

Lab Project Number: 95-86-2077/02-90: 1801. Unpublished study prepared by 

IBR Bioanalytisches Zentrum. 28 p. {OPPTS 870.5300}

45115326 McEwen, A. (1996) P4198: Toxicokinetic Study in the Rat: Lab Project Number: 

LZA 103/961230: 2706. Unpublished study prepared by Huntingdon Life 

Sciences Ltd. 65 p. {OPPTS 870.8500}

45151901 Korn, W. (1992) Final Report: 90-Day Oral Toxicity Study with P4150 in Rats 

Followed by a 4-Week Recovery Period: Lab Project Number: 20-04-0843-90: 

1083. Unpublished study prepared by IBR Bioanalytisches Zentrum. 539 p. 

{OPPTS 870.3100}

45151902 Johnson, W. (2000) Subchronic Dermal Toxicity/Immunotoxicity Study with 

Lonzabac 12 in Rats: Lab Project Number: 1076 SN3. Unpublished study 

prepared by IIT Research Institute. 405 p. {OPPTS 870.7800}

45151903 Barton, S. (1994) P4150: Developmental Toxicity Study in Rats: Lab Project 

Number: 490730: 2283. Unpublished study prepared by Inveresk Research 

International. 81 p. {OPPTS 870.3700}

45151904 Barton, S. (1995) P4150: Two Generation Reproduction Study in Rats: Lab 

Project Number: 490924: 2420. Unpublished study prepared by Inveresk 

Research International. 172 p. {OPPTS 870.3800}

46309705 Roper, C. (2003) The In Vitro Percutaneous Absorption of [Carbon-14]-Lonzabac 

12 Through Human Skin at an Incorporation Rate of 1 Percent (w/v) in Water. 

Project Number: 23362, 204648. Unpublished study prepared by Inveresk 

Research International. 36 p.

46342601 Erexson, G. (2004) In Vivo Mouse Micronucleus Assay with Lonzabac 12: 

Amended Final Report. Project Number: 7483/101, 25872/0/455OECD. 

Unpublished study prepared by Covance Laboratories, Inc. 58 p.

46603601 Merkel, D. (2005) Acute Dermal Toxicity Study in Rats with LNZ-64. Project 

Number: 17362, P322/TRS, 041215/7D. Unpublished study prepared by Product 

Safety Laboratories. 14 p.

46603602 Merkel, D. (2005) LNZ-64: Dermal Sensitization Test in Guinea Pigs (Buehler 

Method). Project Number: P328/TRS, 16758, 041215/7D. Unpublished study 

prepared by Product Safety Laboratories. 26 p.

46603603 Merkel, D. (2005) Acute Inhalation Toxicity Study in Rats - Limit Test. Project 

Number: P330/TRS, 17363, 041215/7D. Unpublished study prepared by Product 

Safety Laboratories. 26 p.

Page 42 of 53
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47272201 Durando, J. (2007) Acute Inhalation Toxicity Study in Rats- Limit Test with 

Lonzabac 12. Project Number: 22102, P330/TRS. Unpublished study prepared by 

Eurofins/Product Safety Laboratories. 25 p.

48658501 Hansen, B.; Leuschner, J. (2011) Combined Chronic Toxicity and 

Carcinogenicity Study of N-(3-aminopropyl)-N-dodecylpropane-1,3-diamine by 

Dietary Administration to CD Rats. Part I: 104-Week Carcinogenicity Study. 

Project Number: 4680 20570/06//PART/1/OCR. Unpublished study prepared by 

Laboratory of Pharmacology & Toxicology. 4798p.

48658502 Hansen, B.; Leuschner, J. (2010) Combined Chronic Toxicity and 

Carcinogenicity Study of N-(3-Aminopropyl)-n-dodecylpropane-1,3-diamine by 

Dietary Administration to CD Rats. Project Number: 20570/06/OCR. 

Unpublished study prepared by Laboratory of Pharmacology & Toxicology. 

1162p.

48980409 Bain, J. (2012) An Acute Toxicity Study of Sanitizing Wash N Walk by 

Inhalation Administration in Rats: Final Report. Project Number: 672427, 33695, 

1200006CL6. Unpublished study prepared by Charles River Laboratories. 75p.

48980410 Lemoncelli, A. (2012) Delayed Contact Hypersensitivity in Hartley Guinea Pigs

(Buehler Method) with Sanitizing Wash n Walk: Final Report. Project Number: 

0424GE31/003, 1200006CL4. Unpublished study prepared by Calvert Preclinical 

Services, Inc. 59p.

48980413 Lemoncelli, A. (2012) Primary Eye Irritation Study in Rabbits with Sanitizing 

Wash N Walk Use-Solution: Final Report. Project Number: 0421LE31/008, 

1200006CL7. Unpublished study prepared by Calvert Preclinical Services, Inc. 

57p.

48980414 Lemoncelli, A. (2012) Primary Eye Irritation Study in Rabbits with Sanitizing 

Wash N Walk: Final Report. Project Number: 0421LE31/007, 1200006CL1. 

Unpublished study prepared by Calvert Preclinical Services, Inc. 58p.

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Appendix B Environmental Fate

Environmental Fate and Transport Properties of 1,3-PAD

1,3-PAD is a propane diamine compound that is miscible in water and is unlikely to move from 

soil or water into air based on the vapor pressure of 3.3 x 10-6 mm Hg and the Henry’s Law 

constant of 1.3 x 10-10 atm m3 mol-1 (Table 4). While it was not included in the ATMD RED for 

alkyl trimethylene diamines,8,

9 it is a diamine compound with similar structural, chemical and 

physical characteristics to those in the RED. Other than hydrolysis, no additional environmental 

fate data have been submitted for 1,3-PAD. 

Water and Sediment

Hydrolysis

1,3-PAD was stable to hydrolysis at pH 5,7, and 9 (MRID 45115327).

Aqueous and Soil Photolysis

1,3-PAD is not susceptible to photodegradation based on its lack of sorption of UV light between 

290 and 800 nm in wavelength (Table 4).

Octanol-Water Partition Coefficient

1,3-PAD is a polar, miscible substance and data on octanol and water partitioning are not 

required (Table 4). 

Aerobic Aquatic Metabolism

Data on aerobic aquatic metabolism are anticipated to be required based on the registered uses 

that have the potential to create environmental exposure. The metalworking fluid use can create 

down-the-drain exposure from release of used metalworking fluids to WWTPs and the oilfield 

uses can create environmental exposure through runoff or leaching from water holding ponds or 

through effluent water from WWTPs. 

Anaerobic Aquatic Metabolism

Data on aerobic aquatic metabolism are anticipated to be required based on the registered uses 

that have the potential to create environmental exposure. The metalworking fluid use can create 

down-the-drain exposure from release of used metalworking fluids to WWTPs and the oilfield 

uses can create environmental exposure through runoff or leaching from water holding ponds or 

through effluent water from WWTPs. 

8 http://www.epa.gov/oppsrrd1/REDs/atmd-red.pdf 9 The ATMD RED included PC codes (067301, 067302, 067309, 067310, and 067313.

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Soil

Soil Leaching/Adsorption/Desorption Batch Equilibrium

Data on sorption to soil and sediment are anticipated to be required based on the registered uses 

that have the potential to create environmental exposure. The metalworking fluid use can create 

down-the-drain exposure from release of used metalworking fluids to WWTPs and the oilfield 

uses can create environmental exposure through runoff or leaching from water holding ponds or 

through sludge from WWTPs.

Aerobic Soil Metabolism

Data on aerobic soil metabolism are anticipated to be required based on the registered uses that 

have the potential to reach soil from sorption to sludge in wastewater treatment plants (WWTPs). 

Anaerobic Soil Metabolism

Data on anaerobic soil metabolism are not anticipated to be required because usable data on 

anaerobic aquatic metabolism may be used as a surrogate.

Fate and Transport in WWTP

Activated Sludge Sorption Isotherm

Data on sorption to activated sludge are anticipated to be required because the registered uses 

have the potential to reach WWTPs where they can sorb to sludge.

Biodegradation in WWTP

Data on ready biodegradability or one of three biodegradation in activated sludge simulation 

tests are anticipated to be required because the registered uses have the potential to reach 

WWTPs where the extent of biodegradation during wastewater treatment is unknown. 

Activated Sludge Respiration Inhibition 

Data on activated sludge respiration inhibition (ASRI) are anticipated to be required because the 

registered uses have the potential to reach WWTPs where they could adversely affect 

microorganisms.

Table B1 – Summary of Chemical, Physical, and Environmental Fate Properties

Table 2. Physical, Chemical, and Environmental Fate Properties for 1,3-PAD

Property OCSPP Guideline No. 

(unless stated)

Value Citation

CAS No. None 2372-82-9 None

Chemical and Physical Properties

Molecular weight (grams/mol) None 299.54 None

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Water solubility (mg/L) 830.7840 Miscible10 Table 4

Vapor Pressure (mm Hg) 830.7950 3.3 x 10-6 Table 4

Henry’s Law (atm m3 mol-1)11 None (calculated) 1.3 x 10-10 None

Log P (unitless) 830.7550 Not required12 Table 4

UV Visible absorption (nm) 830.7050 Sorption at 203-218 nm Table 4

Environmental Fate Properties—Chemical Degradation (half-lives in days unless stated) 

Hydrolysis 835.2120 Stable at pH 5, 7, and 9 46309708

Photodegradation in water 835.2240 Not required13 None

Photodegradation on soil 835.2410 Not required14 None

Environmental Fate Properties—Laboratory Metabolism (half-lives in days unless stated)

Aerobic soil metabolism 835.4100 No data None

Anaerobic soil metabolism 835.4200 No data None

Aerobic aquatic metabolism 835.4300 No data None

Anaerobic aquatic metabolism 835.4400 No data None

Environmental Fate Properties—Sorption to soil (L/kg for Kd and Koc values)

Leaching-adsorption-desorption 835.1230 No data None

Wastewater Treatment Plant Properties—Sorption and Degradation

Activated sludge sorption isotherm (L/kg) 835.1110 No data None

Ready biodegradability or one of three 

biodegradation in activated sludge 

simulation tests (%)

835.3110 or one of:

835.3220

835.3240

835.3280

No data None

Activated sludge respiration inhibition 

(mg/L).

850.3300 No data None

10 10,000 mg/l used in calculations 11 [VP (mm Hg) * molecular weight (grams/mol)]/[760 * water solubility (mg/l)] 12 1,3-PAD is a polar compound and log P data are not required and not applicable 13 Not required based on lack of UV sorption from 290-800 nm 14 Not required based on lack of UV sorption from 290-800 nm

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Environmental Fate and Transport References:

45115304 Sloan, R. (1999) Lonzabac 12-Physical and Chemical Properties: Lab Project 

Number: SP-99043-A. Unpublished study prepared by Lonza, Inc. 30 p. {OPPTS 

830.6315, 830.7000, 830.7050, 830.7100, 830.7300} 

45115305 Sarff, P.; Edgar, L. (1999) Boiling Point Determination of Lonzabac 12: Lab 

Project Number: SP-99005-A: 45066. Unpublished study prepared by ABC 

Laboratories, Inc. 14 p. {OPPTS 830.7220}

45115307 Sloan, R. (1999) Lonzabac 12-Stability to Normal and Elevated Temperatures, 

Metals and Metal Ions: Lab Project Number: SP-99010-A. Unpublished study 

prepared by Lonza Inc. 24 p. {OPPTS 830.6313} 

45115308 Lonza, Inc.; Lewis and Harrison, LLC. (2000) Product Chemistry: Discussion of 

Physical and Chemical Properties: Lonzabac 12. Unpublished study. 7 p. {OPPTS 

830.6304, 830.6317, 830.6320}

45115309 Lonza, Inc.; Lewis and Harrison, LLC. (2000) Product Chemistry: Vapor Pressure 

for Lonzabac 12. Unpublished study. 8 p. {OPPTS 830.7950}

45115327 Flack, I. (1996) P4198: Abiotic Degradation: Hydrolysis as a Function of pH: Lab 

Project Number: LZA 102/960267: 2651. Unpublished study prepared by 

Huntingdon Life Sciences Ltd. 20 p.

46309706 Sarff, P. (1999) Corrosion Characteristics of Lonzabac 12. Project Number: 45065, 

SP/99004/A. Unpublished study prepared by ABC Laboratories, Inc. 15 p.

46309708 Spare, W. (2004) Aqueous Hydrolysis of (Carbon-14)-Lonzabac 12 Under 

Laboratory Conditions. Project Number: 065/002, EXP/065/002. Unpublished study 

prepared by Exygen Research. 106 p.

46332202 Sloan, R. (2000) Procedure for Determining Dodecylamine Content in Lonzaback 

12. Unpublished study prepared by Lonza, Inc. 5 p.

U.S. EPA. September, 2007. Reregistration Eligibility Decision (RED) for

Alkyltrimethylenediamines (Case 3014). EPA 739-R-07-004. 

http://www.epa.gov/oppsrrd1/REDs/atmd-red.pdf 

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Appendix C Ecotoxicology Profile

Toxicity to Terrestrial Organisms

Birds, acute oral

One available acute-oral (LD50) study categorizes 1,3-PAD as being highly toxic to birds. The 

guideline (850.2100) is satisfied. No additional data are anticipated to be required.

Table C1 Avian Acute-oral Toxicity

Test Species Test Material

(% ai) Toxicity ToxicityCategory

EPA Study

ID

Northern bobwhite

(Colinus virginianus)

Lonzabac 12

(24.3%) LD50 = 25 mg ai/kg bw Highly toxic 45115310

Supplemental1

1 test material was not the TGAI

Toxicity to Aquatic Organisms

Freshwater Fish, acute and chronic 

The available acute toxicity studies categorize 1,3-PAD as being highly toxic to freshwater fish. 

The guideline (850.1075) for acute toxicity testing is satisfied. No chronic data are available. 

Because there may be continuous or repeated down-the-drain exposures, chronic data are 

anticipated as being needed (fish early-life stage, 850.1400). However, the anticipated testing 

would be conducted with the most sensitive fish, either freshwater or estuarine/marine fish. The 

need for a freshwater early life-stage toxicity test (850.1400) cannot be determined until 

estuarine/marine fish toxicity data are available. 

Table C2 Acute Toxicity of Iodine to Freshwater Fish

Test Species Test Material

(% ai)

Toxicity Endpoint

(mg ai/L)

Toxicity

Category

EPA Study

ID

Rainbow Trout

(Oncorhynchus mykiss) Lonzabac 12 (30.0% 

aqueous solution)

96-hr LC50 = 0.681

(2.26 mg/L nominal) Highly toxic 45115311

Supplemental2

Bluegill

(Lepomis macrochirus)

95.2

(radio-labeled) 96-hr LC50 = 0.45 Highly toxic 45115312

Acceptable

1 adjusted for the purity of the test material

2 numerous guideline deficiencies, including test material was not the TGAI, concentrations were not measured for 

all nominal concentrations, and high variability in percent recovery (62.4-127.6 %)

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Freshwater Invertebrates, acute and chronic

The acute toxicity studies for the waterflea categorizes 1,3-PAD as being very highly toxic to 

freshwater invertebrates. The guideline (850.1010) for acute toxicity testing is satisfied. Because 

there may be continuous or repeated down-the-drain exposures, chronic data are anticipated as 

being needed (life-cycle, 850.1300). However, the anticipated testing would be conducted with 

the most sensitive invertebrate, either freshwater or estuarine/marine. A freshwater life-cycle

toxicity test (850.1300) would be needed only if the acute tests indicate that the freshwater 

species is more sensitive than the estuarine/marine species for which data are not currently 

available. 

Table C3 Freshwater Invertebrates

Test Species Test Material

(% ai)

Toxicity Endpoint

(mg ai/L) Toxicity Category EPA Study ID

Waterflea

(Daphnia magna) 29.3 48-hr EC50 = 0.073 Very highly toxic 45115313

Acceptable

Estuarine/Marine Fish and Invertebrates

No acute or chronic data are available. Acute toxicity studies needed for the TGAI include tests 

for a fish sp. (850.1075), a bivalve sp. (850.1025 or 850.1055), and one additional invertebrate 

sp. (850.1035). Chronic toxicity testing with estuarine/marine organisms (850.1400, 850.1350)

would be needed only if the acute tests indicate that the estuarine/marine species are more 

sensitive than freshwater species. 

Aquatic Plants

No toxicity data are available. To support the TGAI, two studies are anticipated as needed: a Tier 

II test with a vascular species (850.4400) and an algal toxicity Tier II test for green algae 

(850.4500). If the green algae EC50 is <1 mg ai/L (ppm), then additional testing would be 

needed for freshwater and marine diatoms (850.4500) and cyanobacteria (850.4550).

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Ecotoxicity References:

45115310 Gallagher, S.; Grimes, J.; Beavers, J. (2000) Lonzabac 12: An Acute Oral Toxicity 

Study with the Northern Bobwhite: Final Report: Lab Project Number: 289-114. 

Unpublished study prepared by Wildlife International, Ltd. 54 p. {OPPTS 

850.2100} 

45115311 Ritter, A. (1989) P4150: 96-Hour Acute Toxicity Study (LC50) in the Rainbow 

Trout: Lab Project Number: 232604: 0767. Unpublished study prepared by RCC 

Umweltchemie AG. 42 p. {OPPTS 850.1075} 

45115312 Drottar, K.; Kendall, T.; Kruegar, H. (2000) Lonzabac 12: 96-Hour Flow-Through 

Acute Toxicity Test with the Bluegill (Lepomis machrochirus): Lab Project 

Number: 289A-151A. Unpublished study prepared by Wildlife International, Ltd. 

57 p. {OPPTS 850.1075} 

45115313 Drottar, K.; Kendall, T.; Kruegar, H. (2000) Lonzabac 12: A 48-Hour FlowThrough Acute Toxicity Test with the Cladoceran (Daphnia magna): Lab Project 

Number: 289A-150. Unpublished study prepared by Wildlife International, Ltd. 59 

p. {OPPTS 850.1010} 

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Appendix D Screening Level Down-theDrain Analysis

No Down-the-Drain analysis was performed for 1,3-PAD for this Final Work Plan (see section 

4.3.2).

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Appendix E Product Chemistry

1,3-Propanediamine,N1-(3-aminopropyl)-N1-dodecyl- product chemistry information is 

summarized in Table E1 (Source: MRID Nos. 46332202, 45115304, 45115305, 46309706, 

45115307, 45115308, 45115309 and Lonza MSDS).

Table E1– Product Chemistry of 1,3-Propanediamine,N1-(3-aminopropyl)-N1-dodecylGuideline

Numbers Physical and Chemical Properties 1,3-Propanediamine,N1-(3-aminopropyl)-N1-dodecyl830.1550 Product identity and composition Refer to Table 6

830.1600 Description of materials used to produce 

the product Confidential Business Information (CBI)

830.1620 Description of production process CBI

830.1650 Description of Formulation Process CBI

830.1670 Description of Formulation Impurities CBI

830.1700 Preliminary analysis CBI

830.1750 Certified limits CBI

830.1800 Enforcement analytical method GC

830.1900 Submittal of samples CBI

830.6302 Color Clear liquid

830.6303 Physical State Liquid

Viscous oily liquid

830.6304 Odor Mild amine-like

830.6313 Stability Stable

Materials to avoid: Acids

830.6314 Oxidation/Reduction Not reported

830.6315 Flammability Flash point over 149 oF

830.6316 Explodability Not explodable

830.6320 Corrosion Characteristic Not corrosive to packaging

830.7000 pH at 25 °C 10.6 (1% aqueous solution)

830.7050 UV/Visible Absorption 203.6 nm; 201.6 nm; 218.4 nm; in methanol, acidic 

methanol and alkaline methanol solutions

830.7100 Viscosity 24.08 cSt at 20oC

10.93 cSt at 40oC

830.7200 Melting point (°C) Setting point ≥10oC

830.7220 Boiling point (°C) The boiling point could not be determined due to 

decomposition of the test substance at approx. 280oC

830.7300 Density (g/cm3) 0.87 g/ml at 20oC

830.7370 Dissociation Constant pKa(s) pKa values: 9.3 ± 0.104 and 7.15 ±0.054 at 20oC 

830.7520 Particle size, fiber length, & diameter Not required

830.7550 Log Kow PAD is a polar chemical substance and therefore log Kow is 

not required.

830.7840 Solubility in water (mg/L) at 25oC Completely and infinitely soluble in water

830.7860 Solubility in organic solvents

Soluble in organic solvents.

Completely miscible at 20oC in Acetone, Ethyl acetate, and 

Methanol.

830.7950 Vapor pressure (mm Hg) 3.3 x 10-6 at 25oC

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Product Chemistry References:

Lonza. Lonzabac 12 MSDS. 

http://bio.lonza.com/uploads/tx_mwaxmarketingmaterial/Lonza_ProductDataSheets_

Lonzabac_12_PDS.pdf

MRID 45115304. Sloan, R. (1999) Lonzabac 12-Physical and Chemical Properties: Lab Project 

Number: SP-99043-A. Unpublished study prepared by Lonza, Inc. 30 p. {OPPTS 

830.6315, 830.7000, 830.7050, 830.7100, 830.7300}

MRID 45115305. Sarff, P.; Edgar, L. (1999) Boiling Point Determination of Lonzabac 12: Lab 

Project Number: SP-99005-A: 45066. Unpublished study prepared by ABC 

Laboratories, Inc. 14 p. {OPPTS 830.7220}

MRID 45115307. Sloan, R. (1999) Lonzabac 12-Stability to Normal and Elevated Temperatures, 

Metals and Metal Ions: Lab Project Number: SP-99010-A. Unpublished study 

prepared by Lonza Inc. 24 p. {OPPTS 830.6313}

MRID 45115308. Lonza, Inc.; Lewis and Harrison, LLC. (2000) Product Chemistry: Discussion 

of Physical and Chemical Properties: Lonzabac 12. Unpublished study. 7 p. {OPPTS 

830.6304, 830.6317, 830.6320}

MRID 45115309. Lonza, Inc.; Lewis and Harrison, LLC. (2000) Product Chemistry: Vapor 

Pressure for Lonzabac 12. Unpublished study. 8 p. {OPPTS 830.7950}

MRID 46309706. Sarff, P. (1999) Corrosion Characteristics of Lonzabac 12. Project Number: 

45065, SP/99004/A. Unpublished study prepared by ABC Laboratories, Inc. 15 p.

MRID 46332202. Sloan, R. (2000) Procedure for Determining Dodecylamine Content in 

Lonzaback 12. Unpublished study prepared by Lonza, Inc. 5 p.

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