Page 2 of 58 Propylene Glycol, Dipropylene Glycol and Triethylene Glycol Registration Review Team

Human Health

Nathan Mottl

Michelle Centra

William Hazel

Environmental Fate and Effects Siroos Mostaghimi

Srini vas Gowda Najm Shamim David Bays

Risk Management

Elizabeth Hernandez Andrew Bryceland

Office of General Counsel Philip RossPage 3 of 58 

### Table of Contents

1 Introduction

................................ ................................ ................................ ............................. 5

1.1 Statutory and Regulatory Authority

................................ ................................ ................. 5

1.2 Case Overview

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

1.3 Chemical Identification and Properties

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

1.4 Use/Usage Description

................................ ................................ ................................ ... 10

1.4.1 Registrations

................................ ................................ ................................ ........... 10

1.4.2 Summary of Registered Uses

................................ ................................ .................. 10

1.4.3 Usage Information

................................ ................................ ................................ .. 11

1.5 Regulatory History

................................ ................................ ................................ ......... 11

1.5.1 Recent/Pending Regulatory Actions

................................ ................................ ....... 11

1.5.2 Tolerance Information

................................ ................................ ............................ 11

1.6 Incidents

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

1.6.1 Human Health

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

1.6.2 Ecological

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

2 Anticipated Data Needs

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

3 Human Health Risk Assessment

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

3.1 Existing Toxicological Endpoints

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

3.2 Dietary Exposure

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

3.2.1 Food

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

3.2.2 Drinking Water

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

3.3 Occupational and Residential Exposures

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

3.3.1 Occupational Handler Exposure

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

3.3.2 Residential Handler Exposures

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

3.3.3 Occupational Post

- Application Exposures

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

3.3.4 Residential Post

- Application Exposures

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

3.4 Aggregate and Cumulative Exposure

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

3.4.1 Aggregate Exposures

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

3.4.2 Cumulative Expo sures

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

4 Environmental Risk Assessment

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

4.1 Environmental Fate Assessment

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

4.2 Conceptual Models for Environmental Exposure Pathways

................................ .......... 17

4.3 Ecological Effects Assessment

................................ ................................ ....................... 17

4.3.1 Mechani sm of Action

................................ ................................ .............................. 17

4.3.2 Measures of Effect (Ecotoxicology Endpoints)

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

4.4 Exposure Analysis Plan

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

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

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

4.5 Effects Analysis Plan

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

4. 5.1 Endangered Species Effects Determination

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

5 Endocrine Disruptor Screening Program (EDSP)

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

6 Guidance for Commenters

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

6.1 Preliminary Work Plan

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

6.1.1 Trade Irritants

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

6.1.2 Water Quality

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

6.1.3 Environmental Justice

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

6.1.4 Structure Activity Relationships

................................ ................................ ............. 22Page 4 of 58 6.1.5 Additional Information

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

7 Next Steps

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

8 References

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

Appendix A T oxicology Profile

................................ ................................ ............................... 34 Appendix B Product Chemistry

................................ ................................ ............................... 46 Appendix C Ecotoxicology Profile for Propylene Glycol and Dipropylene Glycol

............... 48 Appendix D Ecotoxicology Profile for Triethylene Glycol

................................ ..................... 55

List of Tables

Table 1

– Summary of Anticipated Risk Assessments and Data Needs: Propylene Glycol

.......... 6

Table 2

– Summary of Anticipated Risk Assessments and Data Needs: Dipropylene Glycol

...... 6

Table 3

– Summary of Anticipated Risk Assessments and Data Needs: Triethylene Glycol

....... 7

Table 4

– Anticipated R egistration Review Schedule

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

Table 5

- Chemical Identification of Triethylene, Propylene and Dipropylene Glycols

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

Table 6

– Physical

- Chemical and Fate Properties for Triethylene, Propylene and Dipropylene Glycols

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

Table 7

– Summary of Triethylene Propylene and Dipropylene Glycols Registered Uses

........... 10

Table 8

– Occupational Handler Exposure Scenarios for Triethylene, Propylene and Dipropylene Glycols

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

Table 9

– Residential Handler Exposure Scenarios for T riethylene, Propylene and Dipropylene Glycols

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

Table 10

– Occupational Post

- Application Exposure Scenarios for Triethylene, Propylene, and Dipropylene Glycols

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

Table 11

– Residential Post

- Application Exposure Scenarios for Triethylene, Propylene, and Dipropylene Glycols

................................ ................................ ................................ ..................... 16 Table 12 Selected Endpoints for Assessment of Pr opylene and Dipropylene Glycols

................ 18 Table 13 Selected Endpoints for Assessment of Triethylene Glycol

................................ ........... 19 Table 14 Acute Toxicity Profi le of Dipropylene Glycol

................................ .............................. 35 Table 15 Acute Toxicity Profile of Propylene Glycol

................................ ................................ .. 36

Table 16 A c u t e T o x i c i t y P r o f il e of T r i eth y l e n e G l y c ol

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

Table 17

– Product Chemistry of Triethylene, Propylene and Dipropylene Glycols

.................... 46 Table 18 Acute Oral Toxicity of Propylene and Dipropylene Glycol to Birds

........................... 48 Table 19 Toxicity of Propylene and Dipropylene Glycol to Mammals (excerpted from Appendix A)

................................ ................................ ................................ ................................ .................. 49 Table 20 Acute Toxicity of Propylene and Dipropylene Glycol to Freshwater Fish

.................. 49 Table 21 Acute Toxicity of Propylene/Dipropylene Glycol to Freshwater Invertebrates

........... 50 Table 22 Open Literature Freshwater Invertebrate Acute Toxicity Data for Propylene Glycol

. 51 Table 23 Acute Toxicity of Propylene Glycol to Inland Saltwa ter Lake Species

....................... 51 Table 24 Chronic Toxicity of Propylene Glycol and Dipropylene Glycol to Aquatic Animals

.. 52 Table 25 Toxicity o f Triethylene Glycol to Mammals (excerpted from Appendix A)

............... 55 Table 26 Acute Toxicity of Triethylene Glycol to Freshwater Fish

................................ ............ 55 Table 27 Open Literature Estuarine/Marine Fish and Invertebrate Acute Toxicity Data for Triethylene Glycol

................................ ................................ ................................ ........................ 56 Table 28 Chronic Toxicity of Triethylene Glycol to Aquatic Animals

................................ ....... 57Page 5 of 58 

## 1 Introduction

This document is the Environmental Protection Agency’s (EPA or “the A gency”) Preliminary Work Plan (PWP) for propylene glycol, dipropylene glycol and triethylene glycol. The PWP document explains what EPA's Office of P esticide Programs knows about propylene glycol, dipropylene glycol and triethylene glycol , 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 the propylene glycol, dipropylene glycol and triethylene glycol review.

Initially

, two separate Registration Review cases were scheduled to address t riethylene glycol ( Case 3146 ) and propylene glycol and dip ropylene glycol ( Case 3126 ). However, because of

their similar use p atterns

, comparable chemical, physical, and environmental fate characteristics

, low mammalian toxicity

, and low toxicity to non

- target aquatic and terrestrial organisms this

document wil l address propylene glycol (PC code 068603), diprop ylene glycol (PC code 068604), and triethylene glycol (PC code 083501)

. T he agency is grouping these active ingredients together and merging them into the Propylene Glycol, Dipropylene Glycol and Triethyl ene Glycol Registration Review case pursuant to 40 CFR Part 155.42(a) and 40 CFR Part 155.42(b)(4).

The registration review process was designed to include a public participation component to solicit input from interested stakeholders. The Agency intend s, by sharing this information in the docket, to inform the public of what it knows about propylene glycol, dipropylene glycol and triethylene glycol and what types of new data or other information would be helpful for the Agency to receive as it moves tow ard a decision on propylene glycol, dipropylene glycol and triethylene glycol

. The Agency encourages all interested stakeholders to review the PWP and to provide comments and additional information that will help the Agency’s decision

- making process for t his chemical.



## 1.1 Statutory and Regulatory Authority

The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distributed or sold in the United States generally must be registered by the U.S.

Environmental Protect ion Agency (USEPA, EPA, or the Agency) based on scientific data showing that they will not cause unreasonable risks to human health or the environment when used as directed on product labeling. The registration review program is intended to make sure

that , as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects to human

health or the environment. Changes in science, public policy, and p esticide 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 provide d at http://www.epa.gov/oppsrrd1/registration_review/

.

The Agency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticid e Act (FIFRA) and will review each registeredPage 6 of 58 pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration. The regulations governing registration review begin at 40 CF R 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the Agency’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. After reviewing and responding to comments and data received in the docket during this initial comment period, the Agency will develop and commit to a F inal W ork P lan ( FWP) and anticipated schedule for the Propylene Glycol, Dipropylene Glycol and Triethylene Glycol Case.

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

in docket s EPA

- HQ

- OPP

- 2013

- 0218 and EPA

- HQ

- OPP

- 2013

- 0219

. Below is a summary of the issues relevant to this registration review case.

Table 1

– Summary of Anticipated Risk Assessments and Data Needs : Propylene Glycol

Risk Assessment Assessment Necessary to Support Registration

Review Date of

Most

Recent

Assessment Type of

Assessment Required (New/Updated) Data Anticipated as Needed

Dietary (food) No (See 3.2.1) 2/5/2007 None None

Dietary (drinking water) No (See 3.2.2) 2/5/2007 None None

Occupational Handler No (See 3.3.1) 2/ 5/2007 None None

Residential Handler No (See 3.3.2) 2/5/2007 None None

Residental Post Application No (See 3.3.3) 2/5/2007 None None

Aggregate No (See 3.4.1) 2/5/2007 None None

Cumulative No (See 3.4.2) 2/5/2007 None None

Tolerance Review No (See 1.5.2) 2/5/2007 Updated None

Ecotoxicity No (See 4.3) 2/5/2007 None None

Table 2

– Summary of Anticipated Risk Assessments and Data Needs : Dipropylene Glycol

Risk Assessment Assessment Necessary to Support Registration

Revie w Date of

Most

Recent

Assessment Type of

Assessment Required (New/Updated) Data Anticipated as Needed

Dietary (food) No (See 3.2.1) 2/5/2007 None None

Dietary (drinking water) No (See 3.2.2) 2/5/2007 None None

Occupational Handler No (See 3.3.1) 2/5/2007 None None

Residential Handler No (See 3.3.2) 2/5/2007 None None

Residental Post Application No (See 3.3.3) 2/5/2007 None NonePage 7 of 58 Risk Assessment Assessment Necessary to Support Registration

Revie w Date of

Most

Recent

Assessment Type of

Assessment Required (New/Updated) Data Anticipated as Needed

Aggregate No (See 3.4.1) 2/5/2007 None None

Cumulative No (See 3.4.2) 2/5/2007 None None

Tolerance Review Ye s (See 1.5.2) 2/5/2007 None None

Ecotoxicity No (See 4.3) 2/5/2007 None None

Table 3

– Summary of Anticipated Risk Assessments and Data Needs : Triethylene Glycol

Risk Assessment Assessment Necessary to Support Registration

R eview Date of

Most

Recent

Assessment Type of

Assessment Required (New/Updated) Data Anticipated as Needed

Dietary (food) No (See 3.2.1) 1/25/2006 None None

Dietary (drinking water) No (See 3.2.2) 1/25/2006 None None

Occupational Handler No (See 3.3.1) 1/25/2006 None None

Residential Handler No (See 3.3.2) 1/25/2006 None None

Residental Post Application No (See 3.3.3) 1/25/2006 None None

Aggregate No (See 3.4.1) 1/25/2006 None None

Cumulative No (See 3.4.2) 1/25/2006 None None

Toleran ce Review No (See 1.5.2) 1/25/2006 None None

Ecotoxicity No (See 4.3) 1/.25/2006 None None

Table 4

– Anticipated Registration Review Schedule

Anticipated Activity Target Date * Completion Date Phase 1: Opening the Docket

O pen Docket and 60

- Day Comment Period for Preli minary Work Plan 2013

- 06 2013

- 06

- 20

Close Public Comment Period 2013

- 08 Phase 2: Case Development

Issue Final Work Plan 2013

- 12

Issue Data Call

- In (DCI) N/A

Receive Data to be Considered in Risk Assessment N/A Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) N/A

Close Public Comment Period N/A Phase 3: Registration Review Decision and Implementation Open 60

- Day Public Comment Period for Pro posed Decision 2014

- 12

Close Public Comment Period 201 5

- 02

Issue Final Decision 2015

- 06 Begin Post

- Decision Followup 2016

- 01Page 8 of 58 Anticipated Activity Target Date * Completion Date Total (years) 2 .5

* The anticipated schedule will be revised as necessary ( e.g. , need arising under the Endocrine Disruptor Screening Program w ith respect to the active ingredients in this case).



## 1.2 Case Overview

The docket for the p ropylene g lycol, d ipropylene g lycol and t riethylene g lycol Case (Case 3126 & 3146) has been established at http://www.regulation s.gov in docket numbers EPA

- HQ

- OPP

2013

- 0218 and EPA

- HQ

- OPP

- 2013

- 0219.

Initially, separate Registration Review cases were scheduled to address triethylene glycol ( Case

3146 ) and propylene glycol and dipropylene glycol (Case 3126). However, because of th eir similar use p atterns

, comparable chemical, physical, and environmental fate characteristics

, low mammalian toxicity and low toxicity to non

- target aquatic and terrestrial organisms , this

document will address propylene glycol (PC code 068603), dipropyl ene glycol (PC code 068604), and triethylene glycol (PC code 083501)

. The agency is grouping these active ingredients together and merging them into the Propylene Glycol, Dipropylene Glycol and Triethylene Glycol Registration Review C ase.

According to th e 2011

- 2014 public Registration Review schedule, case s 3146 and 3126 were

p lanned to begin in fiscal year 2013

. To ensure the public is able to locate infor mation associated with case 3146 and case 3126, EPA has created and will maintain a separate docket

for each case. All EPA documents relevant to the two cases will be posted in the two dockets.

This case will be referred to as the Propylene Glycol, Dipropylene Glycol and Triethylene Glycol Case . As a result of this grouping and merger, the Propylene G lycol, Dipropylene Glycol and Triethylene Glycol C ase will now include:

1. Case 3146 : triethylene glycol (PC code 083501) ;

2. Case 3126: propylene glycol (PC code 068603) and dipropylene glycol (PC code 068604)



## 1.3 Chemical Identification and Properties

Table 5 presents the active ingredients to be assessed in Case 3146: t riethylene g lycol (PC Code 083501); and Case 3126 : p ropylene g lycol (PC Codes 068603) d ipropylene g lycol (PC Code 068604).

Table 5

- Chemi cal Identification of Triethylene

, Propylene and Dipropylene Glycol s

Common

Name Triethylene Glycol Propylene Glycol Dipropylene Glycol

Classifica tion Glycol Dihydroxy alcohols Oxygenated Hydrocarbon Glycol Dihydroxy alcohols Glycol Dihydroxy alcohols Oxygenated hydrocarbon

Case # 3146 3126 3126Page 9 of 58 Common

Name Triethylene Glycol Propylene Glycol Dipropylene Glycol

PC Code 083501 068603 068604

CAS No. 112

- 27

- 6 57

- 55

- 6 25265

- 71

- 8

Case No. 3146 3126 3126

Molecular

Formula C 6 H 14 O 4 C 3 H 8 O 2 C 6 H 14 O 3

Molecular Weight 150.17 g/mol 76.09 g/mol 134.20 g/mol

Molecular

Structure:

Triethylene glycol, p ropylene glycol and d ipropylene glycol product chemistry information

re levant to the risk assessment is summarized in Table 6 and more detailed product chemistry

information is provided in Appendix B

. Sources of information used to construct Table 6 consist

of MRIDs 42814401, 42814402, 42814403, 43178601, 431786 03, 43179501, 43179502, 43179503, and EPI Suite v4.1

.

Table 6

– Physical

- Chemical and Fate Properties for Triethylene, Propylene and Dipropylene Glycols

Guideline

No. Property Triethylene Glycol Propylene Glycol Dipropylene Glycol

830.7000 pH 6.0

- 9.5 Neutral Neutral

830.7050 UV/Visible Absorption Does not absorb light at wavelengths >290 nm

and therefore it is not expected to be susceptible to direct photolysis by sunlight. Does not absorb light at wavelengths >290 nm and

the refore it is not expected to be susceptible to direct photolysis by sunlight. Does not absorb light at wavelengths >290 nm and therefore it is not expected to be susceptible to direct photolysis by sunlight.

830.7200 Melting point:

Freezing point: Not applicable. Product is liquid at room

temperature.

− 4.3°C to −7 °C Not applicable. Product is liquid at room

temperature.

− 59°C Not applicable. Product is liquid at room

temperature.

− 59°C

830.7220 Boiling point 288.0°C at 760 mm Hg. 188 °C at 760 mm Hg 230 o C at 760 mm Hg

830.7300 Density 1.1255 g /mL at 25°C 1.032 g/ mL at 25°C 1.022 g/ mL at 25 o C

830.7370 Dissociation Constant ( pKa ) Not applicable. Does not

dissociate in water. Not applicable. Does not

dissociate in water. Not applicable. Does not

dissociate in water.

830.7550 Partition coe fficient (Log Kow ) − 1.75

− 0.92

− 0.67

830.7840 Solubility in water Completely soluble. Completely soluble. Completely soluble.

830.7950 Vapor pressure ( at 25°C ) 1.32 x10 - 3 mm Hg 1.3 x10 - 1 mm Hg 1. 6 x10 - 2 mm Hg

Henry law constant (atm

- m 3 /mole) 3 x 10 - 11 1.29 x 10 - 8 6.58 x 10 - 13

Ready Biodegradation YES YES YES

Stability in air (hours) 3.5 10 4Page 10 of 58 Guideline

No. Property Triethylene Glycol Propylene Glycol Dipropylene Glycol

Koc (L/kg) 0.089 1 0.45

NG STP removal (%) ~ 2 ~ 2 ~ 2

NG Effluent (%) 98 98 98

NG: non

- guideline information



## 1.4 Use/Usage Description

1.4.1 Registrations

There are two EPA

- registered products that contain propylene glycol as an active ingredient (a.i.). The percent a.i. in both products is 4.4% and the formulations include pres surized liquids in aerosol cans and automatic aerosol dispenser

. There is no propylene glycol man ufacturing use product

.

There are two EPA

- registered products that contain dipropylene glycol as an a.i. The percent a.i. in the products is 4.4% and 5.31% and the formulations include pres surized liquids in aerosol cans and automatic aerosol dispenser

. There is no di propylene glycol manufacturing use product

.

There are 18 EPA

- registered products that contain triethylene glycol as an a.i. The percent a.i. ranges from 0.05 % to 86 % and the formulations include pressurized liquids in aerosol cans

, automatic aerosol dispenser , and total release foggers

. There is no triethylene glycol manufacturing use product.



### 1.4.2 Summary of Registered Uses

Table 7 presents a summary of the registered uses of t riethylene glycol, propylen e glycol and dipropylene glycol that will be assessed in this registration review

. Triethyl ene, propylene and dipropylene g lycols can be applied by the following application methods: a erosol c an, a utomatic

a erosol d ispenser, and t otal r elease f ogger

.

Tabl e 7

– Summary of Triethylene Propylene and Dipropylene Glycols Registered Uses

Use Application Method Application

Rate

Commercial, Industrial, Institutional, Premises and Equipment

Space spray and s urface t reatment Aerosol can a nd a utomatic a erosol d ispenser See f ootnote 1

Food Handling/Storage Establishments Premises and Equipment 2

Space s pra y and surface t reatment Aerosol can and a utomatic a erosol d ispens e r See f ootnote 1

Reside ntial and Public Access Premises

Aerosol, f og , s pace spray and s urface Aerosol can, automatic aerosol dispenser, and total See f ootnote 1

1 Many of the aerosol labels specify a surface spray to spray until completely wet for 10 minutes; many labels specify to spray upward in center of room for 3

- 10 seconds in a room of average size 12 by 12 feet.

2 Dipropylene glycol is the only ch emical in this case that has currently registered food uses.Page 11 of 58 treatment release fogger

Medical/Dental/Veterinary Premises and Equipm ent

Space spray and surface t reatment Aerosol can and a utomatic aerosol dispenser, See footnote 1



### 1.4.3 Usage Information

Usage information is not available for the propylene glycol, dipropylene glycol or trieth ylene glycol

. T he Kline Biocides Report for 2004/2005 (Kline, 2005) does not include propylene glycol, dipropylene glycol or triethylene glycol

.



## 1.5 Regulatory History

Propylene glycol and dipropylene glycol were first registered in 1950 and 1959, respective ly

, for use in hospitals as air disinfectants. The Agency completed a Reregistration Eligibility Decision (RED) for propylene glycol and dipropylene glycol in 2006

.

Triethylene glycol was first registered in 1947 for use in hospitals as an air disinfectan t. The Agency completed a RED for triethylene glycol in 2003.



### 1.5.1 Recent/Pending Regulatory Actions

There are no recent regulatory actions for propylene glycol, dipropylene glycol or triethylene glycol.



### 1.5.2 Tolerance Information

EPA has not established a tolera nce or tolerance exemption for residues of propylene glycol, dipropylene glycol or triethylene glycol in food resulting from registered uses as an active ingredient. Based on the current uses for dipropylene glycol, the agency has identified the need

to es tablish a tolerance and/or exemption from the requirement of a tolerance in 40 CFR Section 180. As part of this registration review, EPA intends to establish the appropriate tolerance and/or exemption in response to the petitions expected to be received fr om registrants supporting the following uses for dipropylene glycol: hard nonporous food service use sites. Triethylene glycol and propylene glycol are not used as active ingredients in currently registered food use products. Therefore, tolerances and/or exemptions are not needed for triethylene glycol and propylene glycol. EPA has established exemptions from the requirement of a tolerance when propylene glycol is used as an intentionally

- added inert ingredient (solvent or cosolvent) in pesticide

formulat ions (40 CFR 180.910 and 180.930). Dipropylene glycol has been exempted from the requirement of a tolerance when used as an intentionally

- added inert ingredient (solvent or cosolvent) in pesticide formulations (40 CFR 180.910). Triethylene glycol is exempt ed from the requirement of a tolerance when used as an intentionally

- added inert ingredient (deactivator) in pesticide formulations (40 CFR 180.920). Propylene glycol has been classified as Generally Recognized as Safe (GRAS) by FDA in association with sev eral uses: as an emulsifying agent (21 CFR 582.4666), as a general purpose food additive (21 CFR 582.1666), and as a direct food additive (21 CFR 184.1666). Dipropylene glycol and triethylene glycol are the subject of thePage 12 of 58 following indirect food additive regulations: components of adhesives (21 CFR 175.105), components of paper and paperboard in contact with aqueous and fatty foods (21 CFR 176.170), surface lubricants used to make metallic food contact articles (21 CFR 178.3910), defoaming agent used in c oatings (176.200), as a component of cellophane (21 CFR 177.1200), in packaging materials for food to be irradiated (21 CFR 179.45), as components of resinous and polymeric coatings (21 CFR 175.300), as adjuvants and production aids as plasticizers in poly meric substances (21 CFR 178.3740), and as an optional adjuvant in resinous and polymeric coatings for polyolefin films. No Food Contact Substance Notifications (FCNs) have been determined to be effective by FDA for propylene glycol, dipropylene glycol or triethylene glycol.



## 1.6 Incidents

1.6.1 Human Health

No reports of incidents associated with human exposure to propylene glycol and/or dipropylene glycol have been reported in the OPP Incident Data System during the time period from 2001 to
2012

.

However, for triet hylene glycol, there are 413 incidents which have been reported in the OPP Incident Data System (2001

– 2012) which have been specifically associated with exposure to triethylene glycol. However, triethylene glycol is a high production volume chemical with approximately 5,000,000 pounds produced from 2004 to 2012 for pesticide products. Given the high production volume of the chemical and the 11 year period of which incidents occurred, the

number of incidents is not unusual

. Inhalation exposure is the pri mary exposure route in these reported cases followed by dermal exposure. Most of the inciden ts are related to inhalation irritation and/or allergic

- type reaction. For inhalation exposure incidents, the reported symptoms include respiratory irritation, co ughing, chest tightness, difficulty breathing, shortness of breath and wheezing. For dermal exposure, blisters, hives, welts, rash, and bleeding have been reported. In addition, ocular irritation and fever have also been reported.



### 1.6.2 Ecological

No ecologica l incidents reported for triethylene glycol , propylene glycol and dipropylene glycol

from 2001

- 2012 (IDS).



## 2 Anticipated Data Needs

No data are anticipated to be needed to support a human health or environmental risk assessment

for the t riethylene glycol, pr opylene glycol and dipropylene glycol registration review

.



## 3 Human Health Risk Assessment

The a gency does not anticipate the need to conduct a human health risk assessment for

t riethylene

, p ropylene and d ipropylene g lycols . The a gency does not expect to requ ire additional data for use in conducting the registration review. According to the triethylene glycol RED and propylene and dipropylene glycol RED , p otential for dermal , inhalation, or incidental ingestionPage 13 of 58 exposure may occur during application of the gly cols as well as post

- application following use of glycols may occur following air sanitiz ation, h ard surface disinfect ion and direct use on pets.
However, t here is no evidence of adverse effects at doses of triethylene glycol , propylene glycol or dipropyl ene glycol up to the established limit dose in repeat

- exposure dermal (1000 mg/kg/day) and inhalation (1 mg/L or 1000 mg/m 3 ) toxicity studies . Thus, no toxicological endpoints of concern have been established for either of these chemicals based on review of the available mammalian toxicity data. D ue to the low order of toxicity and low application rates from the current uses of these chemicals, no risks associated with potential exposures have been quantified for use of triethylene glycol, propylene glyco l or dipropylene glycol as active ingredient s in pesticide products

.



## 3.1 Existing Toxicological Endpoints

In the September 2006 Propylene Glycol and Diproylene Glycol RED and the September 2003 Triethylene Glycol RED, the Agency concluded that propylene gly col, dipropylene glycol, and triethylene glycol pose no toxicological concerns due to their low toxicity ; therefore, no toxicological endpoints of concern were developed. Based on a review of the available toxicity

data (see Appendix A) , the a gency conclud e s that for registration review these chemicals pose no toxicological concerns when used according to pesticide labeled uses

. No additional toxicity data requirements are anticipated at this time for registration review. This conclusion is based on

the re sults of toxicity testing of propylene glycol and dipropylene and triethylene glycol at dose levels near or above testing limits (as established in the OPPTS 870 series harmonized test guidelines). No significant toxicity was observed in any of the animal toxicity studies in the existing toxicological database for registration review. A detailed description of the toxicity

studies for triethylene glycol, propylene glycol and dipropylene glycol for registration review is provided in Appendix A

.



## 3.2 D ietary Exposure

3.2.1 Food

Although h uman dietary exposure to the subject glycols could potentially occur as a result of the registered use s, there is no risk associated with these related compounds because they do not induce adverse systemic effects except at doses much higher than could be expected from pesticidal uses (EPA 2013a and 2013b)

. As part of this registration review, EPA intends to

esta blish the appropriate tolerance and/or exemption in response to the petitions expected to be

rec eived from registrants supporting the following uses for dipropylene glycol : hard nonporous

food service use sites

. Triethylene glycol and propylene glycol are not used in currently registered food use products

. T herefore, tolerance s and/or exemption s are not needed for triethylene glycol and propylene glycol

.



### 3.2.2 Drinking Water

Although h uman dietary exposure via drinking water to the glycols may occur as a result of the registered use s, there is no risk associated with these related compounds because they do not induce adverse systemic effects except at doses much higher than could be expected from pesticidal uses (EPA 2013a and 2013b) . Therefore, no additional data are anticipated to bePage 14 of 58 needed and dietary risk assessments reflecting exposures to the glycols in drinking water are not expected to be necessary

.



## 3.3 Occupational and Residential Exposures

The a gency does not anticipate that a new occupational and residential risk assessment will be

need ed based on the lack of toxicological endpoints. N o toxicological endpoints of concern have

been established for either of these chemicals based on review of the available mammalian toxicity data. D ue to the low order of toxicity and low application rates from the current uses of these chemicals, no risks associated wit h potential exposures have been quantified for use of triethylene glycol, propylene glycol or dipropylene glycol as active ingredients in pesticide products

. The earlier risk assessments for propylene and dipropylene glycol completed in February 5, 2007 a nd triethylene glycol on May 24, 2005 do not need to be updated (EPA 2007a and EPA 2005)

.



### 3.3.1 Occupational Handler Exposure

The agency does not anticipate the need to revise the occupational handler assessments that were already conducted during reregistratio n

. Although there is p otential for occupational dermal and/or inhalation exposure , no toxicological endpoints of concern were identified. Therefore no

risk assessments can be conducted or are anticipated as needed

.

Potential exposure may occur during app lication of the glycols as well as post

- application following air sanitization, hard surface disinfection, and direct use on pets. No chemical

- specific handler data were submitted to estimate the potential exposures associated with these uses of triethylen e, propylene and dipropylene glycol (nor are they anticipated as needed at this time since a risk assessment cannot be conducted without toxicological endpoints ).

Table 8

– Occupational Handler Exposure Scenarios for Triethylene, P ropylene and

D ipropylene G lycol s

Scenario Exposure Route(s) Duration

Occupational Exposures

Applying disinfectant spray to hard surfaces and the air using an aerosol can Dermal / Inhalation Short, Intermediate, and Long Term

Applying disinfectant s pray to the air using an automatic aerosol dispenser Inhalation Short, Intermediate, and Long Term

Applying disinfectant to the air using t otal release foggers or misters Inhalation Short and Intermediate Term



### 3.3.2 Residential Handler Exposures

EPA does not a nticipate the need to revise the residential handler assessment conducted in support of reregistration. Potential for residential dermal and/or inhalation exposure may occur during application of the glycols as well as post

- application following air saniti zation, hard surface disinfection, and direct use on pets

. No chemical

- specific handler data were submitted to estimate the potential exposures associated with these uses of triethylene, propylene and dipropylene glycol (nor are they anticipated as needed at this time since a risk assessment cannotPage 15 of 58 be conducted without toxicological endpoints). However, because no toxicological endpoints of concern were identified, the exposures have not been quantified and no handler data were required in the RED and none are anticipated as needed for registration review

.

Table 9

– Residential Handler Exposure Scenarios for Triethylene, P ropylene and

D ipropylene Glycols

Scenario Exposure Route(s) Duration

Residential Exposures
Applying disinfec tant spray to hard surfaces and the air using an aerosol can Dermal / Inhalation Short and Intermediate

Term
Applying disinfectant spray to the air using an automatic aerosol dispenser Inhalation Short and Intermediate

Applying disinfectant to the air us ing total release foggers or misters Inhalation Short and Intermediate

Term



### 3.3.3 Occupational Post

- Application Exposures

Potential for occupational post application exposure may occur to individuals reentering treated rooms and/or contacting sprayed surfaces

. Disinfectant properties are utilized in the household for hard, nonporous surfaces including windows, shower stalls, countertops, refrigerators, microwave ovens, and tubs ( i.e. , non

- food contact surfaces). As an air sanitizer, this active ingredient has numerous listed active use sites including industrial/institutional use in washrooms, auditoriums, public rooms, hotel lobbies, theaters, hospitals, classrooms, railroads, airplanes, buses, taxicabs, sitting rooms, locker rooms, factories, mills, and depar tment stores. However, because no toxicological endpoints of concern were identified, the exposures have not

been quantified and no post application data were required during reregistration and none are anticipated as needed for registration review.

Tab le 10

– Occupational Post

- Application Exposure Scenarios for Triethylene, Propylene, and Dipropylene Glycols

Scenario Exposure Route(s) Duration

Post application exposure bystanders to aerosols and vapors released from

air deodori zing treatments Inhalation Short and Intermediate

Term



### 3.3.4 Residential Post

- Application Exposures

Potential for residential post application exposure may occur to individuals reentering treated rooms and/or contacting sprayed surfaces

. Disinfectant propertie s are utilized in the household for hard, nonporous surfaces including windows, shower stalls, countertops, refrigerators, microwave ovens, and tubs ( i.e. , non

- food contact surfaces). Children could become exposed to

residues from hand

- to

- mouth or from der mal contact. As an air sanitizer, this active ingredient

has numerous listed active use sites in bathrooms

. However, because no toxicological endpoints of concern were identified, the exposures have not been quantified and no post application data

were r equired during reregistration and none are anticipated as needed for registration review

.Page 16 of 58 Table 11

– Residential Post

- Application Exposure Scenarios for Triethylene, Propylene, and Dipropylene Glycols

Scenario Exposure Route(s) Du ration
Postapplication exposure to children from dermal and hand

- to

- mouth

contact from treated floors. Incidental ingestion/dermal Short and Intermediate

Term

Post application exposure bystanders to aerosols and vapors released from air deodorizing treat ments Inhalation Short and Intermediate

Term



## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

In examining aggregate exposure, EPA takes into account the available and reliable information concerning exposures to pesticide residues in food and drink ing water, and non

- occupational pesticide exposures. An aggregate risk assessment cannot be conducted because toxicological endpoints for propylene glycol, dipropylene glycol, and triethylene glycol have not been

established.



### 3.4.2 Cumulative Exposures

Unlike o ther 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 propylene glycol, dipropylene glycol, and triethylene glycol and any other substanc es . 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 the policy statements released by EPA’s Office of Pesticide Programs concerning comm on mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on

EPA’s website at http://www.epa.gov/pesticides/cumulative/.



## 4 Environmental Risk A ssessment

T he agency does not anticipate the need to conduct an environmental risk assessment for

t riethylene glycol, p ropylene glycol and d ipropylene g lycol because the indoor air and surface disinfection uses with the given application methods are not ex pected to result in exposure of terrestrial or aquatic organisms. No changes to the use patterns have occurred for the glycols since the Propylene and Dipropylene Glycol RED or the Triethylene Glycol RED (See Section

1.5.1 ). There are new models and approaches that the agency has been implementing since the publication of these REDs. Application methods using aerosol cans, automatic aerosol dispensers, and foggers are not expected to result in down

- the

- drain disposal and ther e is no direct exposure to non

- target organisms

. The agency does not anticipate requiring additional

data for this registration review.



## 4.1 Environmental Fate Assessment

The Agency does not anticipate requiring additional environmental fate data at this tim e because triethylene glycol, dipropylene glycol and propylene glycol are not persistent in the environment

.Page 17 of 58 In 2003, the Agency issued a n Ecological Risk A ssessment for triethylene g lycol which

concluded : “T riethylene glycol is miscible in water, mobile in soils, and stable to abiotic hydrolysis, as well as soil and aquatic photolysis. River dye

- away t ests indicate that triethylene glycol degrades in soils from a few days to weeks. It undergoes ready biodegradation, according

t o the activated sludge stu dies.” In 2006, t he Agency completed a n Ecological Risk Assessment for propylene glycol and dipropylene g lycol. In its fate assessment, t he Agency concluded that “ Propylene glycol and dipropylene g lycol are miscible in water, mobile in soils, have low

ab sorp tivity to soil, and are stable to abiotic hydrolytic degradation as well as it does not undergo abiotic photodegradation in soil and in water

. However, in aerobic soils propylene glycol

bio degrades to carbon dioxide ( CO 2 ) in 4 days, whereas biodegrada tion of dipropylene glycol may be a slightly slower process according to biological (biodegradability) screening tests. However, this process may still be an important mechanism for removal of dipropylene glycol

from aerobic soil s.” The physical and chem ical properties and fate data are summarized in Table

6

.

The low K

ow of

- 1.75,

- 0.92 and

- 0.67 for triethylene glycol, propylene glycol and

, dipropylene glycol , respectively, are not lik ely to bioaccumulate in aquatic organisms. With a vapor pressure

of 0.00132 mmHg at 25 o C

, 0.1 3 mm Hg and 1.6 x10 - 2 mm Hg at 25 o C, for triethylene glycol, propylene glycol and dipropylene glycol , respectively, these glycols would exist in large part in the vapor phase in the atmosphere but degrade rapidl y (half

- life approximately between 3.5 to 10 hours) by reaction with photo

- chemically produced hydroxyl radicals. Therefore, t he presence of triethylene glycol, propylene glycol, dipropylene glycol in the environ ment, including the atmosphere, will be transient and not persistent

.

Additional fate parameters obtained from the Agency’s EPI Suite v 4.1 estimation program indicate that these glycols have low K

oc values of 1, 0.45 and 0.089 which make them have a high mobility in soils; but as observed earlier, these glycols degrade fast in soils. All three glycols are ready biodegradable and dye

- away test ing shows these glycols have a tendency to mineralize within a few days to two weeks. Because of their high solubility in water from 811 to 1000 g/L , these glycols will not likely be adsorbed to sediments. The Agency does not anticipate requiring additional environmental fate data at this time for this registration review

.



## 4.2 Conceptual Model s for Environmental Exposure Pathways

All registered pesticid e uses of propylene glycol, dipropylene glycol and triethylene glycol as active ingredients are considered to have no exposure to non

- target organisms

. The indoor air and surface disinfection using aerosol cans, automatic aerosol dispensers, and foggers a s application methods are not expected to result in down

- the

- drain disposal and as a result, there is no direct exposure to non

- target organisms. The lack of exposure means, except for spills or accidental releases, there is no ecological risk of concern from their use.



## 4.3 Ecological Effects Assessment

4.3.1 Mechanism of Acti on

Propylene glycol, dipropylene glycol and triethylene glycol are all alcohols and dipropylene glycol and triethylene glycol are also esters . They inactivate target pests by denaturing p roteins found in cell membranes and viral protein coats. This leads to the target pests losing structuralPage 18 of 58 integrity and losing t he ability to cause infections (USEPA, 2004, 2006b)

. For non

- target aquatic

animals , these chemicals act acutely by narcosis, a non

- specific mechanism of action.



### 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

Propylene glycol and dipropylene glycol show very low acute toxicity to terrestrial and aquatic

animals ( Table 12 and Appendix C) . The toxicity end points presented below are based on the results of toxicity studies submitted by registrants to meet the Agency’s ecological effects data requirements for the uses of propylene glycol and dipropylene glycol. Additional information

was located in EPA/ORD’s ECOTOX database, which provides summary endpoints from the open scientific literature as well as studies submitted to the Agency . For missing data, the structure activity program ECOSAR v1.10 was used to estimate endpoint values

. While ECOSAR v1.10 pr ovided estimates for chronic fish and invertebrate endpoints

, these results

, while in Appendix C

, are not in Table 12 because they are not required for the assessment.

Table 12 Selected Endpoints for Assess ment of Propylene and Dipropylene Glycol s

Receptor Group Surrogate Species Risk

Scenario Toxicity Endpoint a Reference (MRID)

Birds Northern

bobwhite quail Acute oral LD 50 >2

, 000 mg/kg

- bw 43762301

43760607 Subacute dietary Data not required

-- Chroni c Data not required

--

Mammals Rat Acute LD 50 >5,000 mg/kg

- bw See Appendix A

Chronic Data not required

Freshwater fish Fathead

minnow Acute 96

- hr LC 50 = 790 ppm propylene glycol ECOSAR v1.10 See Appendix C

Chronic Data not required

--

Freshwater

invertebrates Waterflea Acute 48

- hr EC 50 > 100 ppm a Several MRIDs see Appendix C

Chronic Data not required

-- Estuarine/marine

fish Generic fish Acute 96

- hr LC 50 > 24,000 ppm a ECOSAR v1.10 See Appendix C Chronic Data not required

Estuarine/marine

invertebrates Eastern

O yster Acute Data not required

--

Mysid Acute 96

- hr LC 50 >100,000 ppm a ECOSAR v1.10 See Appendix C Chronic Data not required

Aquatic Plants Green algae Nonlisted species 96

- hr IC 50 >5,000 ppm a ECOSAR v1.10 See Appendix C L isted Species 96

- hr Chv >300 ppm a

a For definitive values see Appendix C. Non

- definitive values are provided in the table to show that both chemicals have low toxicity, and are considered potentially non

- toxic. For the propylene and dipropylene gylcol uses, green algae data and acute animal data were required only for hazard labeling purposes . No risk assessment is anticipated.

Triethylene glycol show very low acute toxicity to terrestrial and aquatic animals ( Table 13 and App endix D) . The toxicity endpoints presented below are based on the results of toxicity studies submitted by registrants to meet the Agency’s ecological effects data requirements for the uses of triethylene glycol. Additional information was located in EPA /ORD’s ECOTOX database, which provides summary endpoints from the open scientific literature as well as studies submitted to the Agency . For missing data, the structure activity program ECOSAR v1.10 was used to estimate endpoint values

. However, t he ECOS AR v1.10 neutral organics model may not be appropriate for triethylene gylcol. Estimates of acute values were higher than actualPage 19 of 58 laboratory studies in some cases. While ECOSAR v1.10 provided estimates for chronic fish and invertebrate endpoints

, these re sults

, while in Appendix D

, are not in Table 13 because they are not required for the assessment.

Table 13 Selected Endpoints for Assessment of Triethylene Glycol

Receptor Group Surrogate Species Risk

Scen ario Toxicity Endpoint a Reference (MRID)

Birds Northern

bobwhite quail Acute oral None None Subacute dietary Data not required

-- Chronic Data not required

--

Mammals Rat Acute LD 50 = 1 5,000 mg/kg

- bw See Appendix A

Chronic Data not required

F reshwater fish Bluegill

sunfish Acute 96

- hr LC 50 = 10,000 ppm Verschuren, 1983

Chronic Data not required

--

Freshwater

invertebrates Waterflea Acute 48

- hr EC 50 =116,000 ppm a ECOSAR v1.10 See Appendix D

Chronic Data not required

-- Estuarine/marine

fish Inland

Silverside Acute 96

- hr LC 50 = 10 ,000 ppm Verschuren, 1983 Chronic Data not required

Estuarine/marine

invertebrates Eastern

O yster Acute Data not required

--

Mysid Acute 96

- hr LC 50 = 11,000 ppm 40228401 Chronic Data not required

Aqu atic Plants Green algae Nonlisted species 96

- hr IC 50 = 67,640 ppm ECOSAR v1.10 See Appendix C Listed Species 96

- hr Chv = 2,486 ppm



## 4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Since the agency does not anticipating condu cting an environmental risk assessment, no exposure analysis plan is needed. The agency does not anticipate exposure of aquatic and terrestrial organisms.



## 4.5 Effects Analysis Plan

Since the agency does not anticipating conducting an environmental risk asses sment, no effects analysis plan is needed.



### 4.5.1 Endangered Species Effects Determination

Based on the low likelihood of exposure of triethylene glycol, dipropylene glycol and propylene glycol in various environment al media like water, soils, and air

, the Agency intends to conclude that the registered uses of triethylene glycol, dipropylene glycol and propylene glycol will have

'no effect' on endangered or threatened terrestrial or aquatic species, or their designated critical habitats, as listed by the U.S. Fis h and Wildlife Service (USFWS) and the National Oceanic and Atmospheric Administration's (NOAA) National Marine Fisheries Service (NMFS). EPA anticipates conducting no further analysis of potential risks to endangered or threatened speciesPage 20 of 58 unless public c omment or other submissions provide data or information that would otherwise

inf orm the Agency's determination. However, the Agency will review any comments made by the public on this document and will conduct an environmental risk assessment if new

inform ation warrants such action.



## 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 a nd 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 tar get organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, d evelopmental and reproductive effects in different taxonomic groups. As part of reregistration decision , for propylene glycol, dipropylene glycol and triethylene glycol

, EPA re viewed these data and selected the most sensitive endpoints for

relevant risk as sessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), propylene glycol, dipropylene glycol and triethylene glycol are 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 effec ts 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 es trogen, 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 whi ch, 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 iner t ingredients. P ropylene glycol, dipropylene glycol and triethylene glycol are not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for p ropylene glycol, dipropylene glycol and triethylene glycol

.

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists , the test guidelines and the Tier 1 screening battery, please visit our

website: http://www.epa.gov/endo/

.Page 21 of 58 

## 6 Guidance for Commenters

6.1 Preliminary Work Plan

The public is invited to comment on EPA’s Preliminary Work P lan and rationale. The Agency will carefully consider all comments as well as any additional information or data provided in a timely manner prior to issuing a final work plan for the P ropylene G lycol, D ipropylene G lycol

and T riethylene G lycol registration review case.



### 6.1.1 Trade Irritants

Through the registration review process, the Agency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The Agency

will work to harmonize toleran ces and international maximum residue limits (MRLs) and may modify tolerance levels to do so, when possible. Stakeholders are asked to comment on any trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and MRLs in key e xport markets, providing as much specificity as possible regarding the nature of

the concern.



### 6.1.2 Water Quality

Glycols, specifically ethylene glycol and propylene glycol (one of the three glycols in the present case) are identified as a ca use of impairment o f Yeader Creek, Polk County in De s Moines,

Iowa. This water body is listed as impaired under section 303(d) of the Clean Water Act 3

. Yeader Creek is across the De s Moines International Airport where the use of ethylene glycol for deicing of planes occurs . All sites listed for pesticides and organics were reviewed and only this site was identified as impaired. Total Maximum Daily Load ( TMDL ) for De s Moines

International A irport to Yeader Creek for ethylene glycol was: 125 mg/L (30

- day average), and

190 m g/L for daily maximum. TMDL for propylene glycol was: 100 mg/L (30

- day average), and 150 mg/L for the daily maximum. Effects on b enthic m acroinvertebrate s w ere recognized as the biological target (I ndex of Biotic Integrity ( IBI ) = 43 a 4 )

. However, th e im pairment was due

to a non

- pesticidal use of propylene glycol.

More information on impaired water bodies and TMDLs can be found at EPA’s website 5

. The Agency invites submission of water quality data for this pesticide. To the extent possible,

data should c onform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 6 in order to ensure they can be used qu antitatively or qualitatively in pesticide risk assessments.

3 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_i d=885

4 TMDL for Priority Organics, Yeader Creek, Polk County, 2005

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

6 http://www.epa.gov/oppsrrd 1/registration_review/water_quality_sop.htmPage 22 of 58 

### 6.1.3 Environmental Justice

EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all people, regardless of race, color, national origin, or income, in the develo pment, implementation, and enforcement of environmental laws, regulations, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who, as a result of their location, cu ltural practices, or other factors, may have atypical, unusually high exposure to p ropylene glycol, dipropylene glycol and triethylene glycol compared to the general population. Please comment if you are aware of any sub

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



### 6.1.4 Structure Activity Relationships

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

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

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

decision

- making proces s. In the SAR process, a chemical's molecular structure is compared to

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

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

- by

- study approach to an approach in which the use of predicted data, generated using validated models, is considered along with information from open literature and studies specifically generated under

Pa rt 161 requirements. All relevant information would be considered as part of a weight

- of

- the

evidence evaluation.

At this time, EPA believes that for certain endpoints, especially physical/chemical and fate properties, that SAR and QSAR might be effective ly utilized to fulfill these data requirements for many antimicrobial pesticide chemicals. When considering biological properties, at this time, EPA believes that SAR and QSAR can be most effectively utilized in the evaluation of

chemicals that exhibit low er toxicity for human health and/or ecotoxicity parameters. This is appropriate because the risk assessment for lower toxicity chemicals can be stream

- lined, i.e. , a screening

- level assessment procedure rather than multiple tiers of assessments with progre ssively more data requirements.Page 23 of 58 If stakeholders believe that submission of predicted data can fulfill one of the data needs for the

P ropylene G lycol, D ipropylene G lycol and T riethylene G lycol Case, then the Agency invites

submission of this information. T he submitter would be expected to supply a rationale describing the utility of the information and provide documentation on the scientific validity of the information. The determination that the predicted data fulfills the data requirement would be at

the sole discretion of the Agency. Pre

- submission consultation with the Agency is encouraged.



### 6.1.5 Additional Information

Stakeholders are also specifically asked to provide available information and data that will assist the Agency in refining its risk assessmen ts, including any species

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

1. Confirmation on the following label information:

A. Sites of application

B. Formulations

C. Application methods and equipment

D. Maximum application rates

E. Frequency of application, application intervals and maximum number of applications

F. Geographic limitations on use

2. Use or potential use distribution

3. Use history

4. Usage/use information for non

- agricultural uses ( e.g. , materials preservation)

5. Typical application interval

6. State or local use restrictions

7. Ecological incidents (non

- target plant damage and avian, fish, reptilian, amphibian and mammalian mortalities) not already reported to the Agency

8. Monitoring data



## 7 Next Steps

Aft er the 60

- day comment period closes in August 2013 , the Agency will review and respond to
any comments received in a timely manner, and then issue a Final Work Plan for the Propylene
Glycol, Dipropylene Glycol and Triethylene Glycol case.Page 24 of 58 

## 8 References

Agen cy for Toxic Substances and Disease Registry (ATSDR). 1997. Toxicological Profile for
Propylene Glycol. U.S. Department of Health and Human Services, Public Health

Service, Atlanta, GA. 176 pp. http://www.atsdr.cdc.gov/ToxProfiles/tp189.pdf

Amdur, M.O., J. Doull, et al. (1991). Casarett and Doull's Toxicology: The Basic Science of

Poisons . pp 705. MRID 46892501

ATSDR. 2008. Addendum to the Toxicological Profile for Propylene Glycol. Division of
Toxicology and Environmental Medicine, Atlanta, GA. 17 pp.
http://www.atsdr.cdc.gov/toxprofiles/propylene_glycol_addendum.pdf

Bartsch, W., G. Sponer, et al. (19 76). Acute Toxicity of Various Solvents in the Mouse and Rat.

LD 50 of Ethanol, Diethylacetamide, Dimethylformamide, Dimethyl

- Sulfoxide, Glycerine,

N

- Methylpyrrolidone, Polyethylene Glycol 400, 1, 2

- Propanediol and Tween 20.

Arzneimittelforsch 26:1581

- 158 3.

Braun, H.A. and G.F. Cartland. (1936). The Toxicity of Propylene Glycol. J. Am. Pharm.

Assoc. 25:746

- 749.

Budden, R., U.G. Kuehl, et al. (1979). Experiments on the Toxic, Sedative, and Muscle Relaxant Potency of Various Drug Solvents in Mice. Meth ods Toxicol. 102:467

- 474.

Bridie, A.L., C.J.M. Wolff, and M. Winter. 1979. The Acute Toxicity of Some Petrochemicals
to Goldfish. Water Res. 13(7):623

- 626. (ECOTOX reference #623).

B o ss e r t

, N

. L

. , e t a l

. ( 1992 ) R ep r o duc t i v e T o x i c it y o f Tr i e t h y l e n e G l y c o l a n d it s D i ace t a t e a n d

D im e t h y l e t h e r De r i v a t i v e s i n a C o n t i n u o u s B r eed i n g P r oto c o l i n S w i s s CD

- 1 mi ce. F u n d.

A

pp l

. P h a r m ac o l

. 18: 602

- 608.

B ud a v a r i

, S

. , M

. J

. O ’ Ne ill

, A

. S mi t h

, a n d P .E

. Hec k e lm a n ( e d s .) 1989. T h e M e r c k I n de x : A n
E n c y c l o p ed i a o f C h e mi ca l s
, D r ugs
, a n d B i o l o g i ca l s

. Ra h wa y ( e l e v e n t h ed it i o n )

, NJ : M e r c k

& C o

. , I n c

.

Campbell and Beavers, 1995. Acute oral toxicity of dipropylene glycol to Northernbobwhite.
Unpublished data. MRID 43760807.

Campbell and Beavers, 1995. Acute oral toxicity of propylen e glycol to Northern bobwhite.
Unpublished data. MRID 43762301.

Clark C.R., T.C. Marshall, et al. (1979). Toxicological Assessment of Heat Transfer Fluids Proposed for Use in Solar Energy Applications. Toxicology and Applied Pharmacology

51: 529

- 535.Page 25 of 58 C l a y to n
, G

. D. a n d F .E

. C l a y to n ( e d s .)

. Pa tt y ’ s I n du s t r i a l H y g i e n e a n d T o x i c o l o g y : V o l u m e 2 A

, 2 B

, 2 C : T o x i c o l o g y

. 3 rd ed. New Y o r k: J o h n W il e y S o n s
, 1981

- 1982. 3839.

Collins, 1995. Acute toxicity of propylene glycol to the waterflea ( Daphnia m agna ). Unpublished

data. MRID 43888003.

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Exposure Chapter for the Triethylene Glycol Reregistration Eligibility Decision (RED)
Document (Case No. 3146). PC Code 083501 (Memorandum: T. Leighton, 9/26/03).

U.S. Environmental Protection Agency (EPA). 2004. Ecological Hazard and Environmental

Risk Characterization. PC Code 0835 01, Case 3146 , Antimicrobials Division, ( Memorandum, Kathryn Montague, August 4, 2004).

U.S. Environmental Protection Agency (EPA). 2005. AD’s Occupational and Residential Exposure Chapter f or the Triethylene Glycol Reregistration Eligiblity Decision (RED) Document (Case No. 3146). PC Code083501 (Memorandum: T. Leighton, 5/24/05).

U.S. Environmental Protection Agency (EPA). 2006 a

. TRIETHYLENE GLYCOL: Revised

Antimicrobials Division’s Revie w of the Disciplinary Sciences for Issuance of the
Reregistration Eligibility Decision (RED)Document. Reregistration Case No.: 3146. PC
Code: 083501. CAS Registry No.: 112

- 27

- 6. DP#: 305169. (Memorandum M. Centra,
January 25, 2006).

U.S. Environmental Prot ection Agency (EPA). 2006b. Propylene/Dipropylene Glycol Revised Ecological Hazard and Environmental Risk Characterization Chapter for the Reregistration Eligibility Decision (RED) Document, Case 3126. (Memorandum Kathryn Montague, February 14, 2006).

U.S. Environmental Protection Agency (EPA). 2007a. AD’s Revised Occupational and
Residential Exposure Chapter for the Propylene and Dipropylene Glycol Reregistration
Eligibility Decision (RED) Document. Case No. 3126. PC Code 068603, 068604.
(Memorandu m: Timothy Leighton, February 5, 2007).

U.S. Environmental Protection Agency (EPA). 2007b. AD ’s Risk Assessment for Issuance of
the Reregistration Eligibility Decision (RED) Document. Reregistration Case No.: 3126.

PC Code s : 068603, 068604. CAS Registry No.: Propylene Glycol, 57

- 55

- 6; Dipropylene
Glycol, 25265

- 71

- 8. (Memorandum M. Centra, February 5, 2007 ).Page 33 of 58 U.S. Environmental Protection Agency (EPA). 2013 a

. PROPYLENE GLYCOL/

DIPROPYLENE GLYCOL : Hazard Characterization/ Toxicology Chapter in Support of

R egistration Review. DP Barcode(s)/No(s): 408349 . (Memorandum M. Centra, March
13, 2013).

U.S. Environmental Protection Agency (EPA). 2013 b

. TRIETHYLENE GLYCOL : Hazard

Characterization/ Toxicology Chapter in Support of Registration Review. DP
Barcode(s)/No (s): 408349 . (Memorandum M. Centra, March 13, 2013).

U.S. Environmental Protection Agency. High Production Volume Information System (HPVIS).
http://www.epa.gov/hpvis/

Van Winkle, W., Jr. (1941). Quantitative Gast rointestinal Absorption and Renal Excretion of Propylene Glycol. Journal Pharmacol. 72:344

- 353.

Weatherby, J.H. and H.B. Haag. (1938). Toxicity of Propylene Glycol. Journal of Amer.

Pharm. Assoc. 27:466

- 471.

Weil, C.S. and R.A. Scala. (1971). Study of Intra

- and Inter

- laboratory Variability in the Results of Rabbit Eye and Skin Irritation Tests. Toxicology and Applied Pharmacology 19:276.

MRID 46892104Pa ge 34 of 58 

# Appendix A T oxicology Profile

Acute Toxicity for Product Labeling

Dipropylene glycol

The dipropylene g lycol (DiPG) toxicological database is comprised of studies submitted by the Glycols Joint Venture Consortium and published literature studies. Low acute toxicities for DiPG were established in rodents, rabbits, and guinea pigs. Acute LD 50 values appear to be relatively high concentrations and fall within the toxicity classification of category IV for all of the acute experiments (Table 1). Acute oral LD 50 values were greater than 5010 mg/kg/day when DiPG was administered to Sprague

- Dawley male and female rats (43760801). When DiPG was administered topically to NZW rabbits, the dermal LD 50 was also greater than 5010 mg/kg/day (highest dose tested). No toxicological effects were observed at the doses tested in the acute dermal toxicity study (43760802).

In a 4

- hour inhalation whole

- body exposure study with Sprague

- Dawley rats, the LC 50 was found to be greater than 2.34 mg/L. There were no treatment

- related effects observed in rats exposed to DiPG and all of the animals survived the exposure and obser vation period with no indication of toxicity (43760803).

Instillation of 0.1 mL DiPG in eyes of New Zealand White (NZW) rabbits showed no evidence of corneal damage and was classified as a slight irritant based on observed conjunctival irritation

that subs ided within 24 hours (43760804). DiPG (0.5 mL of 100% TGAI) was administered to NZW rabbits in a primary dermal irritation study. There was evidence of erythema in a single

site that subsided in 24 hours while there were no traces of edema observed in tre ated animals; DiPG was classified as a non irritant (43760805).

A study for dermal sensitization assessed a single challenge application of 0.5 mL DiPG (100% purity) to guinea pigs that had previously been treated with DiPG. The topical administration d id not produce any evidence of dermal sensitization in treated animals (43760806).

In multiple open literature reports, when rats were exposed to DiPG, the acute oral toxicity LD 50 values were similar to PG values and ranged from greater than 5000 to 150 00 mg/kg/day for treated animals (46892504). DiPG was found to be an irritant to rabbits when administered in an undiluted dose of 510 mg in a primary eye irritation study (NIOSH, 1981).

Intraperitoneal and intravenous injections to rodents resulted i n toxicity values similar to other acute studies, with LD 50 values ranging from 4600

- 10000 and 5800

- 11500 mg/kg/day, respectively (Latven, 1939; Bartsch, 1976; Sax, 1979; Fischer, 1949; Weatherby, 1938; Budden, 1979).Pa ge 35 of 58 Table 14 Acut e Toxicity Profile of Dipropylene Glycol

Guideline Study Type MRID Number

and/or Citation Results Toxicity Category

870.1100 Acute Oral

- Rat 43760801 LD 50 = > 5010 mg/kg IV

870.1100 Acute Oral

- Rat 46892504; NIOSH, 1981 LD 50 > 5 000

- 1500 0 mg/kg IV

870.1200 Acute Dermal

- Rabbit 43760802 LD 50 = > 5010 mg/kg IV

870.1300 Acute Inhalation

- Rat 43760803 LC 50 = > 2.34 mg/L IV

870.2400 Acute Eye Irritation

- Rabbit 43760804 S light irritant IV

870.2400 Acute Eye Irritation

- Rabbit NIOSH, 1981 I rritant IV

870.2500 Acute Skin Irritation

- Rabbit 4376080 5 N on irritant IV

870.2600 Skin Sensitization

- Guinea Pig 43760806 Non sensitizer N/A

N/A = Not applicable

Propylene glycol

The toxicological database for p ropylene glycol (PG) is comprised of published literature studies (Table 1)

. Acute oral toxicity studies yielded similar, low acute toxicities with relatively high

LD 50 values (all considered to be Toxicity Category IV) ranging from 8000

- 46000 mg/kg/day

P G for rodents and 18000

- 20000 mg/kg/day for both rabbits and guinea pigs. Signs of nervous system toxicity were reported in the rabbit and guinea pig at lethal doses whereas effects of this nature (loss of balance, marked depression, and analgesia) were o nly evident in one study with

mice at LD 50 values of 23000

- 24900 mg/kg/day (46892501; 46892509; Clark, 1979; Bartsch, 1976; Sax, 1979; Layton, 1987).

PG induced degeneration of goblet cells (+69%) in the tracheal lining of rabbits after 20 and 120

minute s of aerosol exposure in an acute inhalation toxicity study; no other toxicological effects were observed (Konradova, 1978). In primary eye irritation studies, PG was instilled in the eyesPa ge 36 of 58 of rabbits (0.1

- 0.5 mL). There were no treatment

- related effects on the corneas of the animals

and PG was classified as a non

- irritant (46892104; 46892502; 46892507; Clark, 1979; Draize, 1944; Guillot, 1982). Acute dermal toxicity studies were not available for PG. In a series of skin sensitization tests, no reactions were observed in guinea pigs exposed to solutions of PG up to 70% active ingredient (46892104).

Additionally, several studies established intraperitoneal and intravenous LD 50 values for mice, rats, and rabbits. The acute LD 50 values for intraperitoneal i njection of PG ranged from 11200

- 13000 mg/kg/day for rodents. Similar, but lower, values were observed in intravenous injections experiments; with LD 50 ranges of 6200

- 8000 mg/kg/day for rodents and 6500 mg/kg/day for rabbits ( Latven, 1939 ; Bartsch, 1976; Sax, 1979; Fischer, 1949; Weatherby, 1938; Budden, 1979).

Table 15 Acute Toxicity Profile of Propylene Glycol

Guideline Study Type MRID Number

and/or Citation Results Toxicity Category

870.1100 Acute Oral

- Rat 46892501; 46892509;

Clark, 1979; Bartsch,

1976; Sax, 1979;

Layton, 1987 LD 50 = 8000

- 46000 mg/kg IV

870.1300 Acute Inhalation

- Rat Konradova, 1978 L C 50 > 2.0 mg/L (no deaths) IV

870.2400 Acute Eye Irritation

- Rabbit 46892104 ; 46892502; 46892508; Clark, 19 79; Draize, 1954;

Guillot, 1982 N on irritant IV

870.2500 Acute Skin Irritation

- Rabbit Clark, 1979 N on irritant IV

870.2600 Skin Sensitization

– Guinea pig Kero, 1980 Non sensitizer NA

N/A = Not applicable

Triethylene Glycol

P u b li s h e d li t e r a t u r e s t ud i e s su b mi tt e d b y t h e G l y c o l s J o i n t Ve n t u r e c o n s o r t i u m s h o w l o w

to x i c i t y (T o x i c i t y C a t e g o r i e s II I a n d I V ) f o ll o w i n g ac u t e e x p o s u r e s ( Table 16 )

. T h e ac u t e o r a l

a n d de r m a l to x i c i t y o f t h e c h e mi ca l appea r s t o b e l o w
, w i t h r ep o r t e d o r a l L D 50 v a l u e s r a n g i n g
f r o m 15

- 2 2 g / k g c o m p il e d f r o m m o n o g r ap h s a n d r e v i e w a r t i c l es

. T h e da t a a v a il a b l e o n acu t ePa ge 37 of 58 de r m al to x i c i t y we r e not su ff i c i e n t t o es t a b li s h a de r m a l L D 50 , b ut t h e d a t a r e qu i r e m e n t wa s

wa i v e d b a s e d o n t h e l o w o r d e r o f to x i c it y o b s e r v e d i n ot h e r s t ud i e s w it h t r i e t h y l e n e g l y c o l

. Da t a o n i nh a l a t i on to x i c it y s h o w ed a m a x im um to l e r a t e d l e v e l o f 800 m g/ m 3 i n r a t s
, b ut
i n t r a t r ac h ea l i n s t ill a t i o n o f 0

. 2 5 c c u n d il u t e d c h e mi ca l cause d m a r k e d pu lm o n a r y i rr it a t i o n
, ede m a
, a n d l a t e r
, f i b r o s i s a n d a b ce s s f o r m a t i o n i n t h e s e a n im a l s ( i n t r a t r ac h ea l i n s t ill a t i o n i s n o t

a n accep t e d r o u t e o f ad mi n i s t r a t i o n f o r t h e A g e n c y ’ s to x i c i t y t es t i n g gu i de li n es )

. P u b li s h e d

lit e r a t u r e da t a o n t h e sk i n a n d e y e i rr i t a t i o n a s we l l a s sk i n se n s i t i za t i o n s h o we d t r i e t h y l e n e

g l y c o l t o b e n o n

- i rr it a t i n g t o t h e sk i n a n d e y e ( w h e n t es t e d a t t h e limi t d o se s es t a b li s h e d b y t h e
A g e n c y f o r acu t e to x i c it y t es t i n g) a n d n o t a de r m a l se n s it i ze r (Safety Assessment of Triethylene Glycol and PEG

- 4, 2003; Budavari, 1989; Clayton, 19 81

- 1982; Smyth, 1941)

.

Tr i e t h y l e n e g l y c o l wa s e v a l ua t e d f o r acu t e i nh a l a t i o n to x i c it y i n m a l e a n d f e m a l e S p r ague

Daw l e y a l b i n o r a t s i n a s t ud y su b mi tt e d t o t h e A g e n c y ’ s O ff i c e o f T o x i c S u b s t a n ces

. A r e v i e w

o f t h i s s t udy b y t h e A gency e s t a b li s h e d a f o ur h o ur L C 50 g r ea t e r t h a n 5

. 2 m g/ L a n d p l ace s acu t e
i nh a l a t i o n i n T o x i c it y Ca t eg o r y I V

. Base d o n t h es e r esu l t s
, t h i s s t ud y is considered adequa t e f o r

r egu l a to r y pu r p o se s a n d i t n o w r ep l ace s t h e ea r li e r su b mi tt e d acu t e i nh a l a t i o n i n f o r m a t i o n (Nachreiner, 1991 )

.

Table 16 A c u t e T o x i c i t y P r o f il e of T r i et h y l e n e G l y c ol

Guideline Study Type MRID Number

and/or Citation Results Toxicity Category

870

. 1100 A c u t e O r al

- R a t 42814404 L D 5 0 = 15

- 22 g / kg I V

870

. 1200 A c u t e D e r m al

- R a bb i t 42814404 L D 5 0 n o t de t e r mi ned S t udy

R e qu ir e m e nt

W a i v e d

870

. 1300 A c u t e I nha l a ti o n

- R a t Nachreiner, 1991 L C 5 0 > 5

. 2 m g / L I V

870

. 2400 A c u t e E y e I rrit a ti o n

- R a t 42814404 M il d irrit a nt II I

870

. 2500 A c u t e Sk i n I rrit a ti o n

- R a bb i t 42814404 S li g ht irrit a nt I V

870

. 2600 Sk i n Sen s iti z a ti o n 42814404 S o n

- se n s iti z e r N / APa ge 38 of 58 

## Subchronic Toxicity Subchronic Toxicity

Propylene glycol

Subchronic toxicity studies for PG were available from published open literature studies. With relatively high

- dose an d no

- observed

- adverse

- effect levels (NOAEL), PG exhibits low toxicity to animals exposed over a moderate period of time. In a 15

- week feeding study, there were no adverse toxicological effects observed in rats administered 2500 mg/kg/day PG (46892504). I n another subchronic toxicity study, PG was administered to rats i n drinking water for 140 days. Although there were clinical signs (CNS depression and minor liver toxicity) exhibited in animals at a dose of 13200 mg/kg/day, these effects occurred well ab ove the testing limit dose of 1000 mg/kg/day established for an oral su bchronic toxicity study in rats (Seindenfeld, 1932).

In a 90

- day inhalation study, female rats were exposed to PG vapors (1.0 or 2.2 mg/L) for 6 hours/day, 5 days/week over a period of 90 days. Animals experienced decreases in body weight and food consumption, although there were no changes in respiratory rates, minute volumes, or tidal volumes during exposure. With the exception of a significant increase in the number of goblet cells in the nasal passages of the mid

- and high

- dose animals (both male and female) males were unaffected by PG treatment (0.16, 1.0, or 2.2 mg/L) in this subchronic inha lation study (46892103).

Dipropylene glycol

Two published literature studies were availab le to address the subchronic toxicity of DiPG. In a

drink ing water study, DiPG was administered to mice at concentrations of 715, 1350, 2620, 4790, or 11000 mg/kg/day for males and 1230, 2140, 4020, 7430, or 14700 mg/kg/day for females over a period of 90 days. There were treatment

- related increases in mortality at the high

dose for both males and females and increased body weight in females treated with 2140 mg/kg/day DiPG. Minimal toxicity was observed at these relatively high doses of DiPG; 11000

and 1 4700 mg/kg/day for males and females, respectively (46892101).

In a similar study, male and female rats exhibited reductions in body weight at 425 and 1690 mg/kg/day, respectively, when exposed to DiPG in drinking water for 90 days (425, 890, 1840, 3890, o r 12800 mg/kg/day for males and 460, 920, 1690, 3340, or 8950 mg/kg/day for females). Water consumption increased at the high

- dose for all animals by the second week and continued throughout the remainder of the study. There were i ncreases in weight and the appearanc e of lesions in liver and kidneys of treated animals at concentrations exceeding those that induced body weight reductions. High

- dose (12800 mg/kg/day) males experienced testicular effects,

h ypoactivity and poor hair coats (46892208).

Triethe thylene Glycol

Repeat o r al d o s i n g s t ud i es c o n duc t ed i n r a t s t o de t e r mi n e t r i e t h y l e n e g l y c o l to x i c i t y s h o wed

, i n

ge n e r a l

, t h at t h e c h e mi cal was e it h er w i t h o ut a n y ad v e r s e e ff ec t s o r p r o duced to x i c it i es o n l y at
d o s es at o r g r ea t er t h an t h e limi t d o s es e s t a b l i s h ed f o r E P A gu i de li n e t e s t r equ i r e m e n t s

. Tr i e t h y l e n e g l y c o l ad mi n i s t e r ed i n t h e d r i n k i n g wa t er t o r a t s at c o n ce n t r a t i o n s o f 3% a n d 5% b y

v o l u m e f o r 30 da y s s h o wed s i g n s o f to x i c i t y ( we i g h t l o ss, a l o pec i a a n d p oo r g r oo mi n g) at t h ePa ge 39 of 58 l o wer c o n ce n t r a t i o n w i t h o n e a n im al d y i n g o n day 25 o f t h e s t ud y

. A l l r a t s i n t h e 3% t est g r o up

s u r v i v ed t o s t udy c o m p l e t i o n w it h n o s i g n s o f to x i c i t i e s (Lauter, 1940)

. I n a 14

- day o r al to x i c it y

s t ud y
, F i s c h er 344 r a t s r ece i v i n g t r i e t h y l e n e g l y c o l i n t h e f eed ( d o s es equ i v a l e n t t o 1132, 2311, o r 3916 m g/kg/day f o r m a l es a n d 1177, 2411, o r 6209 m g/kg/day f o r f e m a l es) s h o wed o n l y c h a n ges i n u r i n a l y s i s ( i n c r eased u r i n e v o l u m e, dec r eased u r i n e pH, a n d dec r eased u r i n e t r i p l e p h o s p h a t e

c r y s t a l s ) at t h e h i g h est r espec t i v e d o ses t es t ed i n m a l e a n d f e m a l e r a t s (Union Carbide, 1989)

. I n

a t h i r d o r al to x i c i t y s t udy c o n duc t ed f o r 90

- da y s i n r a t s
, t r i e t h y l e n e g l y c o l was ad mi n i s t e r ed i n t h e d i et at d o s es o f 748, 1522 o r 3849 m g/kg/day ( m a l e s ) a n d 848, 1699, o r 4360 m g/kg ( f e m a l e s )

. A l t h o ugh to x i c i t i es we r e n ot ed at t h e h i gh d o s e i n m a l e a n d f e m a l e r a t s ( dec r eases i n b o dy

we i g h t

, s li g h t dec r eases i n h e m o g l o b i n a n d h e m a to c r i t

, s li g h t i n c r eases i n m ean c o r puscu l ar

v o l u m e, a n d i n c r eased r e l a t i v e k i d n ey a n d b r a i n we i g h t s )

, t h ese e ff ec t s we r e n ot e d at d o se l e v e l s

t h at e x ceed t h e e s t a b li s h ed limi t d o s e o f 1000 m g/kg/day f o r s uch s t ud i e s Union Carbide, 1990)

.

I n a 21

- day de r m al to x i c it y s t ud y
, t h e r e was n o e v i de n ce o f de r m al o r s y s t e mi c to x i c it y f r o m

r epea t ed de r m al app li ca t i o n s o f 2 m l ( app r o x im a t e l y 600 m g/kg) t r i e t h y l e n e g l y c o l app li ed t o t h e

s k i n o f r a bb it s (Guillot, 1982)

. T h e s e r e s u l t s a r e s upp o r t ed b y t r i e t h y l e n e g l yc o l s ’ l o w de r m al

i rr i t a n cy a n ega t i v e r e s p o n s e a s a s k i n se n s it i ze r (42814404 )

.

Sp r ague

- Daw l ey r a t s e x p o s ed ( w h o l e b o d y ) t o t r i e t h y l e n e g l y c o l i n an ae r o s o l i nh a l a t i o n s t udy at

c o n ce n t r a t i o n s o f 494, 2011, o r 4842 m g/ m 3 ( 0

. 5, 2

. 0, o r 5

. 0 m g/ L /da y )

, f o r s i x h o u r s a da y
, n i n e

t im es o v er a t w o

- week pe r i o d s h o wed t h e f o ll o w i n g to x i c it i es at t h e h i g h est c o n ce n t r a t i o n l e v el

t es t ed: a t a x i a, p r o s t r a t i o n
, u n kept f u r
, l a b o r ed r esp i r a t i o n ( m a l es o n l y )

, o cu l ar d i sc h a r ge, sw o ll en

pe r i o cu l ar t i ssue, pe r i n asal a n d pe r i o r al e n c r us t a t i o n
, b l ep h a r o spasm a n d r educed b o dy we i g h t

Nec r o p i es r e v ea l ed h y pe r i n f l a t i o n o f t h e l u n gs, o cu l ar o pac it y
, c o n ges t i o n a n d h e m o rr h age i n

m a n y o r ga n s a n d t i ss ues ( p it u i t a r y g l a n d, b r a i n
, n a s al m uc o s a, k i d n e y
, t h y m

us a n d l u n g s )

. A l l

h i gh

- d o s e group rats d i ed o r we r e s ac r i f i ced m o r i b u n d b y day 5 o f t h e s t ud y

. C li n i cal s i g n s o f

to x i c i t y o b se r v ed at t h e l o w

- a n d mi d

- d o se o f 0

. 5 a n d 2

. 0 m g/ L /da y
, r espec t i v e l y
, we r e limi t ed t o

sw o ll en pe r i o cu l ar t i ssues a n d pe r i n asal e n c r us t a t i o n s. Tr ea t m e n t

- r e l a t ed c h a n ges i n o r gan

we i g h t s i n mi d

- d o s e m a l es i n c l uded an i n c r ea s e i n li v er a n d k i d n ey we i g h t s r e l a t i v e t o b o dy

we i g h t ; mi d

- d o se f e m a l es s h o wed i n c r eases i n a b s o l u t e a n d r e l a t i v e ( t o b o dy a n d b r a i n we i g h t s)

li v er a n d k i d n ey we i g h t s. S t a t i s t i ca ll y s i g n i f i ca n t c li n i cal c h e mi s t r y f i n d i n gs f o r m a l es t r ea t ed w it h

2

. 0 m g/ L /day t r i e t h y l e n e g l y c o l i n c l uded an i n c r ease i n A L T ac t i v it y a n d a dec r e ase i n se r um

c r ea t i n i n e l e v e l s

. M i d

- d o se f e m a l es s h o wed i n c r eases i n u r ea n i t r o ge n
, i n o r ga n i c p h o s p h o r us, A L T a n d A L K ac t i v it y
, a n d dec r eases i n g l uc o s e, c r ea t i n i n e, a n d c h l o r i de. H o we v e r
, t h e c h a n ges i n o r gan we i g h t s a n d c li n i cal c h e mi s t r y f i n d i n gs we r e n o t c o rr e l a t ed w it h a n y h i s to pa t h o l o g i cal

o b s e r v a t i o n s (Sun, 1992)

.

Ra t s e x p o se d t o t h e t es t m a t e r i a l v i a a w h o l e

- b o d y i nh a l a t i o n p r oto c o l a r e a l s o r ece i v i n g t h e

c h e mi ca l v i a t h e o r a l a n d de r m a l r o u t es

. T h es e add it i o n a l r o u t e s o f e x p o su r e m a y h a v e i n c r ea sed t h e tot a l d o s e r ece i v e d a n d c o n t r i b u t e d t o t h e to x i c it i e s o b se r v e d i n t h e w h o l e

- b o d y

e x p o su r e i nh a l a t i o n s t ud y

. T h e r e f o r e
, a sec o n d s t ud y wa s c o n duc t e d us i n g a n o se

- o n l y

e x p o su r e f o r 6 h o u r s a da y
, 9 c o n s ecu t i v e da y s

. I n t h i s sec o n d i nh a l a t i o n to x i c it y s t ud y
, m ea n

e x p o su r e c o n ce n t r a t i o n s o f 102, 517, o r 1036 m g/ m 3 ( a pp r o x im a t e l y 0

. 1, 0

. 5, 1

. 0 m g/ L /da y )

t r i e t h y l e n e g l y c o l p r o duce d n o t r ea t m e n t

- r e l a t e d to x i c it i e s a t a n y d o s e t es t ed (Norris, 1994)

.

M o n ke y s e x p o s e d b y i nh a l a t i o n t o app r o x im a t e l y 1 ppm v a p o r f r o m t w o weeks t o 13 m o n t h s

a n d h u m a n v o l u n t ee r s e x p o s e d t o a i r s a t u r a t e d w i t h v a p o r ( a pp r o x im a t e l y 0

. 5 t o 1 pp m )Pa ge 40 of 58 s h o w ed n o ad v e r s e r eac t i o n s o r h i s to p a t h o l o g i ca l c h a n ge s s ugge s t i v e o f to x i c i t y f r o m

p r o l o n ge d e x p o s u r e t o t r i e t h y l e n e g l y c o l (Robertson, 1 947)

.

D o gs g i v e n da il y i n t r a v e n o us i n j ec t i o n s ( 0

. 1 o r 0

. 5 ml /kg) o f t r i e t h y l e n e g l y c o l f o r f o ur weeks

s h o we d n o m o r t a lit y o r to x i c it y w i t h t h e e x cep t i o n o f f l a tt e n e d ep it h e li a l ce ll s i n t h e u r i n e a n d

p h l e b i t i s a t t h e s i t e o f i n j ec t i o n (Stenger, 1968)

.



## Deve lopmental and Reproductive Toxicity

Open literature studies examining the developmental and reproductive toxicity of propylene/dipropylene /triethylene glycol showed minimal evidence of toxicity at relatively high concentrations (10000 mg/kg/day) that excee d the established limit dose of 1000 mg/kg/day.

Propylene glycol

PG, administered to mice at a concentration of 10000 mg/kg/day in drinking water, did not produce any overt adverse effects in fetal developm ent (46892201). In a second study, PG

administe red to mice via subcutaneous injections at a dose of 10400 mg/kg/day on gestation day (GD) 9, 10, and 11 did not exhibit significant i ncreases in fetal malformations (46892203). Two

additional studies involving oral administration of PG in mice up to conc entrations of 10400 mg/kg/day did not induce any maternal, reproduct ive, or developmental toxicity in this study (46892508; Driscoll, 1993).

Several developmental studies were performed on rats, mice, rabbits, and hamsters in which oral

doses of PG

, that ranged from 12.3

- 1600 mg/kg/day

, were administered during gestation. In all four studies, there were no incidents of treatment

- related maternal, reproductive, or

deve lopmental toxicities observed in this study (46892207; FDRL, 1973; NTP, 1973).

PG was a dministered to rats (1600

- 6200 mg/kg/day), mice (1550

- 10000 mg/kg/day), and rabbits (1230 mg/kg/day) during gestation via a stomach tube. There were no adverse reproductive effects observed in any of these experiments. However, a slight maternal toxicity was noted in mice treated with 10000 mg/kg/day PG (highes t dose administered) on GD 8

- 12 (46892508; FDRL, 1973).

In a second reproductive toxicity study, rats from three successive generations were orally

administered 2.5, 5, 7.5, 10, 20, or 30% PG. No adverse effects were observed up to the 20% dose (equivalent to a dietary level of approximately 11900 mg/kg/day), where 50% of the animals failed to produce offspring. No offspring were produced by any of the rats in the 30% high

- dose PG group (Guerrant , 1947).

M ice were administered 1820, 4800, or 10100 mg/kg/day in drinking water over a course of 18

weeks in a third reproductive toxicity study . There were no treatment

- related maternal, reproductive, or offspring effects observed at any of the PG dos es tested in this study (46892204).

Dipropylene glycolPa ge 41 of 58 DiPG was administered to NZW rabbits in a developmental toxicity study at concentrations up to 1200 mg/kg/day on GD 6

- 19 . N o treatment

- related maternal, reproductive, or deve lopmental

toxicities were observed in treated animals (46892205). However, t here were decreases in maternal food consumption and body weight in rats treated with 2000 and 5000 mg/kg/day

DiPG . Increases in liver weight were also observed in these dose groups. No reproductive or developmental toxicity effects were observed in rats at any dose levels of DiPG from 800

- 5000 mg/kg/day (46892206).

Triethylene glycol

Tr i e t h y l e n e g l y c o l was ad mi n i s t e r ed o r a ll y at d o s e s o f 0, 0

. 5, 5

. 6, a n d 11

. 27 g/kg/day i n

t im e d p r eg n a n t C D

- 1 mi c e f r o m g e s t a t i o n Da y s 6 t h r o ug h 15

. T h e r e we r e n o t r ea t m e n t

r e l a t e d m a t e r n a l dea t h s a n d n o a b o r t i o n s

. H y pe r ac t i v it y a n d r ap i d r esp i r a t i o n we r e o b se r v e d

a t t h e h i g h es t d o s e l e v e l tested

. N o e ff ec t s we r e o b se r v e d o n m a t e r n a l we i g h t ga i n o r f oo d

c o n s u m p t i o n a t a n y d o s e l e v e l

. P r eg n a n c y o u t c o me wa s u n a ff ec t e d a t a n y d o s e l e v e l t es t ed

. T h e r e we r e n o t r ea t m e n t

- r e l a t e d e ff ec t s observed for e x t e r n a l o r v i sce r a l m a l f o r m a t i o n s i n

o ff s p r i n g

. S o m e e v i d e n c e o f de l a y e d o ss i f i ca t i o n wa s o b se r v e d a t t h e h i g h d o s e l e v e l (Union Carbide, 1990)

.

I n a sec o n d s t ud y
, p r eg n a n t S p r ague

- Daw l e y r a t s we r e ad mi n i s t e r e d t r i e t h y l e n e g l y c o l b y

ga v a ge o n ge s t a t i o n da y s 6 t h r o ugh 15 at d o s e l e v e l s o f 0, 1

. 0, 5

. 6, a n d 11

. 27 g/kg/da y

. T h e r e

we r e n o e ff ec t s o n m a t e r n a l m o r t a lit y a n d t h e r e we r e n o a b o r t i o n s

. C li n i ca l to x i c it y wa s

o b se r v ed i n m a t e r n a l r a t s a t t h e h i g h d o s e a n d c o n s i s t e d o f aud i b l e r esp i r a t i o n
, pe r i o cu l a r

e n c r us t a t i o n
, a n d pe r i o r a l we t n ess

. Dec r ease d b o d y we i g h t a n d f oo d c o n s u m p t i o n wa s o b se r v e d

i n m a t e r n a l r a t s at t h e 5

. 6 g/kg/day d o s e

. No e ff ec t s we r e o b s e r v ed at t h e 1

. 0 g/kg/day d o s e

. I n

o ff s p r i n g, mean f e t a l b o d y we i g h t wa s dec r ease d a t t h e 11

. 2 7 g / kg / da y d o s e l e v e l

, b ut t h e r e

we r e n o t r ea t m e n t

- r e l a t e d i n c r ease s i n e x t e r n a l

, v i sce r a l

, o r ske l e t a l m a l f o r m a t i o n s Union Carbide, 1991 )

. P u b li s h e d li t e r a t u r e e x a mi n e d t h e e ff ec t o f t r i e t h y l e n e g l y c o l o n r ep r o duc t i o n i n S w i s s CD

- 1 mi ce. D o s e s o f 0, 0

. 3, 1

. 5, a n d 3% we r e ad mi n i s t e r ed i n d r i n k i n g wa t e r u s i n g a

c o n t i n u o us b r eed i n g p r oto c o l

. N o e ff ec t s o n r ep r o duc t i v e f u n c t i o n we r e o b se r v e d a t a n y d o s e l e v e l t es t e d ( up t o t h e h i gh d o s e o f 6

. 78 g/kg) i n c l ud i n g s p e r m c o n ce n t r a t i o n
, m o r p h o l o g y
, a n d

m

ot ili t y

. R e du ce d pup we i g h t was o b s e r v ed at t h e 1

. 5 a n d 3% d o s e s o f t r i e t h y l e n e glycol (Bossert, 1992; Lamb, 1997)

.

I n a s t udy s u b mitt e d t o t h e A g e n c y
, r a t s we r e e x p o s e d t o a n a t m o s p h e r e s a t u r a t e d w i th

t r i e t h y l e n e g l y c o l ( a pp r o x

. 1 pp m ) f o r 12

- 18 m o n t h s w i t h n o ad v e r s e r e p r o duc t i v e e ff ec t s

n ot e d (Robertson, 1947; Goldstein, 1970)

.

T h e a v a il a b l e de v e l o p m e n t a l a n d r ep r o duc t i v e s t ud i e s c o n duc t e d w i t h t r i e t h y l e n e g l y c o l a r e f r o m pu b li s h e d s o u r ce s o r f r o m s t ud i e s su b mitt e d t o t h e O ff i c e o f T o x i c S u b s t a n ce s a n d d o

n o t r e p o r t a l l t h e da t a t h at a r e n o r m a ll y r e p o r t ed u n der t h e OPP T S 870 to x i c it y t e s t

gu i de li n e s

. H o we v e r
, it i s appa r e n t t h a t t h e to x i c i t i e s o b se r v e d i n t h es e s t ud i e s a r e

c o n s i s t e n t l y m a n i f es t ed o n l y a t d o se s o f t r i e t h y l e n e g l y c o l t h a t e x cee d t h e es t a b li s h e d limi t
d o se s f o r a n im a l s t ud i e s a n d a r e o f a n o n

- spec i f i c n a t u r e

. T h e r e f o r e
, t h e r e i s n o c o n ce r n f o r

t h e de v e l o p m e n t a l o r r ep r o duc t i v e to x i c it y o f t r i e t h y l e n e g l y c o l

.Pa ge 42 of 58 

## Chronic Toxicity and Carcinogenicity

Published literature studies examining the chronic toxicity and carcinogenic potential of propylene/dipropylene /triethylene glycol have shown the chemicals to be noncarcinogenic in

rodent and non

- rodent species under the conditions of each study protocol

. In addition, systemic adverse effects were noted only at doses of propylene

, dipropylene , and triethylene glycol that exceed the limit dose of 1000 mg/kg/day established for mammalian chronic to xicity studies

.

Propylene glycol

Several studies in the rat involving dietary, drinking water, and inhalation exposure to PG comprise the chronic toxicity database. There was little evidence of adverse toxicological effects at the relatively high concentr ations used within these studies and chronic toxicity associated with PG was low. With the exception of slight liver damage in treated animals, there were no signs of toxic effects when PG was administered 1230 or 2450 m g/kg/day in the diet for 2 year (Mo rris, 1942). In another study, slight liver damage and no other effects were observed in a 2

- year drinking water study that adminis tered 1834 mg/kg/day PG to rats (46892509; Braun, 1936).

In a continuous

- exposure inhalation study, rats were exposed to 0.17

- 0.35 mg/L PG for 18 months and a chronic toxicity lowest observed adverse effect level (LOAEL) of 0.35 mg/L was established based on a 50% increase in body weight. There were no other effects observed i n treated animals in this study (Robertson, 1947).

A carcinogenicity study in rats fed PG at dietary concentrations of 200, 400, 900, or 1700 mg/kg/day for males and 300, 500, 1000, or 2100 mg/kg/day for females was carried out for 2 years with little evidence of chronic toxicity or signific ant treatment

- re lated neoplasms (46892504). In a dermal carcinogenicity study conducted in mice

, t here was no change in longevity or increase in dermal tumors following chronic treatment with 0.02 mL of 10, 50 or

100% (46892301).

Dipropylene glycol

There were decreases i n survival and body weight of male and female rats treated with 3040 and 2330 mg/kg/day DiPG, respectively, in drinking water for 2 years. Clinical signs of toxicity were noted in males with an increase in focal histiocytic and focal granulomatous inflamm ation in the liver. There was no evidence of carcinogenic activity in rats treated with Di PG over the course of 24 months (NTP, 2003e). In a similar m ouse study, animals experienced decreased survival and body weight at the high

- dose (2390 mg/kg/day for males and 1950 mg/kg/day for females) of DiPG tested in the study. Males in the 2390 mg/kg/day dose group also exhibited reduced water consumption. After 2 years of DiPG administration in drinking water, mice failed to show any ev idence of carcinogenic a ctivity (NTP, 2003d).

Triethylene glycol

P u b li s h e d li t e r a t u r e s o u r ce s e x a mi n i n g t h e c h r o n i c to x i c it y a n d ca r c i n o ge n i c p ot e n t i a l o f

t r i e t h y l e n e g l y c o l h a v e s h o w n t h e c h e mi ca l t o b e n o n to x i c / n e g a t i v e i n r o d e n t s p ec i e s

.Pa ge 43 of 58 I n a 1 2 m o n t h s t ud y
, m o n k e y s r ece i v i n g t r i e t h y l e n e g l y c o l ( 0

. 2 5 m L t o 0

. 5 m L ) o r a ll y i n egg

n o g ( app r o x im a t e l y 5 0 t o 10 0 t im e s t h e qua n t it y a n a n im a l c o u l d a b s o r b b y b r ea t h i n g glycol

saturated a i r) showed no adverse effects in physiological function or organ histopathology (Robertson, 1947).

Tr i e t h y l e n e g l y c o l ad mi n i s t e r e d i n f ee d a t l e v e l s o f 0

, 1

, 2 o r 4 % t o Os b o r n

- M e n de l r a t s f o r 2

y

ea r s s h o we d t h a t t h e b o d y we i g h t ga i n s
, h e m a to l o g i ca l pa r a m e t e r s a n d c li n i ca l c h e mi s t r i e s

we r e n o t a ff ec t e d b y t r ea t m e n t

. U n de r t h e c o n d i t i o n s o f t h i s s t ud y
, t r i e t h y l e n e g l y c o l wa s n o t

ca r c i n o ge n i c i n r a t s

. T h e d o se s t es t e d i n r a t s a r e equ i v a l e n t t o a s m u c h a s 3 t o 4 g /kg / day,

w h i c h a r e we l l a b o v e t h e upper limi t d o s e o f 1 g/kg/day ( 1000 m g/kg/da y ) f o r t e s t i n g pe s t i c i des

v i a t h e o r a l r o u t e i n su b c h r o n i c a n d c h r o n i c to x i c i t y s t ud i es (Fitzhugh, 1946)

. 

## Mutagenicity

Open published literature studies comprise the mutagenicity database for propylene/dipropylene glycol /triethylene glycol . In a battery of studies, propylene and dipropylene glycol did not

exhibit muta genic or genotoxic activity.

Propylene glycol

There were no signs of mutagenicity in several bacterial reverse mutation tests in tester strains TA 1535, TA 1537, TA 100, TA 98, and TA 1538 that were performed with concentrations of PG ranging from 1

- 1000 0 μ g/plate. PG did not induce mutant colonie s and was negative in all cases (46892102; 46892503; Clark, 1979). Similar negative results were observed in additional mutagenicity studies, including an in vitro mammalian cell gene mutation test, an in vitro

m ammalian chromosome aberration test, a mammalian erythrocyte micronucleus te st, and a dominant lethal assay (46892506; Litton Bionetics, 1974; Swenberg, 1976).

Dipropylene glycol

Non

- mutagenic results were observed in both a bacterial reverse mutation and in vitro mammalian cell gene mutation test. There was no increase in mutant frequencies when DiPG was administered (100

- 10000 μ g/plate) to the bacterial tester strains TA 98, TA 100, TA 1535,

and TA 1537 (NCI, 1986) . In an in vitro mammalian cell gene mutation test, mice were given 0.005, 0.01, 0.05 , 0.1, 0.5, 1.0, 5.0, 10, or 50 μ L/mL DiPG and failed to produce a positive

respo nse in either the presence or absence of metabolic activation (NCI, 1987).

Triethylene glycol

Tr i e t h y l e n e g l y c o l wa s t e s t e d f o r m u t age n i c o r ge n oto x i c p ot e n t i a l a n d f o u n d t o b e n ega t i v e i n a b a tt e r y o f s t ud i es : a b ac t e r i a l ge n e m u t a t i o n assa y us i n g Salmo nela typhimu r iu m , a n in v it r o C h i n es e h a m s t e r o v a r y ( C HO ) m u t a t i o n assa y
, a n in v it r o C h i n es e h a m s t e r o v a r y ( C HO)

c h r o m o s o m a l a b e rr a t i o n assa y a n d a n in v it r o s i s t e r c h r o m a t i d e x c h a n g e assa y (Guzzie, 1986a; Guzzie, 1986b; Slensinski, 1986a; Slensinski, 198 6b)

. 

## NeurotoxicityPa ge 44 of 58 From the available toxicity studies, evidence of neurotoxicity was observed in mice, rabbits, and guinea pigs following a single dose of propylene glycol; loss of balance, marked de pression, and analgesia observed at lethal doses of 1840 0

- 24900 mg/kg/day (Braun, 1936; Laug, 1939; Smyth, 1941; Latven, 1939). Central nervous system (CNS) depression was also noted in rats administered propylene glycol at greater than 13200 mg/kg/day in drinking water for 140 days (Seidenfeld, 1932). Howeve r, these CNS effects were observed only at a dose level that far exceeds the established limit dose (1000 mg/kg/day) for an oral subchronic toxicity study. Based on a weight

- of

- evidence evaluation of the available data, the Agency does not anticipate need ing neurotoxicity testing, including a developmental neurotoxicity study for either propylene or dipropylene glycol.



## Metabolism and Excretion

Propylene glycol

In an elimination and metabolism study a maximum concentration of 29.21 ∀ 2.92 mmol/L PG

was found in the blood of rats 2 hours with the high

- dose administration of PG (treatment with 4.83, 9.66, 19.3 2, 38.64, and 77.28 mmol/kg PG) (Morshed, 1988). PG was readily absorbed in the gastrointestinal tract of several animals in other studies. The absorpti on was rapid and complete and P G was broken down into glycogen (Hanzlik, 1939; Opitz, 1958; Salter, 1935; Van Winkle, 1941). PG was administered orally to humans (70 g) and dogs (150 g) in a NTIS study in which a portion of PG was metabolized and an appre ciable fraction was excreted in the urine. Within 10 hours, 20

- 25% of the 70 g dose given to the human subjects was excreted. The dogs

excreted 20% of the 150 g dose within 24 hours (Hanzlik, 1939).

Dipropylene glycol

No metabolism studies conducted with DiPG are available in the toxicity data base.

Triethylene glycol

T h e f a t e o f 14 C

- l a b e l e d t r i e t h yl e n e g ly c o l i n r a t s a n d o f u n l a b e l e d m a t e r i a l i n r a bb i t s wa s r ece n t l y

s t ud i ed

. F o ll o w i n g o r a l d o s i n g, t h e r a t a n d r a bb it e x c r e t e d m o s t o f t h e t r i e t h y l e n e g l y c o l i n b ot h

u n c h a n ge d a n d / o r o x i d i ze d f o r m s ( m o n o

- a n d d i ca r b o x y li c ac i d de r i v a t i v e s o f t r i e t h y l e n e g l y c o l )

. I n r a bb i t s d o s e d w it h 200 o r 2000 m g/kg t r i e t h y l e n e g l y c o l r e s pec t i v e l y e x c r e t ed 34

. 3% o r 28 %

,

o f t h e ad mi n i s t e r e d d o s e i n t h e u r i n e a s u n c h a n ge d t r i e t h y l e n e g l y c o l a n d 35

. 2 % a s a h y d r o x y ac i d

f o r m o f t h i s c h e mi ca l

. I n t h e s t ud i e s w it h r a t s
, litt l e i f a n y C 14

- o x a l a t e o r C 14

- t r i e t h y l e n e g l y c o l i n

c o n j uga t e d f o r m wa s f o u n d i n t h e u r i n e

. Tr ac e a m o u n t s o f o r a ll y ad mi n i s t e r e d 14 C t r i e t h y l e n e

g l y c o l we r e e x c r e t e d i n e x p i r e d a i r a s ca r b o n d i o x i de ( <1 % ) a n d i n de t ec t a b l e a m o u n t s i n f ece s ( 2

t o 5 %)

. T h e tot a l e limi n a t i o n o f r ad i o ac t i v it y ( u r i n e
, f ece s a n d C O 2 ) du r i n g t h e f i v e day pe r i o d

f o ll o w i n g an o r al d o s e o f l a b e l e d c o m p o u n d ( 22

. 5 m g) r a n ged f r o m 9 1 t o 98 %

. T h e m a j o r it y o f

t h e r ad i o ac t i v it y appea r e d i n t h e u r i n e (McKennis, 1962)

.Pa ge 45 of 58 

## Dermal Absorption

Propylene glycol

There ha ve been no reports dealing with PG and skin absorption. PG has been found to penetrate the outermost layer of the epidermis; however, because of this property, PG is commonly used as a cosmetic ingredient in many products. Although absorption through the skin is possible, it is doubtful any appreciable systemic/dermal injury would occur based on the lack of irritation in

acute dermal studies, no evidence of chronic toxicity or tumor response following a 2

- year dermal application study, and the widespread use in co smetics that is considered safe (46892301; Clark, 1979).

Dipropylene glycol

No dermal penetration/skin absorption studies were identified for dipropylene glycol. Similar to PG, DiPG is used in many cosmetic formulations and has be en generally recognized as a low toxicity chemical by the FDA. Dermal and systemic injury from skin exposure to DiPG is unlikely consideri ng its widespread use in cosmetics, the lack of evidence of dermal toxicity in acute studies, and the lack of evidence of skin sensitizati on in repeat

- exposure studies (43760802; 43760805; 43760806).

Triethylene glycol

N o s t ud i e s h a v e b ee n r ep o r t e d dea li n g w i t h t h e sk i n a b s o r p t i o n o f t r i e t h y l e n e g l y c o l

.

A l t h o ug h it i s p o ss i b l e t h a t

, u n de r c o n d i t i o n s o f v e r y s e v e r e p r o l o n ge d e x p o s u r e s t o t h i s c h e mi ca l

,

a b s o r p t i o n t h r o ug h t h e sk i n may occur
, i t i s d o u b t f u l a n y app r ec i a b l e s y s t e mi c /d e r m a l i n j u r y w o u l d

o ccur b e caus e t r i e t h y l e n e g l y c o l h a s 1) a l o w o r de r o f de r m a l i rr it a n c y (42814404)

, ( 2) i s n o t a sk i n

se n s it i ze r (42814404) a n d ( 3) s h o we d n o e v i d e n c e o f de r m a l o r s y s t e mi c to x i c it y f o ll o w i n g

r epea t e d de r m a l app li ca t i o n s o f 2 m l ( a pp r o x im a t e l y 600 m g/kg) t r i e t h y l e n e g l y c o l app li e d t o t h e

s k i n o f r a bb i t s i n a 21

- day de r m al to x i c it y s t ud y (Guillot, 1982)

.Pa ge 46 of 58 

# Appendix B Product Chemistry

Triethylene glycol, Propylene glycol and Dipropylene glycol product chemistry information is

summarized in Table B1 (source: MRIDs 42814401

, 42 814402, 42814403, 43178601

, 43178603 , 43179501, 43179502, 43179503, and EPI Suite v4.1).

Table 17

– Product Chemistry of Triethylene, Propylene and Dipropylene Glycols

Guideline

No. Physical and Chemical Properties Triethylene Glyco l Propylene Glycol Dipropylene Glycol

830.1550 Product identity and composition Refer to Table 5 Refer to Table 5 Refer to Table 5

830.1600 Description of materials used to produce the product Confidential Business Information (CBI) CBI CBI

830.1620 Description of production process CBI CBI CBI

830.1650 Description of

Formulation Process CBI CBI CBI

830.1670 Discussion of

for mulation of impurities CBI CBI CBI

830.1700 Preliminary analysis CBI CBI CBI

830.1750 Certified limits CBI CBI CBI

830.1800 Enforcement analytical

method Gas Chromatography (GC) GC GC

830.1900 Submittal of samples CBI CBI CBI

830.6302 Color Colorl ess viscous liquid Colorless viscous liquid Colorless viscous liquid

830.6303 Physical State Liquid Liquid Liquid

830.6304 Odor Mild, characteristic odor. Slight acrid to none. Practically odorless.

830.6313 Stability to normal and elevated tempera ture,
metals/metal ions Stable at normal temperatures of use and storage. Exposure to elevated temperatures can cause decomposition. Stable at normal temperatures of use and storage. Exposure to elevated temperatures can cause decomposition. Stable at nor mal temperatures of use and storage. Exposure to elevated temperatures can cause decomposition.

830.6314 Oxidation/Reduction:

Chemical Incompatibility: Not applicable. Product contains no oxidizing or reducing agents.

Incompatible with strong acids, s trong bases, and strong oxidizers. Not applicable. Product contains no oxidizing or reducing agents.

Incompatible with strong acids, strong bases, and strong oxidizers. Not applicable. Product contains no oxidizing or reducing agents.

Incompatible with s trong acids, strong bases, and strong oxidizers.

830.6315 Flammability Flash point: 177°C (Closed Cup). Flash point: 191°C (Open Cup). Flash point: 103 o C Flash point: 124 o C

830.6316 Explodability Not applicable. Product is not explosive. Not applicab le. Product is not explosive. Not applicable. Product is not explosive.

830.7000 pH 6.0

- 9.5 Neutral Neutral

830.7050 UV/Visible Absorption Does not absorb light at Does not absorb light at Does not absorb light atPa ge 47 of 58 Guideline

No. Physical and Chemical Properties Triethylene Glyco l Propylene Glycol Dipropylene Glycol

wavelengths >290 nm and therefore it is not expected to be susceptible to direct pho tolysis by sunlight. wavelengths >290 nm

and therefore it is not expected to be susceptible to direct photolysis by sunlight. wavelengths >290 nm

and therefore it is not expected to be susceptible to direct photolysis by sunlight.

830.7200 Melting point:

Freezing point: Not applicable. Product is liquid at room

temperature.

− 4.3°C to −7 °C Not applicable. Product is liquid at room

temperature.

− 59°C Not applicable. Product is liquid at room

temperatur e.

− 59°C

830.7220 Boiling point 288.0°C at 760 mm Hg. 188 °C at 760 mm Hg 230 o C at 760 mm Hg

830.7300 Density 1.1255 g/mL at 25°C 1.032 g/ mL at 25°C 1.022 g/ mL at 25 o C

830.7370 Dissociation Constant ( pKa ) Not applicable. Does not

dissociate in water. Not applicable. Does not

dissociate in water. Not applicable. Does not

dissociate in water.

830.7520 Particle size, fiber length, & diameter

distribution Not Applicable; soluble in

water Not Applicable; soluble

in water Not Applicable; soluble

in water

830.7550 Partition coefficient (Log Kow ) − 1.75

− 0.92

− 0.67

830.7840 Solubility in water Completely soluble. Completely soluble. Completely soluble.

830.7860 Solubility in organic

solvents Soluble in alcohol, benzene, toluene, sparingly soluble in ether and insoluble in petroleum

ether. So luble in ethanol, acetone, and most organic solvents. Soluble in ethanol, acetone, and most organic solvents.

830.7950 Vapor pressure 0.00132 mm Hg at 25°C 0.13 mm Hg at 25°C 0.016 mm Hg at 25°CPa ge 48 of 58 

# Appendix C Ecotoxicology Profile for Propylene Glycol and Dipropyl ene Glycol

Toxicity to Terrestrial Animals

Avian acute oral and dietary toxicity

To establish the toxicity of propylene glycol and dipropylene glycol to birds, the Agency required an acute oral toxicity study using the technical grade of the active ingred ient (TGAI). The preferred test species was either mallard duck (a waterfowl) or bobwhite quail (an upland game bird). The results of submitted studies are provided in the following table ( Table 18 ). The

results indicate that bo th propylene and dipropylene glycol are practically non

- toxic to birds on

an acute oral basis. The studies are acceptable and fulfill guideline requirements (71

- 1/OPPTS 850.2100).

A subacute dietary study using the TGAI was not required for propylene glyc ol or dipropylene glycol because of a lack of acute toxicity in the b obwhite q uail (Table 16)

.

Table 18 A cute Oral Toxicity of Propylene and Dipropylene Glycol to Birds

Species % Active Ingredient (ai) Endpoint (mg/kg) Toxicity

Ca tegory (TGAI) Satisfies

Guidelines/

Comments Reference

Propylene Glycol

Northern bobwhite ( Colinus virginianus ) 100 LD 50 > 2000

NOEL = 2000 Practically non

toxic Yes Campbell and Beavers, 1995

MRID 43762301

Northern bobwhite ( Colinus virginianus ) 99.88 LD 50 > 2150

NOEL = 2150 Practically non

toxic Yes Pedersen, 1995

MRID 43888002

Dipropylene Glycol

Northern bobwhite ( Colinus virginianus ) 100 LD 50 > 2000

NOEL = 2000 Practically non

toxic Yes • core study

• 14

- day test

duration Campbell and
Beavers, 1995

MRID 43760807

Mammals

Both propylene and dipropylene glycol show low acute toxicity to mammals in laboratory studies, and do not produce developmental or reproductive effects at fairly high doses (Table 1 2, Appendix A )

.Pa ge 49 of 58 Table 19 Toxicity of Propylene and Dipropylene Glycol to Mammals (excerpted from Appendix A )

Species Test Type Results

Propylene Glycol

Rat Acute oral LD 50 8000

- 46000 mg/kg (Toxicity Category IV)

Rat 15

- week Subchronic (feeding) NOAEL = 2500 mg/kg/day

Mouse Developmental maternal, reproductive, developmental NOAEL = 10400 mg/kg/day (oral)

Dipropylene Glycol

Rat Acute oral LD 50 >5010 mg/kg (Toxicity category IV)

Mouse 90

- day Subchronic (drinking water) NOAEL = 4790mg/kg/day male, 7430 mg/kg/day femal e

Rat Developmental reproductive, developmental NOAEL = 5000 mg/kg/day



## Toxicity to Aquatic Animals

Freshwater Fish, Acute

In order to establish the acute toxicity of an antimicrobial pesticide to freshwater fish for the listed propylene and dipropylene glycol use patterns , the Agency require d a freshwater fish toxicity study using the TGAI. Data are generally required on only one species for these use patterns unless the active ingredient or principal transformation products are stable in the

environme nt and the LC 50 in the first species is less than or equal to 1 ppm . The preferred test species was rainbow trout (a coldwater fish) or bluegill sunfish (a warmwater fish). No fish acute toxicity testing has been submitted to the Agency. A survey of the EPA/ORD database ECOTOX provided multiple freshwater fish acute toxicity endpoints for propylene glycol, which

are summarized in Table 20

.

The results indicate that propylene glycol

, dipropylene glycol and triethylene glycol are practically non

- toxic to freshwater fish on an acute basis. Since these data are supplemental information, Guideline 72

- 1/850.1075 is not fulfilled; however, because multiple published studies demonstrate very low toxicity to freshwater fish, no further testing is required for propylene glycol

, dipropylene glycol , triethylene glycol

.

Table 20 Ac ute Toxicity of Propylene and Dipropylene Glycol to Freshwater Fish

Species Endpoints Toxicity Category Reference

Propylene Glycol

Gold fish ( Carassius

auratus ) Static 24 hr. LC 50 >5000 ppm ai Practically non

- toxic Bridie et al ., 1979 (ECOTOX reference #623)

Rainbow trout ( Oncorhynchus mykiss ) Static 24

- hr LC 50 = 50,000 ppm Practically non

- toxic Majewski et al ., 1978 (ECOTOX reference # 9 91)

Fathead minnow ( Pimephales promelas ) 48 hr LC 50 = 790 ppm Practically non

- toxic Pillard, 1995 (ECOTOX reference #13727)

Fathead minnow ( Pimephales promelas ) 96 hr LC 50 = 710 ppm Practically non

- toxic Pillard, 1995 (ECOTOX reference #13727)Pa ge 50 of 58 Species Endpoints Toxicity Category Reference

Fathead m innow ( Pimephales promelas ) 96 hr LC 50 = 62,000 ppm ai Practically non

- toxic Pillard, 1995 (ECOTOX reference #13727)

Dipropylene Glycol

Goldfish ( Carassius

auratus ) 24 hr. LC 50 >5000 ppm ai Practically non

- toxic Bridie et al ., 1979 (ECOTOX

reference #623 )

Freshwater Invertebrates, Acute

The Agency required a freshwater aquatic invertebrate toxicity study using the TGAI to establish the acute toxicity of an antimicrobial pesticide to freshwater invertebrates. The preferred test species is Daphnia magna

.

The results of the studies in Table 19 i ndicate that propylene and dipropylene glycol are both practically non

- toxic to freshwater invertebrates. The testing g uideline requirement has been fulfilled (850.1010/72

- 2). Additional data on the acute toxicity of propylene glycol to freshwater

invertebrates were retrieved from the ECOTOX database. Th is information is provided in Table

22 . Because the agency has acceptable, albeit limit 7 study data, no formal agency review of the publ ic literature studies were conducted. The results from the following studies do provide further weight

– of

- evidence that propylene and dipropylene glycol demonstrate very low toxicity

to freshwater invertebrates. While not reviewed t hese results do provi de further weight

- of

evidence that propylene and dipropylene glycol demonstrate very low toxicity to freshwater

invertebrates.

Table 21 Acute Toxicity of Propylene/Dipropylene G lycol to Freshwater Invertebrates

Species % Active Ing redient (ai) Endpoints (ppm) Toxicity Category (TGAI) Satisfies

Guidelines/

Comments Reference

Propylene Glycol

Waterflea ( Daphnia

magna ) 100 48

- hr. EC 50 >110 ppm ai

NOEC > 110 ppm ai Practically

non

- toxic Yes Graves and Swigert, 1995.

MRID 43762302

W aterflea ( Daphnia

magna ) 99.76 48

- hr. EC 50 >1

, 000 ppm ai

NOEC > 1

, 000 ppm ai Practically

non

- toxic Yes Collins, 1995

MRID 43888003

Dipropylene Glycol

Waterflea ( Daphnia

magna ) 100 48

- hr. EC 50 > 109 ppm ai

NOEC > 109 ppm ai Practically

non

- toxic Yes Grave s and Swigert, 1995.

MRID 43760808

7 A limit study or Tier I study refers here to a study where instead of testing several concentrations to establish a dose response and a definitive endpoint value, only a single concentration of at least 100 mg /L (ppm) or the solubility limit, whichever is lower, is tested.Pa ge 51 of 58 Table 22 Open Literature Freshwater Invertebrate Acute Toxicity Data for Propylene Glycol

Species Endpoints Toxicity Category Reference

Waterflea ( Ceriodaphnia

dubia ) 48 hr. LC 50 = 1

, 020 ppm ; NOEC = 660 ppm Practically non

- toxic Pillard, 1995 (ECOTOX reference #13727)
Waterflea ( Ceriodaphnia

dubia ) 48 hr LC 50 = 18

, 340 ppm ai;

NOEC = 13

, 020 ppm ai Practically non

- toxic Pillard, 1995 (ECOTOX reference #13727)
Waterflea ( Ceriodaphnia

dubia ) 48 hr LC 50 = 4

, 919 ppm ai Practically non

- toxic Cornell et al ., 2000 (ECOTOX reference #48385)
Waterflea ( Daphnia

magna ) 48 hr EC 50 > 10

, 000 ppm Practically non

- toxic Kuhn et al ., 1989 (ECOTOX reference #846)

Estuarine and Marine Organisms, Acute Toxicity

Acute toxicity testing with estuarine and marine organisms using the TGAI is required when the

end

- use product is intended for direct application to the marine/estuarine environment or effluent containing the active ingredient is expected to reach this env ironment. Neither propylene gl ycol nor dipropylene glycol has such uses on their labels and neither is exposure expected to occur.

T herefore, testing with marine/estuarine organisms is not anticipated to be required. Some

information on the acute toxici ty of propylene glycol to an inland saltwater lake invertebrate species, brine shrimp, was found in ECOTOX, and the results are provided in Table 23

. Estimates of propylene gylcol and dipropylene gylcol (neutral organics class) ac ute toxicity using ECOSAR v1.10 are 24,391 mg/L and 32,012 mg/L, respectively, for a saltwater fish and 119,000 mg/L and 142,000 mg/L, respectively, for a mysid.

Table 23 Acute Toxicity of Propylene Glycol to Inland Saltwater Lak e Species

Species Endpoints Toxicity Category Reference

Brine Shrimp ( Artemia salina ) Static 24 hr. LC 50 > 10000 ppm Practically non

toxic Price et al ., 1974 (ECOTOX reference #2408)

Aquatic Animals , Chronic Toxicity

There are no submitted chronic data in the files and n o comparable endpoints were found in the open literature ECOTOX database. Estimates of propylene gylcol and dipropylene gylcol (neutral organics class) chronic toxicity to aquatic animals using ECOSAR v1.10 range from 413 to 1,894 mg/L f or freshwater animals and 484 to 26,858 mg/L for saltwater animals ( Table 24 ). Chronic toxicity testing (Fish early life stage, 850.1300/72

- 4a and aquatic invertebrate life cycle,

850.1400/72

- 4b) is not required for the currently registered uses of propylene glycol or dipropylene glycol. Therefore, aquatic animal chronic testing is not anticipated to be required at
this time.Pa ge 52 of 58 Table 24 Chronic Toxicity of Propylene Glycol and Dipropylene Glycol to Aquatic

Animals

Species Propylene Glycol Chv Dipropylene Glycol Chv Reference

Fish, Freshwater 1,422 mg/L 1,894 mg/L ECOSAR v1.10
Daphnid, Freshwater Invertebrate 413 mg/L 569 mg/L ECOSAR v1.10

Fish, Saltwater 484 mg/L 693 mg/L ECOSAR v1.10
Mysid, Estuarine/Ma rine Invertebrate 23,526 mg/L 26,858 mg/L ECOSAR v1.10

Chv = geomet ric mean of a NOEC and LOEC value



## Toxicity to Plants

No data, such as phytotoxicity, were available from submitted studies or open literature to address the risk to plants. Estimates for toxicity to green algae for propylene gylcol and dipropylene gylcol, as neutral organics, from ECOSAR v1.10 consist of 96

- h IC 50 values of 5,611 mg/L and 7,567 mg/L, respectively, and Chv (geometric mean of a NOEC and LOEC) values of 329 mg/L and 476 mg/L , respectively. This information is sufficient for any hazard labeling. Additionally, exposure to plants is not expected from the current registered uses of propylene glycol and dipropylene glycol. Therefore, p lant toxicity testing is not anticipated to be required at this time.



### ECOSAR Version 1.10 Results Page

**— Propylene Glygol** 

SMILES : OCC(O)C
CHEM : 1,2

- Propanediol

CAS Num: 000057

- 55

- 6

ChemID1:

MOL FOR: C3 H8 O2

MOL WT : 76.10

Log Kow:

- 0.782 (EPISuite Kowwin v1.68 Estimate)

Log Kow: (User Entered)

Log Kow:

- 0.92 (PhysProp DB exp value

- for comparison only)
Melt Pt: (User Entered for Wat Sol estimate)

Melt Pt:

- 60.00 (deg C, PhysProp DB exp value for Wat Sol est) Wat Sol: 1E+006 (mg/L, EPISuite WSKowwin v1. 43 Estimate)

Wat Sol: (User Entered)
Wat Sol: 1E+006 (mg/L, PhysProp DB exp value)

-------------------------------------- Values used to Generate ECOSAR Profile

-------------------------------------- Log Kow:

- 0.782 (EPISuite Kowwin v1.68 Estimate)
Wat Sol: 1E+006 (mg/L, PhysProp DB exp value)

------------------------------------------------ Available Measured Data from ECOSAR Training Set

------------------------------------------------

No Data Available

------------------ --------------------Pa ge 53 of 58 ECOSAR v1.1 Class

- specific Estimations

-------------------------------------- Neutral Organics

Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

=========================== ================== ======== ====== ========== Neutral Organics : Fish 96

- hr LC50 19700.475 Neutral Organics : Fish 14

- day LC50 18018.713

Neutra l Organics : Daphnid 48

- hr LC50 8688.484 Neutral Organics : Green Algae 96

- hr EC50 5611.575 Neutral Organics : Fish ChV 1422.289 Neutral Organics : Da phnid ChV 412.807 Neutral Organics : Green Algae ChV 329.329 Neutral Organics : Fish (SW) 96

- hr LC50 24391.777 Neutral Organics : Mysid 96

- hr LC50 1.19e+005 Neutral Organics : Fish (SW) ChV 484.236 Neutral Organics : Mysid (SW) ChV 23526.172 Neutral Organics : Earthworm 14

- day LC50 257.073

No te: * = asterisk designates: Chemical may not be soluble enough to measure this predicted effect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES)
are reported.

----------------- ------------- Class Specific LogKow Cut

- Offs

------------------------------ If the log Kow of the chemical is greater than the endpoint specific cut

- offs presented below, then no effects at saturation are expected for those endpoints.

Neutral Organics:

- --------------- Maximum LogKow: 5.0 (Fish 96

- hr LC50; Daphnid LC50, Mysid LC50) Maximum LogKow: 6.0 (Fish 14

- day LC50; Earthworm LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV)



### ECOSAR Version 1.10 Results Page

**— Dipropylene Glycol** 

SMILES : CC(O)COCC(O)C CHEM : Propanol, oxybis

CAS Num: 025265

- 71

- 8

ChemID1:

MOL FOR: C6 H14 O3

MOL WT : 134.18

Log Kow:

- 0.639 (EPISuite Kowwin v1.68 Estimate)
Log Kow: (User Entered)
Log Kow: (PhysProp DB exp value

- for co mparison only)
Melt Pt: (User Entered for Wat Sol estimate)

Melt Pt:

- 40.00 (deg C, PhysProp DB exp value for Wat Sol est, <

- 40) Wat Sol: 1E+006 (mg/L, EPISuite WSKowwin v1.43 Estimate)

Wat Sol: (User Entered)

Wat Sol: 1E+006 (mg/L, PhysProp DB exp value)

-------------------------------------- Values used to Generate ECOSAR Profile

-------------------------------------- Log Kow:

- 0.639 (EPISuite Kowwin v1.68 Estimate)
Wat Sol: 1E+006 (mg/L, PhysProp DB exp value )Pa ge 54 of 58 ------------------------------------------------ Available Measured Data from ECOSAR Training Set

------------------------------------------------

No Data Available

-------------------------------------- ECOSAR v1.1 Class

- specific Estimations

-- ------------------------------------ Neutral Organics

Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

=========================== ================ == ======== ====== ========== Neutral Organics : Fish 96

- hr LC50 25833.533 Neutral Organics : Fish 14

- day LC50 23787.684 Neutral Organics : Daphnid 48

- hr LC50 1 1541.943 Neutral Organics : Green Algae 96

- hr EC50 7567.450 Neutral Organics : Fish ChV 1894.386 Neutral Organics : Daphnid ChV 569.086 Neutral Organics : Green Algae ChV 476.003 Neutral Organics : Fish (SW) 96

- hr LC50 32012.744 Neutral Organics : Mysid 96

- hr LC50 1.42e+005 Neutral Organics : Fish (SW) ChV 693.606 Neutral Organics : Mysid (SW) ChV 26857.861 Neutral Organics : Earthworm 14

- day LC50 438.047

Note: * = asterisk designates: Chemical may not be soluble enou gh to measure this predicted effect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES)
are reported.

------------------------------ Class Specific LogKow Cut

- Offs

----------------- ------------- If the log Kow of the chemical is greater than the endpoint specific cut

- offs presented below, then no effects at saturation are expected for those endpoints.

Neutral Organics:

---------------- Maximum LogKow: 5.0 (Fish 96

- hr LC50; Daphnid LC50, Mysid LC50) Maximum LogKow: 6.0 (Fish 14

- day LC50; Earthworm LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV)

------------------------------------------------------------------------------Pa ge 55 of 58 

# Appendix D Ecotoxicology Profile for Triethylene Glycol

Toxicity to Terrestrial Animals

Avian acute oral and dietary toxicity

To establish the toxicity of triethylene glycol to birds, the Agency required an acute oral toxicity study using the technical grade of the active ingredient (TGAI). The preferr ed test species wa s either mallard duck (a waterfowl) or bobwhite quail (an upland game bird). The results of submitted studies are provided in the following table

. The results indicate that triethylene glycol

is practically non

- toxic to birds on an acu te oral basis. The studies are acceptable and fulfill guideline requirements (71

- 1/OPPTS 850.2100).

Mammals

Triethylene glycol show s low acute toxicity to mammals in laboratory studies (see Table Appendix A)

.

Table 25 Toxicity of Triethylene Glycol to Mammals (excerpted from Appendix A )

Species Test Type Results

Rat Acute oral LD 50 15,000

- 22,000 mg/kg

- bw (Toxicity Category IV)



## Toxicity to Aquatic Receptors

Freshwater Fish , Acute

The results indicate that triethylene glycol is practically non

- toxic to freshwater fish on an acute basis. Since these data are supplemental information, Guideline 72

- 1/850.1075 is not fulfilled; however, because multiple published studies demonstrate very low toxicity to freshwater fish for the gl cols , no further testing is anticipated to be required for triethylene glycol at this time

.

Table 26 Ac ute Toxicity of Triethylene Glycol to Freshwater Fish

Species Endpoints Toxicity Category Reference Bluegill sunfish ( Lepomis

macrochirus ) 96 hr LC 50 = 10,000 ppm Practically non

- toxic Verschuren, 1983

Fathead minnow ( Pimephales promelas ) 96 hr LC 50 = 59,900

– 77,400

ppm Practically non

- toxic Geiger et al ., 1988Pa ge 56 of 58 Freshwater Invertebrates, Acute

The Agency requires a freshwate r aquatic invertebrate toxicity study using the TGAI to establish the acute toxicity of an antimicrobial pesticide to freshwater invertebrates. The preferred test species is Daphnia magna

.

No data have been submitted for triethylene glycol and no data wa s found in the EPA/ORD

ECOTOX database. An e stimate of triethylene gylcol (neutral organics class) acute toxicity using ECOSAR v1.10 is 116,000 mg/L for a freshwater daphnid (see ECOSAR results page at end of this appendix). Triethylene glycol is expecte d to be practically nontoxic on an acute basis

to freshwater invertebrates. No additional acute data are anticipated to be required for the

assessment.

Estuarine and Marine Organisms, Acute Toxicity

Acute toxicity testing with estuarine and marine organis ms (a fish, a mollusk, and a shrimp) using the TGAI is required when the end

- use product is intended for direct application to the marine/estuarine environment or effluent containing the active ingredient is expected to reach

this environment. The triethy lene glycol uses are not expected to result in such exposure.

T herefore, testing with marine/estuarine organisms is not anticipated to be required. However, a sheepshead minnow study and a mysid study were conducted by EPA (Mayer, 1986). Additionally, t he acute toxicity of triethylene glycol to another fish species (Inland silverside) was found in ECOTOX, and the results are provided in Table 27

. Triethylene glycol is practically nontoxic to estuarine/marine fish and invertebra tes based on this data. No additional

acute data are anticipated to be required for the assessment.

Table 27 Open Literature Estuarine/Marine Fish and Invertebrate Acute Toxicity Data for Triethylene Glycol

Species Endpoints Toxic ity Category Reference
Sheepshead minnow ( Cyprinodon variegatus ) 96 hr LC 50 = 48,000 ppm Practically non

- toxic Mayer, 1986

MRID 40228401

Inland silverside Menidia beryllina 96 hr LC 50 = 10,000 ppm Practically non

- toxic Verschuren, 1983

Mysid ( Mysidopsis bahia ) 96 hr LC 50 = 11,000 ppm Practically non

- toxic Mayer, 1986

MRID # 40228401 Aquatic Animals , Chronic Toxicity

There are no submitted chronic data in the files and n o comparable endpoints were found in the open literature ECOTOX database. Estimates of triethylene gylcol (neutral organics class) chronic toxicity to aquatic animals using ECOSAR v1.10 range from 4,288 to 18,640 mg/L for freshwater animals and 3,885 to 873,000 mg/L for saltwater animals ( Table 28 ). The model

ap pears to underestimate chronic toxicity to aquatic animals. There is a laboratory acute study for a mysid with a 96

- hr LC 50 (concentration at which 50% of exposed organisms are expected to die) of 11,000 ppm but the modeled chronic value is 873,000 ppm, w hich is not appropriate. Chronic toxicity testing (Fish early life stage, 850.1300/72

- 4a and aquatic invertebrate life cycle,

850.1400/72

- 4b) is not anticipated to be required for the currently registered uses of triethylene glycol.Pa ge 57 of 58 Table 28 Chronic Toxicity of Triethylene Glycol to Aquatic Animals

Species Triethylene Glycol Chv Reference

Fish, Freshwater 18,640 mg/L a ECOSAR v1.10
Daphnid, Freshwater Invertebrate 4,288 mg/L ECOSAR v1.10

Fish, Saltwater 3,885 mg/L ECOSAR v1.10
Mysid, Estuarine/Marine Invertebrate 873,000 mg/L b ECOSAR v1.10

Chv = geomet ric mean of a NOEC and LOEC value

b Model may not be appropriate for triethylene gylcol as the laboratory acute 96

- hr LC 50 values for freshwater fish of 10,000 to 77,400 ppm is l ower than the modeled 96

- hr LC 50 value for freshwater fish of 287,000 ppm (see Table

27 )

.
b Model is not appropriate for triethylene gylcol as the chronic value is above the laboratory 96

- hr LC 50 value of 11,000 pp m (see Table 27 )

. 

## Toxicity to Plants

No data, such as phytotoxicity, were available from submitted studies or open literature to address the risk to plants. Estimates for toxicity to green algae for triethylene gy lcol, as a neutral organic, from ECOSAR v1.10 consist of a 96

- h IC 50 value of 67,639 mg/L and a Chv (geometric mean of a NOEC and LOEC) value of 2,486 mg/L. This information is sufficient for any hazard labeling. Additionally, exposure to plants is not e xpected from the current registered uses of triethylene glycol. Therefore, p lant toxicity testing is not anticipated to be required at this time.



### ECOSAR Version 1.10 Results Page

**– Triethylene Glycol** 

SMILES : O(CCOCCO)CCO
CHEM : Ethanol, 2,2

- [1,2

- et hanediylbis(oxy)]bis

CAS Num: 000112

- 27

- 6

ChemID1:

MOL FOR: C6 H14 O4

MOL WT : 150.18

Log Kow:

- 1.748 (EPISuite Kowwin v1.68 Estimate)
Log Kow: (User Entered)

Log Kow:

- 1.75 (PhysProp DB exp value

- for comparison only)

Melt Pt: (User Entered for Wat Sol estimate)

Melt Pt:

- 7.00 (deg C, PhysProp DB exp value for Wat Sol est) Wat Sol: 1E+006 (mg/L, EPISuite WSKowwin v1.43 Estimate)

Wat Sol: (User Entered)
Wat Sol: 1E+006 (mg/L, PhysProp DB exp value)

-------------------------------------- Values used to Generate ECOSAR Profile

-------------------------------------- Log Kow:

- 1.748 (EPISuite Kowwin v1.68 Estimate)
Wat Sol: 1E+006 (mg/L, PhysProp DB exp value)

----------------------------- ------------------- Available Measured Data from ECOSAR Training Set

------------------------------------------------Pa ge 58 of 58 Measured CAS No Organism Duration End Pt mg/L (ppm) Ecosar Class

Ref erence

=========== ========== ========== ====== ========== ===========================

========================= 000112

- 27

- 6 Fish 96

- hr LC50 59900 Neutral organics DUL

000112

- 27

- 6 Fish 96

- hr LC50 70200 N eutral organics DUL

000112

- 27

- 6 Fish 96

- hr LC50 77400 Neutral organics DUL

000112

- 27

- 6 Fish 14

- day LC50 62601.4 Neutral organics

Konemann, 1981

--------------------------------------
E COSAR v1.1 Class

- specific Estimations

-------------------------------------- Neutral Organics

Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

===== ====================== ================== ======== ====== ========== Neutral Organics : Fish 96

- hr LC50 2.87e+005 Neutral Organics : Fish 14

- day LC50 2.51e+005 Neutral Organics : Daphnid 48

- hr LC50 1.16e+005 Neutral Organics : Green Algae 96

- hr EC50 67639.422 Neutral Organics : Fish ChV 18639.736 Neutral Organics : Daphnid ChV 4288.514 Neutral Organics : Green Algae ChV 2486.059 Neutral Organics : Fish (SW) 96

- hr LC50 3.53e+005 Neutral Organics : Mysid 96

- hr LC50 3.32e+006 * Neutral Organics : Fish (SW) ChV 3885.237 Neutral Organics : Mysid (SW) ChV 8.73e+005 Neutral Organics : Earthworm 14

- day LC50 639.014

Note: * = asterisk de signates: Chemical may not be soluble enough to measure this predicted effect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES)
are reported.

------------------------------ Class Specific LogKow Cut

- Offs

------------------------------ If the log Kow of the chemical is greater than the endpoint specific cut

- offs presented below, then no effects at saturation are expected for those endpoints.

Neutral Organics:

---------------- Maxi mum LogKow: 5.0 (Fish 96

- hr LC50; Daphnid LC50, Mysid LC50) Maximum LogKow: 6.0 (Fish 14

- day LC50; Earthworm LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV)

------------------------------------------------------------------------ ------