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Chlorine Dioxide Registration Review Team

Human Health & Environmental Effects

Tim McMahon, Ph.D.

Tim Dole

Kristin Rury

Don Wilbur

David Bays

Jim Breithaupt

Siroos Mostaghimi

Risk Management

Stephen Savage

Rose Kyprianou

Ben Chambliss

Demson Fuller

Office of General Counsel

Philip Ross
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TERMS, ABBREVIATIONS AND SYMBOLS

ACGIH American Conference of Governmental Industrial Hygienists

AEGL acute exposure guideline levels

A.I. or a.i. active ingredient

aPAD acute population adjusted dose 

ASRI activated sludge respiration inhibition

atm-m3

/mole atmospheric pressure-cubic meter per mole

BCF bioconcentration factor 

°C degrees Celsius

CAS Chemical Abstracts Service 

CFR Code of Federal Regulations 

ClO2 chlorine dioxide

CMA Chemical Manufacturers Association

CO2 carbon dioxide

COC concentration-of-concern

cPAD chronic population adjusted dose 

DCI data call-in

EC50 median (or 50 percent) effect concentration

ECOTOX ECOTOXicology

EDI estimated daily intake

EDSP Endocrine Disruptor Screening Program 

E-FAST Exposure and Fate Assessment Screening Tool

EPI Suite Estimation Program Interface Suite

EPA Environmental Protection Agency

EUP end-use product

FCN Food Contact Notification

FDA Food and Drug Administration 

FFDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act 

FWP Final Work Plan

g/mol grams per mole

GLN guideline number

HVAC Heating, Ventilation, and Air Conditioning

IDLH immediately hazardous to life and health

IDREAM Indirect Dietary Residential Exposure Assessment Model

IDS Incident Data System 

Koc organic carbon normalized soil-water partition coefficient

Kd soil-water partition coefficient

Kow octanol-water partition coefficient

LC50 median (or 50 percent) lethal concentration

LD50 median (or 50 percent) lethal dose

LOAEC lowest-observed-adverse-effect-concentration

LOC level of concern

LOD limit of detection

LOEC lowest-observed-effect-concentration

LOAEL lowest-observed-adverse-effect-level

Log Kow logarithm of the octanol-water partition coefficient

μg microgram
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ml/g milliliter per gram

mg/kg milligram per kilogram

mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury

MOE margin of exposure 

MRID Master Record Identification Number

MRL maximum residue limit 

N/A not applicable 

nm nanometers

NIOSH National Institute for Occupational Safety and Health

NOAEC no-observed-adverse-effect-concentration

NOAEL no-observed-adverse-effect-level

NRC National Research Council

OCSPP Office of Chemical Safety and Pollution Prevention

OECD Organization for Economic Co-operation and Development

OPP Office of Pesticide Programs

ORE occupational and residential exposure

OSHA Occupational Safety and Health Administration

PAD population adjusted dose

PC Code Pesticide Chemical Code

PDM Probabilistic Dilution Model

PEL permissible exposure limit

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

PHED Pesticide Handler’s Exposure Data

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

dissociation constant of a solution

POD point of departure

ppb parts per billion 

ppm parts per million

PWP Preliminary Work Plan

RED Reregistration Eligibility Decision

RfC reference concentration

RfD reference dose

ROC residue of concern

RTU ready-to-use

SAR structure activity relationship

SF safety factor

STEL short-term exposure limit

TEP typical end-use product

TGAI technical grade active ingredient

TMDL total maximum daily loads

TLV threshold limit value

TWA time weighted average

UF uncertainty factor

UV/VIS ultraviolet/visible light absorption

WWTPs wastewater treatment plants
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Table of Contents

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

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

1.2 Updates to the Work plan................................................................................................. 7

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

1.4 Chemical Identification and Properties.......................................................................... 10

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

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

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

1.5.3 Usage Information .................................................................................................. 13

1.6 Regulatory History ......................................................................................................... 13

1.6.1 Tolerance Information ............................................................................................ 14

1.6.2 Registration Eligibility Decision (RED)................................................................. 16

1.7 Incidents......................................................................................................................... 17

1.7.1 Human Health ......................................................................................................... 17

1.7.2 Ecological ............................................................................................................... 18

2 Anticipated Data Needs ........................................................................................................ 18

3 Human Health Risk Assessment........................................................................................... 21

3.1 Existing Toxicological Endpoints.................................................................................. 21

3.1.1 Comparison to Other Endpoints.............................................................................. 22

3.2 Dietary Exposure............................................................................................................ 23

3.2.1 Food ........................................................................................................................ 24

3.2.2 Drinking Water ....................................................................................................... 25

3.3 Occupational and Residential Exposures....................................................................... 26

3.3.1 Occupational Handler Exposure ............................................................................. 26

3.3.2 Occupational Post Application Exposures.............................................................. 26

3.3.3 Residential Handler Exposures............................................................................... 27

3.3.4 Residential Post-Application Exposures................................................................. 27

3.4 Aggregate and Cumulative Exposure............................................................................. 30

3.4.1 Aggregate Exposures.............................................................................................. 30

3.4.2 Cumulative Exposures............................................................................................ 30

4 Environmental Risk Assessment........................................................................................... 31

4.1 Environmental Fate Assessment .................................................................................... 31

4.1.1 Water Quality.......................................................................................................... 32

4.2 Conceptual Models for Environmental Exposure Pathways.......................................... 32

4.3 Ecological Effects Assessment....................................................................................... 33

4.3.1 Measures of Effect (Ecotoxicology Endpoints)...................................................... 33

4.4 Exposure Analysis Plan.................................................................................................. 34

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates ............................................ 34

4.4.2 Screening Level Down-the-Drain Analysis............................................................ 34

4.5 Effects Analysis Plan ..................................................................................................... 35

5 Endocrine Disruptor Screening Program (EDSP)................................................................. 35

6 Label Changes....................................................................................................................... 36

7 Next Steps36

8 References............................................................................................................................. 37
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Appendix A Toxicology Profile............................................................................................... 38

Appendix B Environmental Fate ............................................................................................. 52

Appendix C Ecotoxicology Profile.......................................................................................... 54

Appendix D Product Chemistry............................................................................................... 68

Appendix E Comments Received Concerning the Preliminary Work Plan............................ 70

List of Tables

Table 1 – Risk Assessments/Data Needs for Reg. Review: Chlorine Dioxide/Sodium Chlorite... 8

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

Table 3 – Chemical Identification of Chlorine Dioxide/Sodium Chlorite.................................... 10

Table 4 – Physical, Chemical and Fate Properties for Chlorine Dioxide/Sodium Chlorite ......... 10

Table 5 – Chlorine Dioxide (ClO2) and Sodium Chlorite Registered Uses.................................. 12

Table 6 – FDA Food Contact Notifications for Chlorine Dioxide and Sodium Chlorite............. 14

Table 7 – FDA Direct Food Additive Regulations for Chlorine Dioxide and Sodium Chlorite .. 15

Table 8 – FDA Indirect Food Additive Regulations for Chlorine Dioxide and Sodium Chlorite 16

Table 9 – Label Changes Specified in the Chlorine Dioxide/Sodium Chlorite RED................... 16

Table 10 – Studies Anticipated as Needed for the Registration Review of Chlorine 

Dioxide/Sodium Chlorite.............................................................................................................. 19

Table 11 – Studies Required by the Post-RED DCI for Chlorine Dioxide/Sodium Chlorite....... 19

Table 12 – Existing Toxicological Endpoints for Chlorine Dioxide/Sodium Chlorite ................ 21

Table 13 – Summary Table of AEGL Values for Chlorine Dioxide (ppm) ................................. 23

Table 14 – Occupational Handler Exposure Scenarios for Chlorine Dioxide.............................. 26

Table 15 – Residential Handler Exposure Scenarios for Chlorine Dioxide ................................. 27

Table 16 – Maximum and Average Chlorine Dioxide Measurements in Automobiles ............... 28

Table 17 – Residential Post-Application Exposure Scenarios for Chlorine Dioxide ................... 30

Table 18 – Ecological Effects Endpoints Selected for Sodium Chlorite/Chlorine Dioxide......... 33
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1 Introduction

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

Agency”) Final Work Plan (FWP) for chlorine dioxide (including sodium chlorite), herein 

referred to as chlorine dioxide. The FWP document explains what EPA's Office of Pesticide 

Programs (OPP) knows about chlorine dioxide, 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 chlorine dioxide’s

review.

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

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

docket, to inform the public of what it knows about chlorine dioxide and what types of new data 

or other information would be helpful for the Agency to receive as it moves toward a decision on 

chlorine dioxide.

1.1 Statutory and Regulatory Authority

The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All 

pesticides distributed or sold in the United States generally must be registered by the USEPA 

based on scientific data showing that they will not cause unreasonable risks to human health or 

the environment when used as directed on product labeling. The registration review program is 

intended to make sure that, as the ability to assess risk evolves and as policies and practices 

change, all registered pesticides continue to meet the statutory standard of no unreasonable 

adverse effects to human health or the environment. Changes in science, public policy, and 

pesticide use practices will occur over time. Through the registration review program, the 

Agency periodically reevaluates pesticides to make sure that as change occurs, products in the 

marketplace can be used safely. Information on this program is provided at 

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

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

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

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

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

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

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

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

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

1.2 Updates to the Work plan

Since the publication of the Chlorine Dioxide/Sodium Chlorite Preliminary Work Plan (PWP), 

the Agency has made the following updates: 

• Updated the Table 1 Risk Assessment Data Needs 
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• Updated Table 5 to revise application rates for drinking water, metal working fluids and 

secondary oil recovery water.

• Updated Table 10 Studies Anticipated for Registration Review Time Frame, Use Sites

and Footnotes.

• Updated the study review status in Table 11, the “Studies Required by the Post-RED 

DCI.”

• Updated Table 12 and Appendix A, “Existing Toxicological Endpoints for Chlorine 

Dioxide/Sodium Chlorite” and “Toxicity Profile.”

• Deleted “Guidance for Commenters” section.

• Updated numerous EPA website links throughout the document due to EPA’s web 

transformation.

• Updated discussion of label recommendations in Section 6. 

• Updated Section 7, “Next Steps.”

• Added Appendix E, which includes the Agency’s response to comments submitted 

regarding the PWP.

The Agency received one submission during the public comment period on the initial docket and 

one late submission. See Appendix E for the Agency’s response to these comments.

The comments received resulted in modification to the anticipated data needs for the Chlorine 

Dioxide/Sodium Chlorite work plan. This document makes final the work plan for the Chlorine 

Dioxide/Sodium Chlorite registration review process.

1.3 Case Overview

The Preliminary Work Plan (PWP) for Chlorine Dioxide/Sodium Chlorite was published on June 

25, 2015, and the 60-day comment period ended on September 24, 2015. The Agency received 

two submissions. Documents associated with this registration review case can be viewed at 

http://www.regulations.gov in docket EPA-HQ-OPP-2015-0267. Tables 1 and 2 below 

summarize the issues relevant to this registration review case and the anticipated registration 

review schedule. . 

Table 1 – Risk Assessments/Data Needs for Reg. Review: Chlorine Dioxide/Sodium 

Chlorite

Risk Assessment 

Assessment 

Necessary to 

Support 

Registration 

Review

Date of 

Most 

Recent 

Assessment

Type of 

Assessment 

Required 

(New/

Updated)

Data Anticipated as Needed

(See Table 10 for details)*

Dietary (food) Yes 2006 Updated

Immunotoxicity

Acute Neurotoxicity

Subchronic Neurotoxicity

Residue Chemistry Data

Crop Field Trials
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Risk Assessment 

Assessment 

Necessary to 

Support 

Registration 

Review

Date of 

Most 

Recent 

Assessment

Type of 

Assessment 

Required 

(New/

Updated)

Data Anticipated as Needed

(See Table 10 for details)*

Dietary (drinking water) Yes 2006 Updated

Immunotoxicity

Acute Neurotoxicity

Subchronic Neurotoxicity

Occupational Handler Yes 2006 Updated None – Data required by RED DCI

Occupational Post 

Application - Inhalation Yes 2006 Updated None

Residential Handler Yes 2006 Updated None – Data required by RED DCI

Residential Post 

Application - Incidental 

Oral and Dermal 

Yes 2006 Updated Surface Residue Data

Residential Post 

Application - Inhalation Yes 2006 Updated Post Application Inhalation Indoor Exposure

Aggregate Yes 2006 Updated

Immunotoxicity

Acute Neurotoxicity

Subchronic Neurotoxicity Residue 

Chemistry Data

Surface Residue Data

Cumulative No

(see section 3.4.2) N/A None None

Tolerance Review No

(see section 1.5.1) N/A None None

Ecological Yes 2006 Updated None – Data required by RED DCI

N/A = Not applicable

* Table 10 is a summary of the anticipated risk assessments and data needs for Registration Review. For data called in through the 

post-Reregistration Eligibility Decision (RED) Data Call-In (DCI), refer to Table 11.

Table 2 – Anticipated Registration Review Schedule

Anticipated Activity Target Date* Completion Date

Phase 1: Opening the Docket 

Open Docket and 60-Day Comment Period for Preliminary Work Plan 2015-06 2015-06-25

Close Public Comment Period 2015-09 2015-09-24

Phase 2: Case Development 

Issue Final Work Plan 2015-12

Issue Data Call-In (DCI) 2016-12

Receive Data to be Considered in Risk Assessment 2018-12

Open 30-Day Public Comment Period for Preliminary Risk Assessment(s) 2020-06

Close Public Comment Period 2020-07

Phase 3: Registration Review Decision and Implementation 
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Open 60-Day Public Comment Period for Proposed Decision 2020-12

Close Public Comment Period 2021-02

Issue Final Decision 2021-06

Begin Post-Decision Follow-up 2021

Total (years) 6

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

respect to the active ingredients in this case).

1.4 Chemical Identification and Properties

Table 3 presents the active ingredients to be assessed in case 4023: chlorine dioxide (PC Code 

020503) and sodium chlorite (PC Code 020502). A summary of the chemical and physical 

properties for chlorine dioxide and sodium chlorite is provided below.

Chlorine dioxide contains a single electron in its valence shell and this makes it a very reactive 

chemical. It has a short half -life in water and in air. Chlorine dioxide is usually generated at the 

use site, using precursor chemicals, and stored in a closed container. However, it cannot be 

stored for a prolonged period of time as it is highly reactive and breaks down readily into 

chloride and oxygen. The immediate conversion is to chlorite ion. The chlorite ion may also be 

used to generate chlorine dioxide under appropriate acidic conditions.

Table 3 – Chemical Identification of Chlorine Dioxide/Sodium Chlorite

Chemical Name Chlorine dioxide Sodium chlorite

Chemical

Classification Oxide of chlorine Oxide of chlorine

PC Code 020503 020502

CAS Number 10049-04-4 7758-19-2

Molecular Formula ClO2 Na ClO2

Molecular Weight (grams/mole) 67.45 90.45

Molecular Structure

The product chemistry information relevant to risk assessment is summarized in Table 4, and the 

details of the product chemistry and environmental fate information are discussed in Appendix 

D.

Table 4 – Physical, Chemical and Fate Properties for Chlorine Dioxide/Sodium Chlorite

GLN No. Parameter Chlorine dioxide Sodium chlorite Source

830.7200 Melting point (oC) -59 C About 200oC Gates, Don, 1998

830.7220 Boiling point (oC) 11 C NA Gates, Don, 1998
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GLN No. Parameter Chlorine dioxide Sodium chlorite Source

830.7300 Density 1.64 g/ml at 10 C 2.468 g/ml MRID# 41467601

830.7550 Octanol-water partition 

coefficient at 25 oC (Log Kow)

-3.2

Not bioaccumulative

-7.17; not 

bioaccumulative EPI Suite (ver.4.1.)

830.7840 Solubility in water (mg/L) Miscible in water: up to 

60,000 mg/L 608,000 mg/L MRID# 41467601

830.7950 Vapor pressure (mmHg) 490 mm Hg at 0 C;

>760 mm Hg at 25o C

It is a solid; vapor 

pressure has not 

been measured.

MRID# 41467602

835.2120 Hydrolysis at 25 o

C: pH 5, 7 

&9 (days)

At pH 10, and above chlorine 

dioxide hydrolyzes into 

chlorate and chloride ions

Inorganic ionic 

substance, no data EPA RED

835.31101 Ready biodegradation Not Applicable Not Applicable

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

millimeters of mercury;

1. Based on ASRI results, a ready biodegradation study would normally be required for these compounds.

However, these compounds are inorganic and biodegradation data do not apply.

1.5 Use/Usage Description

1.5.1 Registrations

There is one manufacturing use product registration for chlorine dioxide that contains one 

percent active ingredient and six formulation intermediate products registrations for sodium 

chlorite that contain 25-80 percent a.i. There are 19 EPA-registered end use products (EUPs) that 

contain chlorine dioxide as an a.i. The percent a.i. for chlorine dioxide ranges from 0.02 percent 

to five percent, and the formulations include soluble concentrate and ready-to-use (RTU) 

solution. There are 75 EUPs that contain sodium chlorite as an a.i. The percent a.i. for sodium 

chlorite ranges from 0.63 percent to 80 percent, and the formulations include soluble concentrate, 

RTU solution, impregnated material, dust, pelleted/tableted, solid, granular, and wettable 

powder.

1.5.2 Summary of Registered Uses

Table 5 presents a summary of the registered uses of chlorine dioxide that will be assessed in this 

registration review. Chlorine dioxide as an aqueous solution can be applied by the following 

application methods: open pour, meter in, mop or sponge, dip, spray and fog. Chlorine dioxide

can also be applied as a gas for fumigation treatments. Because chlorine dioxide gas is not stable, 

it is generated on-site by using sodium chlorite and a weak acid such as sodium citrate. When 

used as a fumigant for the purposes of sterilizing areas potentially contaminated with 

microorganisms of public health concern, such as anthrax, large scale computer controlled gas 

generation systems are used to achieve and maintain a target air concentration of 3000 ppm for 

specified period of time. When used as a deodorizing treatment for the purposes of killing odor 

causing bacteria, passive gas generation systems are used and the target air concentrations are 

orders of magnitude lower.
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Table 5 – Chlorine Dioxide (ClO2) and Sodium Chlorite Registered Uses

Use Application Rate 

(PPM ClO2) Application Methods

Aquatic Areas

Ornamental ponds/aquaria

Retention Basins/ponds

5 to 10 

3 to 5 

Open Pour

Open Pour

Agricultural Premises and Equipment

Animal and poultry houses 

Mushroom Houses – empty

Greenhouse irrigation and evaporative cooling systems

Potato Seed Piece Storage

Poultry Drinking Water

Shoe Baths

Transportation Vehicles

200

200 to 1039 

20

5 to 500 

1 to 18

5 to 50 

200 to 2000

Mop, Spray, Fog

Spray, Fog

Open Pour

Dip, Spray

Meter In

Open Pour

Spray or Foam

Commercial/Institutional/Industrial (CII) Premises and Equipment

Commercial Transportation Vehicles and Vessels

Shipping and storage containers

General Premises and Equipment

Laundry (Commercial)

160 to 2000

Unknown

100 to 2000

2000

Mop, Spray, Fog

Pouch Fumigation

Mop, Spray, Fog, Fumigate

Mop, Spray, Fog

Food Handling Premises and Equipment

Beverage plants and breweries

Conveyor Belt Lubricant

Eating Establishments

Equipment and Utensils

Egg Handling Rooms and Packing Plants

Egg Washing Treatments

Fish/Seafood Processing Plants 

Food Processing Plants

Food Processing Water Systems

Fresh fruit and vegetable packing plants

Fruit and Vegetable Wash

Meat and Poultry Processing Plants

Pasteurizer, warmer, cannery cooling water systems

Potatoes1

20 to 520

20

208 to 2000

20 to 1000

2000

200 to 208

20 to 520

20 to 1000

5 to 23

3 to 1039

3

20 to 2000

4 to 20

200 to 400

Dip, Spray, Fog

Open Pour

Mop, Spray, Fog

Dip, Spray, Fog

Dip, Sponge, Spray, Fog

Spray

Dip, Spray, Fog

Open Pour, Meter In

Dip, Open Pour, Meter

Dip, mop, Spray, Fog

Dip, Spray

Dip, Spray, fog

Meter In

Fog or Fumigation

Human Drinking Water Systems

Drinking Water

Drinking Water Storage

1 to 5

50 to 100

Open Pour

Open poor

Industrial Processes and Water Systems

Commercial/Industrial Cooling Water Systems

Evaporative Condenser Water Systems

Pulp and Paper Mill Water Systems

Secondary Oil Recovery Injection Water

Wastewater Treatment

5 to 344

250 to 400

5 to 18

4 to 33

5

Open Pour, Meter In

Mop, Spray, Fog

Open Pour, Meter In

Open Pour, Meter In

Open Pour, Meter In

Material Preservation

Metal Working Fluids

Wax paper for flowers and shoes

Bed rail covers, diaper pail liners, disposable apparel

0.1 to 13

0.63%

5000

Open Pour

Not Applicable2

Open Pour
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Use Application Rate 

(PPM ClO2) Application Methods

Packing films, wraps, box liners, trays 2000 to 5000 Open Pour

Medical Premises and Equipment

Anthrax decontamination and mold remediation

Hard Surface Treatments

391 to 3000

43 to 3000

Fumigation

Mop, Spray, Fog

Residential and Public Access Premises

HVAC Ductwork and Filters

Anthrax decontamination and mold remediation

Hard non porous surface treatments

Carpets, rugs, bedding and mattresses

Humidifier Water

Automobiles, RVs, Boats, Porta potties

500 to 1000

391 to 3000

160 to 2000

188 to 2000

41

Unknown3

Spray, Fog

Fumigation

Mop, Spray, Fog

Spray, dust

Open Pour

Passive Gas Generation

Swimming Pools/Spas

Swimming Pool Water Systems 5 Open Pour, Meter 

1 The recently added potato use will be reassessed, and the work plan revised, if necessary, as part of registration 

review.

2

Wax paper containing 0.63% sodium chlorite as the a.i. is used for packaging flowers and shoes. The sodium 

chlorite reacts with the moisture in the air to release chlorine dioxide. The resulting chlorine dioxide air 

concentration is dependent upon the amount of product in the paper, the volume and ventilation rate of the area 

treated.

3

A pouch or sachet containing of 25 to 100 grams of product containing sodium chlorite is placed in the area to be 

treated, and it is activated with sodium citrate and/or water to release chlorine dioxide. The resulting chlorine 

dioxide air concentration is dependent upon the amount of product in the sachet, the amount of sodium chlorite in 

the product, the volume and ventilation rate of the area treated, and the amount of sodium citrate and water added.

1.5.3 Usage Information

Chlorine dioxide gas is registered for sterilizing manufacturing and laboratory equipment, 

environmental surfaces, tools, and clean rooms. One of the major antimicrobial uses of chlorine 

dioxide is to treat drinking water. In addition, the largest use of chlorine dioxide is the nonpesticidal bleaching use in the pulp and paper industry (US EPA, 2006a).

1.6 Regulatory History

EPA first registered the aqueous form of chlorine dioxide for use as a disinfectant and a sanitizer 

in 1967. In 1988, EPA registered chlorine dioxide gas as a sterilant. In 2013, EPA registered 

chlorine dioxide for use in potato storage facilities to fumigate against non–pathogenic spoilage 

organisms on potatoes. The recently added potato use will be reassessed, and the work plan 

revised, if necessary, as part of registration review. The Reregistration Eligibility Decision 

(RED) for chlorine dioxide and sodium chlorite was published in August 2006. The post RED 

Generic Data Call-in (GDCI) was issued June 3, 2010 (see Table 11 for list of generic data 

requirements).
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1.6.1 Tolerance Information

EPA has established three tolerance exemptions under the Federal Food, Drug and Cosmetic Act 

(FFDCA) Section 408. 

Exemptions from the requirement of a tolerance are listed under 40 CFR 180.940(b) and 40 CFR 

180.940(c) for oxychloro species (including chlorine dioxide) when applied to dairy processing 

equipment, food processing equipment, and utensils (b), and for food processing equipment and 

utensils (c). There is no tolerance or tolerance exemption for chlorine dioxide or sodium chlorite 

under 40 CFR 180.940(a) for public eating establishments, restaurants, etc. These uses need to be 

removed from the labels or a tolerance exemption should be proposed or established. Although 

some labels allow active ingredient concentrations of up to 1,200 ppm, this concentration is 

greater than the currently established tolerance exemption which specifies that application 

concentrations may not exceed 200 ppm under 180.940(b) and will need to be addressed through 

label changes or a registrant submission of a petition to support these uses above the exemption.

The need for or exemption from the requirement of a tolerance for the potato use will be 

reassessed, and the work plan will be revised, if necessary. 

Sodium chlorite is also exempted from a tolerance for residues when used as a seed-soak 

treatment in the growing of the following raw agricultural commodities: vegetable, Brassica, 

leafy group 5, and radish, roots, and radish, tops. This exemption is listed under 40 CFR part 

180.1070.

Chlorine dioxide and sodium chlorite have been listed as food contact substances by the US 

Food and Drug Administration (FDA) under FFDCA Section 409. There are 12 food contact 

notifications (FCNs) for chlorine dioxide and two FCNs for sodium chlorite. These FCNs are 

only effective for the manufacturer or supplier identified in the notification.

Table 6 – FDA Food Contact Notifications for Chlorine Dioxide and Sodium Chlorite 

FCN 

No.

Food Contact Substance (CAS Reg No.) Manufacturer Effective Date

1421 Chlorine dioxide (10049-04-4) Clordisys Solutions, Inc. Jul 1, 2014

1400 Chlorine dioxide (10049-04-4) Clordisys Solutions, Inc. Apr 1, 2014

1370 Chlorine dioxide (10049-04-4) CDG Environmental, LLC Feb 25, 2014

1158 An aqueous solution of chlorine dioxide 

(10049-04-4)

CDG Environmental, LLC May 18, 2012

1137 Chlorine dioxide (10049-04-4) Dripping Wet Water, Inc. Mar 2, 2012

1123 Chlorine dioxide (10049-04-4) Nalco Company Feb 23, 2012

1052 An aqueous solution of chlorine dioxide 

(10049-04-4)

CDG Environmental, LLC Mar 23, 2011
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1011 An aqueous solution of chlorine dioxide 

(10049-04-4)

CDG Environmental, LLC Oct 28, 2010

949 Chlorine Dioxide (10049-04-4) ICA TriNova, LLC Mar 2, 2010

668 Chlorine dioxide (10049-04-4) Drew Industrial Division, 

Ashland Specialty Chemical 

Company, Ashland, 

Incorporated

Mar 16, 2007

644 Chlorine Dioxide (10049-04-4) Diversey, Inc. Dec 15, 2006

391 Chlorine dioxide (10049-04-4) Nalco, An Ecolab Company Feb 20, 2004

900 Sodium Chlorite (7758-19-2) Bio-Cide International, Inc. Aug 21, 2009

807 Mixture of sodium chlorite (7758-19-2) 

and sodium chloride (7647-14-5)

Xyrex Ltd. Jun 5, 2008

Chlorine dioxide and sodium chlorite have been listed as both direct and indirect food additives 

under 21 CFR part 172 and part 175, respectively. These food additive regulations are 

summarized below in Tables 7 and 8.

Table 7 – FDA Direct Food Additive Regulations for Chlorine Dioxide and Sodium 

Chlorite 

CFR Section Use Residue Level

173.300 Chlorine 

Dioxide

Used in water for poultry processing 3 ppm residual Chlorine Dioxide

Water used to wash fruits and vegetables that 

are not RACs

3 ppm residual Chlorine Dioxide. Must be 

followed by a potable water rinse.

173.325 Acidified 

Sodium Chlorite 

Solutions

Poultry processing or chilling water

For spray or dip solution: Concentrations 

between 500 and 1,200 ppm;

Prechiller or chiller solution 50 to 150 ppm

Red meat processing Applied as a dip or spray of concentrations 

between 500 and 1,200 ppm.

In water used to rinse, wash, transport, or 

store seafood 40 to 50 ppm

During harvesting, handling, heading, 

butchering, etc. of finfish 1,200 ppm

RAC commodities in preparing, packing, or 

holding of the food for commercial purposes

500 to 1,200 ppm followed by a potable 

water rinse or blanching, cooking, or 

canning.

Processed, comminuted, or formed meat 

products Dip or a spray 500 to 1,200 ppm
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Water applied to fruits and processed root, 

tuber, bulb, legume, fruiting, and cucurbit 

vegetables

Spray or dip of 500 to 1,200 ppm followed 

by a potable water rinse and a 24-hour 

holding period prior to consumption.

However, for processed leafy vegetables 

(i.e., vegetables other than root, tuber, bulb, 

legume, fruiting, and cucurbit vegetables) 

and vegetables in the Brassica [Cole] 

family, application must be by dip treatment 

only, and must be preceded by a potable 

water rinse and followed by a potable water 

rinse and a 24-hour holding period prior to 

consumption.

Table 8 – FDA Indirect Food Additive Regulations for Chlorine Dioxide and Sodium 

Chlorite 

CFR Section Chemical Commodity Notes/Residue Level

137.105

Chlorine Dioxide

Flour Quantity not more than sufficient 

for bleaching or artificial aging.

137.200 Whole Wheat Flour 45 ppm

165.110 Bottled Water 0.8 mg/L

172.892 Sodium Chlorite Food Starch - Modified 0.5%

173.300 Chlorine Dioxide Secondary Food Additive 

Permitted for Food Consumption

175.105 Sodium Chlorite Adhesives for packing, 

transporting, or holding food

178.1010 Sodium Chlorite & 

Chlorine Dioxide Sanitizing Solution 200 ppm

186.1750 Sodium Chlorite Paper Slimicide 125 to 250 ppm

1.6.2 Registration Eligibility Decision (RED)

In the 2006 RED for chlorine dioxide and sodium chlorite, the Agency determined that chlorine 

dioxide and sodium chlorite were eligible for reregistration. Additional data were required to 

support this decision and risk mitigation measures were outlined in the RED. The generic data 

requirements are listed in Table 11. The mitigation measures and label amendments are listed in 

Table 9. The reregistration process is ongoing for these products, and a product-specific postRED DCI for efficacy data was issued on June 25, 2015.

Table 9 – Label Changes Specified in the Chlorine Dioxide/Sodium Chlorite RED

Description Amended Label Language

End Use Products Intended for Occupational Use

Application to Hard Surfaces Handlers applying chloride dioxide in an occupational setting must wear 

gloves.
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Tablets into public swimming pools Occupational handlers must wear gloves while placing the tablet into 

swimming pools.

Fogging Use People must vacate the premises during fogging treatments; a one-hour 

restricted entry interval (REI) is required.

Carpet Treatment Not for residential use. For non-residential use, a one hour restricted entry 

interval is required.

Once Thru Use Reduce the application rate from 25 ppm to 5 ppm for intermittent 

applications.

End Use Products Intended for Residential Use

Tablets into pools/spas Residential handler (homeowner) must wear gloves while placing the 

tablet in the swimming pool/spa.

Continuous Release Deodorizers Restrict to outdoor use only. Do not use indoor (e.g., use in shoes, closets, 

laundry hampers, bags, drawers, basements, boat cabins, trash bags and 

any additional deodorizing uses)

Carpet Treatment Residential use is prohibited.

Dietary

Fruit and Vegetable Wash Fruits and vegetables treated with chlorine dioxide must be blanched, 

cooked, or canned before consumption or distribution in commerce.

1.7 Incidents

1.7.1 Human Health 

There are twelve incidents listed in the OPP Incident Data System (IDS) for chlorine dioxide or 

sodium chlorite for the period 8/01/2006, when the RED was completed, to 4/02/2015, when the 

IDS was queried. All of these incidents are rated as moderate (i.e. HC). These incidents are listed 

below: 

1. Customer mixed product with HCl acid in violation of label causing release of chlorine 

dioxide gas.

2. Chlorine dioxide gas was released when product was added to chiller water used to 

process poultry carcasses. The application rate was too high given that no carcasses were 

being processed and the excess chlorine dioxide was released into the workroom air.

3. Workers in a food processing facility that had switched to a chlorine dioxide water 

treatment experienced inhalation exposure when steam arose from the surfaces being 

cleaned with the treated water. The water temperature was 70 F and the surface 

temperature was 36 F.

4. Workers in a tomato processing plant were hospitalized after flume water treatment 

system using sodium chlorite malfunctioned.

5. Female worker experienced breathing difficulties after draining of product from tank 

during general sanitation of the wash down room. 
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6. Sensor malfunction in dosing system at tomato processing plant caused excessive 

application of product.

7. Malfunction in tomato plant dosing system caused excessive application of product to 

flume water resulting in release of chlorine dioxide gas.

8. Vegetable processing plant workers exposed to chlorine dioxide in wash water.

9. Workers at a food processing plant experienced respiratory irritation after product was 

used to treat process water. Product reacted with biofilm in water system resulting in 

release of gas.

10. Chlorine dioxide generating system malfunction causing release of chlorine dioxide gas 

in a tomato cannery.

11. Lab worker exposed to chlorine dioxide gas while testing efficacy for hurricane cleanup 

in a lab that did not have adequate ventilation. Suffered severe respiratory irritation. 

12. Product used to get rid of smell left after "Chinese drywall" was taken out of house. The 

product left a sharp smell in the house and the family felt that it burned their throats.

1.7.2 Ecological

No incidents have been reported in the OPP Incident Data System (IDS) for chlorine dioxide or 

sodium chlorite for the period from 8/3/2006, when the RED was completed, to 4/2/2015, when 

the IDS was queried.

2 Anticipated Data Needs

The RED published for chlorine dioxide and sodium chlorite in 2006 listed several studies as

generic or confirmatory data needed for reregistration eligibility. In addition to the post-RED 

GDCI data, the following studies as listed in Table 10 are expected to be needed for the 

registration review of chlorine dioxide and sodium chlorite. Table 11 outlines the data 

requirements required by the post-RED GDCIs issued for both chemicals on June 3, 2010. The 

Agency anticipates reviewing any data received in response to the post-RED GDCI as well as 

data required for this registration review in connection with the registration review risk 

assessments for chlorine dioxide.
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Table 10 – Studies Anticipated as Needed for the Registration Review of Chlorine Dioxide/Sodium Chlorite

GLN Study Name Test Substance

Time Frame 

(Measured in months 

from DCI Receipt)

Risk Assessment(s) Data 

Will Support

Use Site(s) Triggering 

Anticipated Data 

Requirement

Applicable 

Exposure Scenario

860.1340

Residue analytical 

method for data 

collection

ROC 24 months Dietary Hard Surface Disinfection

Direct Food Treatment Dietary (food)

860.1360 Multi-residue 

method testing TGAI or ROC 24 months Dietary Direct Food Treatment Dietary (food)

860.1380 Storage stability TEP or ROC 24 months Dietary Hard Surface Disinfection Dietary (food)

860.1460 Food-handling TEP 24 months Dietary Hard Surface Disinfection Dietary (food)

860.1480 Meat/ milk/ poultry/

eggs

TGAI or ROC 24 months Dietary Direct Food Treatment Dietary (food)

860.15001, 2 Crop Field Trials TEP 24 months Dietary Direct Food Treatment Dietary (food)

None2 Nature of residue on 

surfaces TGAI 24 months Dietary Hard Surface Disinfection Dietary (food)

None2 Migration studies TEP 24 months Dietary Hard Surface Disinfection Dietary (food)

870.62002, 3

Acute and 

subchronic 

neurotoxicity—rat

TGAI 24 months Dietary Direct Food Treatment Dietary (food)

870.7800 Immunotoxicity TGAI 12 months Dietary a nd non-dietary All All

875.23004 Indoor Surface 

Residues TGAI 12 months Non-Dietary Carpets Incidental oral and dermal exposure

875.2500 Inhalation Exposure TGAI 12 months Residential Post 

Application 

Sodium Chlorite Foggers 

and Deodorizers5 Inhalation Exposures

ROC = residue of concern; TGAI = technical grade of the active ingredient; TEP = typical end-use product

1. Crop field trials are required for the fruit and vegetable wash use. All potential residues should be analyzed. 

2. A protocol should be submitted to the Agency for approval prior to conducting the anticipated studies.

3. Acute (study due 12 months after receipt of DCI) and subchronic (study due 24 months after receipt of DCI) neurotoxicity studies are anticipated to be required.

4. A protocol should be submitted for approval prior to testing.

5. Data needed for products that release chlorine dioxide gas when activated with acid or water.

Table 11 – Studies Required by the Post-RED DCI for Chlorine Dioxide/Sodium Chlorite

GLN Study Name Test Substance Risk Assessment(s) Data 

Will Support

Use Site(s) Triggering 

Anticipated Data 

Requirement

Applicable 

Exposure Scenario Status

850.1300 Daphnid chronic toxicity test Chlorine dioxide 

Sodium chlorite Ecological risk assessment Recirculating and one-pass Cooling Water Towers Down-the-drain Under review
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850.1400 Fish early-life stage toxicity test Chlorine dioxide 

Sodium chlorite Ecological risk assessment Recirculating and one-pass Cooling Water Towers Down-the drain Under review

850.42251 Seedling emergence, Tier II Chlorine dioxide 

Sodium chlorite Ecological risk assessment Recirculating and one-pass Cooling Water Towers Down-the-drain Under review

850.42502 Vegetative Vigor, Tier II Chlorine dioxide 

Sodium chlorite Ecological risk assessment Recirculating and one-pass Cooling Water Towers Down-the-drain Under review

850.4400 Aquatic plant toxicity test using 

Lemna spp., Tiers I & II

Chlorine dioxide 

Sodium chlorite Ecological risk assessment Recirculating and one-pass Cooling Water Towers Down-the-Drain Under review

850.54003 Algal toxicity, Tiers I & II Chlorine dioxide 

Sodium chlorite Ecological risk assessment Recirculating and one-pass Cooling Water Towers Down-the-Drain Under review

870.4200 Carcinogenicity TGAI Dietary (food and water) Potable Water Treatment This study is 

outstanding

875.1200 Dermal exposure - Indoor Chlorine dioxide 

Sodium chlorite

Occupational/Residential 

Exposure Assessment All use sites Occupational and Residential Handlers

Surrogate data 

AEATF4

875.1400 Inhalation Exposure - Indoor Chlorine dioxide 

Sodium chlorite

Occupational/Residential 

Exposure Assessment All use sites Occupational and Residential Handlers

Surrogate data 

AEATF

875.1600 Application exposure monitoring 

data reporting

Chlorine dioxide 

Sodium chlorite

Occupational/Residential 

Exposure Assessment All use sites Occupational and Residential Handlers

Surrogate data 

AEATF

875.2800 Description of Human Activity Chlorine dioxide 

Sodium chlorite

Occupational/Residential 

Exposure Assessment All use sites Occupational and Residential Handlers

This study is 

outstanding

1 In a Federal Register Notice dated June 27, 2012, test guidelines 850.4100 and 850.4225 were merged and harmonized into OCSPP 850.4100. See “Final Test Guidelines; OCSPP 

850 Series; Notice of Availability” 77 FR 38282, June 27, 2012. http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0154-0028. 

2 In a Federal Register Notice dated June 27, 2012, test guidelines 850.4150 and 850.4250 were merged and harmonized into OCSPP 850.4150. See “Final Test Guidelines; OCSPP 

850 Series; Notice of Availability” 77 FR 38282, June 27, 2012. http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0154-0028.

3 In a Federal Register Notice dated June 27, 2012, EPA split the Public Draft OPPTS 850.5400 test guideline into two test guidelines: OCSPP 850.4500 and OCSPP 850.4550. See 

“Final Test Guidelines; OCSPP 850 Series; Notice of Availability” 77 FR 38282, June 27, 2012. http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0154-0028.

4 Antimicrobial Exposure Assessment Task Force
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3 Human Health Risk Assessment

The Agency anticipates the need to update the human health risk assessment for chlorine dioxide

and sodium chlorite. An assessment for chlorine dioxide and sodium chlorite was conducted in 

2006 for the reregistration eligibility decision (RED), and posted to www.regulations.gov under 

docket number EPA-HQ-OPP-2006-0328. A data gap for carcinogenicity was identified at the 

time of the RED, and a GDCI was issued that included a requirement for carcinogenicity data. 

This data requirement has not yet been satisfied. An immunotoxicity study and an acute 

neurotoxicity study are anticipated to be required under registration review (see Table 10). When 

these data become available and are reviewed, they will be included in the revised human health 

risk assessment for chlorine dioxide and sodium chlorite.

3.1 Existing Toxicological Endpoints

Table 12 presents the existing toxicological endpoints used in the Agency’s most recent risk 

assessments for chlorine dioxide and sodium chlorite. The Agency anticipates the need to revise 

these endpoints as part of registration review. All available information including existing 

toxicology studies, valid scientific literature, and the studies that are expected to be required for 

registration review will be considered in revising the existing toxicology endpoints for chlorine 

dioxide and sodium chlorite. Appendix A contains a detailed description of the toxicity studies.

Table 12 – Existing Toxicological Endpoints for Chlorine Dioxide/Sodium Chlorite

Exposure 

Scenario

Dose Used in Risk 

Assessment 

(mg/kg/day)

Target Margin of 

Exposure (MOE), 

Uncertainty Factor (UF), 

FQPA Safety Factor (SF)

Study and Toxicological Effects

Acute Dietary NOAEL = 3 

mg/kg/day

UF = 100 (10x interspecies extrapolation, 10x 

intra-species variation)

FQPA SF = 1

Acute PAD = 0.03

mg/kg/day

Developmental Toxicity - Rat (Orme et al., 1985)-

neurobehavioral and exploratory deficits in rat pups 

at LOAEL of 14 mg/kg/day

Co-critical: Two-generation reproduction toxicity 

study (MRID 45358901) - decreases in absolute 

brain and liver weight, and lowered auditory startle 

amplitude at the LOAEL of 6 mg/kg/day

Chronic 

Dietary

NOAEL = 3 

mg/kg/day

UF = 100 (10x interspecies extrapolation, 10x 

intra-species variation)

FQPA SF = 1

Chronic PAD = 0.03

mg/kg/day

Developmental Toxicity - Rat (Orme et al., 1985) -

neurobehavioral and exploratory deficits in rat pups 

at LOAEL of 14 mg/kg/day.

Co-critical: Two-generation reproduction toxicity 

study (MRID 45358901) - decreases in absolute 

brain and liver weight, and lowered auditory startle 

amplitude at LOAEL of 6 mg/kg/day.

Incidental Oral 

(short- and 

intermediateterm

NOAEL = 3 

mg/kg/day MOE = 100

Developmental Toxicity - Rat (Orme et al., 1985) -

neurobehavioral and exploratory deficits in rat pups 

at LOAEL of 14 mg/kg/day.

Co-critical: Two-generation reproduction toxicity 

study (MRID 45358901) - decreases in absolute 

brain and liver weight, and lowered auditory startle 

amplitude at LOAEL of 6 mg/kg/day.

Short-Term 

DermalA

NOAEL= 3 

mg/kg/day MOE = 100 See summary for dietary assessment
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Exposure 

Scenario

Dose Used in Risk 

Assessment 

(mg/kg/day)

Target Margin of 

Exposure (MOE), 

Uncertainty Factor (UF), 

FQPA Safety Factor (SF)

Study and Toxicological Effects

(1-30 days)

Intermediateterm Dermal 

(30 days-6 

months)

NOAEL= 3 

mg/kg/day MOE = 100 See summary for dietary assessment

Long-term 

Dermal (> 6 

months)

NOAEL= 3 

mg/kg/day MOE = 100 See summary for dietary assessment

Inhalation

(occupational 

and 

homeowner 

short-term)

Occupational ‘RfC’ 

= 0.09 mg/m3 (0.03 

ppm)B

Homeowner shortterm ‘RfC’ = 0.14 

mg/m3 (0.05 ppm)B

MOE (occupational) = 30

MOE (homeowner shortterm) - 300

Inhalation toxicity studies- Rat 

homeowner short-term: Dalhamn, 1957 [LOAEL of 

28 mg/m3 (10 ppm)]

Occupational exposure: Ogata et al. (2012), using 

NOAEC of 1.0 ppm (2.8 mg/m3)

Inhalation

(homeowner 

long-term)

Agency RfC methodology used to derive an 

RfC value of 2 x 10-4 mg/m3 (USEPA, 2000)

Paulet and Debrousses, 1970, 1972) selected as cocritical studies (USEPA, 2000)

A Based on the use of an oral endpoint for dermal risk assessment and the lack of a dermal absorption study, a 

dermal absorption value of 100% as default is used.

B Unit Conversion: ppm = (mg/m3 x 24.45)/ MW. For chlorine dioxide 1 ppm = 2.8 mg/m3

3.1.1 Comparison to Other Endpoints

Because of the non-FIFRA regulated uses of chlorine dioxide as an industrial chemical, 

toxicological endpoints for occupational inhalation exposure to chlorine dioxide have been 

established by other government agencies such as the Occupational Safety and Health 

Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH)

and professional organizations such as the American Conference of Governmental Industrial 

Hygienists (ACGIH). Toxicological endpoints for emergency response workers and the general 

population have also been established by National Research Council (NRC) for use in 

emergency response planning for chemical releases.

OSHA PELs and ACGIH TLVs

The OSHA permissible exposure limit (PEL) for chlorine dioxide is 0.1 ppm as an eight hour 

time weighted average (TWA). This PEL was established in 1970 based on the Threshold Limit 

Value (TLV) that was established in 1960 by the ACGIH. This TLV was updated in 1976 to 

include a Ceiling Limit of 0.3 ppm (ACGIH, 2001). A Ceiling limit is an exposure limit that 

should not be exceeded at any time during the workday and is normally assessed as a 15 minute 

exposure. These values are only applicable to worker populations because they do account for 

the increased sensitivity of some members of the general population. The OSHA PEL is 

enforceable by law, and the ACGIH TLV is a guideline or recommendation to assist in the 

evaluation and control of potential workplace health hazards. 

IDLH and AEGL
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The immediately hazardous to life and health (IDLH) value established by NIOSH is 5.0 ppm 

(NIOSH, 2004). According to NIOSH, the definition of the IDLH is a condition that “poses a 

threat of exposure to airborne contaminants when the exposure is likely to cause death or 

immediate or delayed permanent adverse health effects or prevents escape from such an 

environment.” The purpose of establishing an IDLH exposure concentration is to “ensure that the 

worker can escape from a given contaminated environment in the event of failure of the 

respiratory protection equipment” (NIOSH, 1997). 

The Acute Exposure Guideline Levels (AEGL) established by National Advisory Committee for 

Acute Exposure Guideline Levels for Hazardous Substance and reviewed by the NRC for 

chlorine dioxide are listed in Table 13 below. These values are used in emergency response 

planning to protect workers and the general population from high level short duration exposures.

Table 13 – Summary Table of AEGL Values for Chlorine Dioxide (ppm)

Classification 10 

Minute

30 

Minute

1 hour 4 hour 8 hour End Point

AEGL-1

(Nondisabling)

0.15 0.15 0.15 0.15 0.15 Slight salivation, slight lacrimation, and 

slight chromodacryorrhea in rats exposed 

to 3 ppm for 6 hours (Dupont, 1955)

AEGL-2

(Disabling)

1.4 1.4 1.1 0.69 0.45 Lacrimation, salivation, dyspnea, 

weakness and pallor in rats exposed to 12 

ppm for 6 hours (Dupont, 1955)

AEGL-3

(Lethal)

3.0 3.0 2.4 1.5 0.98 No lethality in rats exposed to 26 ppm for 

6 hours (Dupont, 1955)

During the RED process it was acknowledged that there was a discrepancy between the 

occupational inhalation endpoint of 0.003 ppm selected by the EPA for use in assessing 

occupational exposures to chlorine dioxide and the endpoint of 0.1 ppm established by OSHA 

for regulating industrial exposures to chlorine dioxide. It was stated in the RED that 

reconciliation would occur at a later date. Data from the Chlorine Dioxide Panel (DP 426508) 

has been submitted and reviewed by the Agency. As a result, the occupational RfC for chlorine 

dioxide has been revised, as indicated in Table 12.

3.2 Dietary Exposure

EPA anticipates the need to conduct an updated dietary exposure (food and drinking water) 

assessment to support registration review of chlorine dioxide and sodium chlorite since there are 

multiple labeled uses that could result in both direct and indirect food contact. The registered 

uses of chlorine dioxide and sodium chlorite that result in dietary exposure include: (1) as a 

sanitizer in poultry houses; (2) a sanitizer for food contact surfaces in residential areas, in food 

processing plants, and for food processing water; (3) as a poultry carcass dip sanitizer; (4) as a 

poultry chiller water sanitizer; and (5) as a slimicide in paper production.
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Dietary risk is characterized in terms of the Population Adjusted Dose (PAD) which reflects the 

reference dose (RfD), either acute or chronic, that has been adjusted to account for the FQPA 

Safety Factor (SF). This calculation is performed for each population subgroup for which an 

endpoint exists. A risk estimate that is less than 100% of the acute or chronic PAD is not of 

concern. Acute and chronic dietary risk for chlorine dioxide will be assessed by comparing 

dietary exposure estimates expressed in mg/kg/day to the acute Population Adjusted Dose 

(aPAD) and chronic Population Adjusted Dose (cPAD).

3.2.1 Food

Dietary exposure assessments will be conducted during registration review since currently 

registered uses of chlorine dioxide and sodium chlorite may result in dietary (food) exposure. A 

screening-level (food only) analysis was conducted for this work plan using established 

toxicological points of departure (PODs) and an active ingredient concentration of 200 ppm for 

hard surface cleaners in residential and commercial settings using the screening-level Food and 

Drug Administration (FDA) model for food contact (hard surfaces) in commercial and residential 

areas. Although some labels allow active ingredient concentrations of up to 1,200 ppm, this 

concentration is greater than the currently established tolerance exemption of 200 ppm.

Therefore, the Agency anticipates conducting a dietary exposure assessment using the 

established tolerance exemption level of 200 ppm and will work with registrants to adjust their 

labels accordingly or apply for a new tolerance. The acute population adjusted dose (aPAD) is 

0.03 mg/kg/day and the chronic population adjusted dose (cPAD) is 0.03 mg/kg/day.

Additionally, the recently added potato use will be reassessed, and the work plan revised, if 

necessary, as part of registration review.

Dietary Exposure Assessment - Residential Areas

In residential areas, the acute and chronic dietary (food only) exposure and risk estimates exceed 

the level of concern (LOC) [i.e., >100% of the PAD] for all infants <1 year old and children 1-2 

years old when using the screening-level FDA model. However, when calculating the risk 

estimates using the Indirect Dietary Residential Exposure Assessment Model (IDREAM), which 

is a refined Tier II model for uses for hard surface cleaner uses, all population subgroups are not 

of concern for both acute and chronic durations.

For residential scenarios assuming a countertop surface area of 2000 cm2

, the screening-level 

FDA model for food contact (hard) surfaces results in a total estimated daily dietary intake of 

chlorine dioxide and sodium chlorite in food exceeding 200 ppb for the US population and all 

population subgroups for both acute and chronic durations of exposure. When calculating total 

estimated daily dietary intake using IDREAM for acute exposures, the refined total estimated 

daily direct intake in food is > 200 ppb for the US population and all population subgroups.

However, when calculating total estimated dietary intake using IDREAM for chronic exposures, 

the refined daily direct intake in food is < 200 ppb for the US population and all population 

subgroups.

Dietary Exposure Assessment - Commercial Areas
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In commercial areas, the acute and chronic dietary (food only) exposure and risk estimates 

exceed the LOC [i.e., >100% of the PAD] for all infants <1 year old, children 1-2 years old, and 

children 3-5 years old.

For commercial scenarios assuming a countertop surface area of 4000 cm2

, the screening-level 

FDA model for food contact (hard) surfaces results in a total daily dietary intake exceeding 200 

ppb for all the US population, all infants <1 year old, children 1-2 years old, children 3-5 years 

old, children 6-12 years old, youth 13-19 years old, adults 50+ years old, and females 13-49 

years old for both acute and chronic exposures (all population subgroups except adults 20-49 

years old).

Conclusions & Data Requirements

The screening-level analysis for hard surface cleaners using the screening-level FDA model for 

food contact (hard surfaces) in commercial and residential areas results in risks above the 

Agency’s level of concern for some population subgroups. Additionally, the total daily dietary 

intake for acute exposures in residential areas and acute and chronic exposures in commercial 

areas is > 200 ppb for the US population and some population subgroups.

Therefore, under 40 CFR 158.2230, a total daily dietary intake for residential and commercial 

scenarios greater than 200 ppb triggers additional (Tier II) toxicity data that should be submitted 

to the Agency. Additional residue data will also be required because the level of concern is 

exceeded using the screening-level assessments, per 40 CFR 158.2290. These data are listed in 

Table 10 and include several guideline studies (860.1340, 860.1360, 860.1380, 860.1460, 

860.1480, 860.1500, 870.7800), and two non-guideline studies (nature of the residues on 

surfaces, and residue migration studies). 

Additionally, there are registered uses of chlorine dioxide and sodium chlorite that were not 

included in the screening-level assessment. As no screening-level methodologies are available to 

assess the direct treatment of fruits and vegetables, residue data are anticipated to be required to 

support these uses as listed in Table 10 (guideline 860.1500). For the anticipated DCI, the

registrant should submit a protocol for Agency review prior to the initiation of residue studies.

It is important to note that if the toxicological PODs change during registration review, 

additional residue chemistry and/or toxicity data may be required. The dietary exposure 

contribution from the currently registered uses of chlorine dioxide and sodium chlorite will be 

considered in the aggregate assessments conducted during registration review.

3.2.2 Drinking Water

A drinking water assessment was conducted in 2006 as part of the Reregistration Eligibility 

Decision document for chlorine dioxide/chlorite. The assessment was based on the registered use 

of chlorine dioxide as an antimicrobial pesticide for potable water disinfection. The Agency 

anticipates the need to revise the drinking water assessment for chlorine dioxide based on the 

anticipated carcinogenicity data and updated information on occurrence of chlorine 

dioxide/chlorite in drinking water that is obtained from the EPA’s Office of Water. The Office of 
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Water has set maximum contaminant levels (MCLs) for sodium chlorite and chlorine dioxide in 

drinking water: 0.8 ppm for chlorine dioxide and 1.0 ppm for chlorite ion.

3.3 Occupational and Residential Exposures

The Agency anticipates the need to revise the occupational and residential exposures (ORE) 

assessment (US EPA, 2006) conducted in support of the 2006 RED because assumptions that 

possibly underestimate exposures were used and will need to be reassessed using updated values. 

3.3.1 Occupational Handler Exposure

Occupational handler dermal exposures to chlorine dioxide were assessed in the ORE assessment 

for the RED (US EPA, 2006b) for hard surface application using low pressure handwands, 

trigger pump sprayers, mops and foam application equipment, meter-in applications for water 

treatment, open pour liquid application for metal working fluid and oil systems treatment, solid 

place application for swimming pool treatment, and airless sprayer applications and fogger 

applications for HVAC treatment. 

All of the handler scenarios that were assessed in the ORE assessment for the RED (US EPA, 

2006) will need to be revised during registration review upon receipt of the unit exposure data 

that were required by the post-RED GDCI to supplement or replace the unit exposure data that 

were used in the RED. It will also be necessary to reassess the fogger handler exposures for 

fogging applications that are made using hand held foggers. Occupational handler scenarios to be 

assessed are presented in Table 14.

Table 14 – Occupational Handler Exposure Scenarios for Chlorine Dioxide

Scenario Exposure 

Route(s) Duration

Open Pour Liquids for Industrial Processes and Water treatment Dermal 

Inhalation 

Short, Intermediate, and 

Long Term 

Applying disinfectant using low pressure handwands, high pressure 

handwands, trigger sprayers, mops and wipes. 

Dermal 

Inhalation 

Short, Intermediate, and 

Long Term 

Applying disinfectant using handheld foggers or misters Dermal 

Inhalation 

Short and Intermediate 

Term 

3.3.2 Occupational Post Application Exposures

Occupational post application dermal exposures were not assessed in the RED because they were 

assumed be less than that of dermal contact of children playing on treated floor surfaces, which 

did not exceed EPA’s LOC. Because the exposure assumption has not changed, these exposures 

will not be assessed during registration review.

Occupational post application inhalation exposures were assessed for the RED (US EPA, 2006) 

for non-fogging use by obtaining 8 hour time weighted average air concentration measurements 

from OSHA and comparing these results to the RfC of 0.003 ppm. The summary results of the 

33 observations from OSHA were above the RfC of 0.003 ppm. This was not surprising given 

that the OSHA PEL is 0.1 ppm and the limit of detection (LOD) for the OSHA sampling method 
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is 0.003 ppm. The fact that the occupational RfC of 0.003 ppm was below the OSHA PEL of 0.1 

ppm was noted as a discrepancy in the RED with reconciliation to occur during registration 

review. These exposures will be re-assessed during registration review using updated exposure 

data from OSHA.

Occupational inhalation exposures following fogging and misting applications were assumed to 

be of concern because the labels allowed entry when the chlorine dioxide levels dropped to the 

OSHA-PEL of 0.1 ppm. To ensure that exposures would not exceed the RfC of 0.003 ppm, the 

RED specified that the labels must be changed to prohibit re-entry for one hour after treatment.

These exposures will be re-assessed during registration review if the RfC is changed.

3.3.3 Residential Handler Exposures

Residential handler dermal and inhalation exposures to chlorine dioxide were assessed in the 

ORE Assessment for the RED (US EPA, 2006) for spraying and mopping of surfaces and 

placing of tablets into swimming pools. The dermal MOEs for mopping and spraying were 1300 

and 3200, respectively, which was above the target MOE of 100 and therefore not of concern.

The dermal MOE for placing tablets was 46 without gloves and 500 with gloves. Since the MOE 

without gloves was of concern, the RED specified that gloves be worn when placing tablets into 

swimming pools. Inhalation exposure for trigger spray application and mopping were assessed 

using Exposure and Fate Assessment Screening Tool (EFAST), which yielded an average air 

concentration of 0.003 ppm. Since this air concentration was less than the short term RfC of 0.05 

ppm, inhalation exposures were not of concern.

The mop and trigger spray scenarios that were assessed for the RED will need to be revised 

during registration review upon receipt of the unit exposure data that was required by the RED 

GDCI to supplement or replace the unit exposure data that were used for the RED. The solid 

place scenario will not be reassessed because new unit exposure data are not being required for 

this scenario due to the low potential for exposure. The following scenarios, which are presented 

in Table 15, will be assessed during registration review.

Table 15 – Residential Handler Exposure Scenarios for Chlorine Dioxide

Scenario Exposure Route(s) Duration

Mop application to hard surfaces. Dermal and Inhalation Short and Intermediate Term 

Trigger Spray/Wipe application to hard surfaces Dermal and Inhalation Short and Intermediate Term

3.3.4 Residential Post-Application Exposures

Exposures Assessed in the ORE Assessment for the RED (US EPA, 2006)

Residential post-application dermal and incidental oral exposures to residues arising from the 

hard surface disinfection of floors were assessed. The MOE of 280 for dermal exposure and the 

MOE of 2300 for incidental oral were not of concern because they were greater than the target 

MOE of 100. Residential post application inhalation exposures were assessed for HVAC system 

treatments and the use of continuous release deodorizers. The estimated air concentration for 

HVAC treatments was <0.01 ppm which was less than the short term RfC of 0.05 ppm and 
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therefore not of concern. The estimated air concentration for continuous release deodorizers was 

<0.52 ppm which was greater than the long term RfC of 0.00007 ppm and therefore of concern. 

To address this concern, the RED specified that continuous release deodorizers be restricted to 

outdoor use only as listed in Table 9.

Residential post application inhalation exposures from the use of deodorizer products in 

automobiles was assessed in the ORE assessment for the RED (US EPA, 2006) using data from 

two submitted studies that measured chlorine dioxide air concentrations in automobiles (Wood 

and Gallo 1997, and Speronello 1998).

Wood and Gallo (1997) measured chlorine dioxide in a total of 16 automobiles (8 cars parked 

outside and 8 cars parked inside a garage). The study author indicated that “approximately half 

the chlorine dioxide released was consumed by sunlight.” Cars parked outside were treated with 

5, 15, 25, and 50 gram sachets while cars parked inside were treated with 5 and 25 gram sachets. 

An Interscan chlorine dioxide Analyzer was used to measure chlorine dioxide inside the cars 

(LOD appears to be 0.01 ppm). Each car was sampled from 1 to 4 days. The maximum and 

average readings for all sampling intervals are reported in Table 16. Although some of the 

maximum single reading values of chlorine dioxide exceed the short-term residential inhalation 

toxicity of concern (i.e., level of concern is the RfC of 0.05 ppm), these maximum single 

readings are not meaningful to determine risk concerns when compared to the short-term 

inhalation RfC. It is more appropriate to compare the peak measurements to the ACGIH STEL 

which is based on a 15-minute average. The highest maximum single reading of 0.19 ppm from 

this study does not exceed the STEL of 0.3 ppm. The average of all of the instantaneous readings 

is below the RfC and the STEL. In conclusion, the data indicated that the concentration of 

chlorine dioxide remains below the STEL and the average of the single measurements does not 

exceed the RfC of 0.05 ppm. However, a more appropriate measurement would have been to 

sample over a period of time that is representative of the duration people spend in cars to obtain a 

TWA. 

Table 16 – Maximum and Average Chlorine Dioxide Measurements in Automobiles

Chlorine dioxide Reading (ppm) Weight of Sodium Chlorite Sachets

5 grams 15 grams 25 grams 50 grams

Cars Parked Outdoors

Maximum single reading 0.01 0.06 0.1 0.19

Average of all readings* 0.0005 0.009 0.011 0.029

Cars Parked Indoors

Maximum single reading 0.008

Not Sampled

0.19 Not Sampled

Average of all readings* 0.002 0.008

*Represents the average where non-detects (LOD = 0.01 ppm) are counted as zero.

Speronello (1998) provided limited additional information on chlorine dioxide measurements 

inside of automobiles. Two cars using different application rates were monitored in this study 
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(problems were encountered with the 3rd car and this experiment was discontinued). One car was 

treated with a 20 gram sachet and the other car was treated with three 20 gram sachets. Air 

concentrations in this study were measured with an INTERSCAN Portable Analyzer (model 

4335DG). This device recorded chlorine dioxide measurements at 10 second intervals for 5 

minutes. Sampling intervals were 0, 1, 2, 4, 6, 8, 24, 101, 149, and 192 hours after initial 

placement of the sachet. All of the 5 minute samples in the car treated with 20 grams of Chlorine 

dioxide are below the detection limit of 0.05 ppm. The results from the car with the exaggerated 

application rate indicated a maximum chlorine dioxide concentration of 0.091 ppm. However, 

the text did not indicate if this was a 5 minute sample or peak 10 second interval within the 5 

minute measurement. It also appears that some of the data tables in Speronello (1998) are 

missing from the experiment identified as “Run 3.” The data table for “Run 3” only includes the 

10 second measurements for the 0 hours after treatment interval. The results of this second study 

do not raise any additional concerns for peak measurements, however, the data are of limited use 

to determine a TWA concentration over the time period people spend in cars.

Exposure Assessed after the RED

Residential post application inhalation exposures were assessed for a new product (Odor Rescue)

to be used for deodorizing automobiles, RV and boat cabins and an existing product (Nosguard) 

that is used to deodorize similar areas. These assessments were based on chlorine dioxide air 

concentration data that was submitted by each registrant.

In the assessment of Odor Rescue (US EPA, 2011a) chlorine dioxide levels inside the vehicles 

being treated reached a maximum of 3 to 6 ppm. Some of these levels exceed the NIOSH IDLH 

of 5 ppm and/or the AEGL-3 value of 3 ppm which means that serious health effects would

occur if the vehicle were occupied during the treatment process when the doors and windows 

were closed. Once the doors are opened, however, the chlorine dioxide levels drop below the 

above mentioned levels within one or two minutes and generally reach the residential RfC of 

0.05 ppm in an hour or less. To prevent the occupancy of the vehicle during treatment, the label 

includes a warning placard that is affixed to the outside of the vehicle during treatment.

In the assessment of NosGuard (US EPA, 2011b), chlorine dioxide levels were measured inside 

an unventilated room and in an automobile. The room test results indicate that chlorine dioxide

levels inside rooms reach a maximum of 0.25 to 13 ppm under fast release conditions depending 

upon the distance from the source. The lower values measured at 4, 6 and 8 feet from the source 

exceed the short term RfC of 0.05 ppm and the maximum value of 13 ppm measured at one foot 

from the source exceeds the NIOSH IDLH of 5 pm and the AEGL-3 value of 3 ppm. This means 

that risks of concern will occur if people are present in rooms during treatment and that these 

risks will be severe or even life threatening if they are within one foot of the source. By contrast, 

the maximum chlorine dioxide levels in rooms undergoing slow release treatment range from 

non-detectable at 0.01 ppm to 0.08 ppm depending upon the distance from the source and the 

duration of the treatment. With the exception of the 0.08 ppm value, which was measured at one 

foot from the source, these values are below the short term RfC of 0.05 ppm and indicate that the 

risks are not of concern for short term exposures.

The NosGuard automobile test results indicate that chlorine dioxide levels inside a subcompact 

car reached a maximum of 0.30 to 0.35 ppm within 15 to 20 minutes of activating the treatment 
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and remained at these levels for only a few minutes before beginning a decline. After the doors 

were opened, the levels declined to the short term RfC of 0.05 ppm within a few minutes.

Because this testing was done during daylight hours and the car was parked in an open area 

without shade, the interior of the car was exposed to ultraviolet light which would have degraded 

the chlorine dioxide as it was released.

Exposures to be Assessed during Registration Review

Because the residential carpet use has not been deleted from the labels as specified by the RED,

it will be necessary to re-assess the dermal and incidental oral exposures that were assessed for 

the RED. In order to do this assessment, the residues on the carpets will need to be quantified 

and thus an indoor surface residue study (870.2300) is anticipated to be needed for registration 

review (See Table 10). In addition, it will be necessary to assess inhalation exposures from 

fogging and deodorizing products that were not assessed previously because the exposures are 

product specific. Post application inhalation exposure studies (870.2500) are therefore 

anticipated to be needed for each product (See Table 10). A listing of the scenarios that will be 

assessed during registration review is included in Table 17.

Table 17 – Residential Post-Application Exposure Scenarios for Chlorine Dioxide

Scenario Exposure Route(s) Duration

Treated floors and carpets Dermal 

Incidental Oral Short and Intermediate Term 

Aerosols and gases released from fogging treatment Inhalation Short and Intermediate Term 

Gases released from deodorizing treatments Inhalation Short and Intermediate Term 

3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures 

The Agency anticipates the need to revise the aggregate assessment conducted in support of the 

2006 RED risk assessment. Upon a reevaluation and selection of toxicology endpoints, combined 

with the human health exposure assessments expected as a part of this registration review case, 

aggregate exposures will need to be assessed. This assessment will include dietary (food and 

water) exposures and residential exposures. 

3.4.2 Cumulative Exposures 

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a 

cumulative risk approach based on a common mechanism of toxicity, EPA has not made a 

common mechanism of toxicity finding for chlorine dioxide and sodium chlorite. 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 common mechanism determinations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/guidancecumulative-risk-assessment-pesticide.
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4 Environmental Risk Assessment

The Agency has not previously conducted a risk assessment that supports a complete endangered 

species determination for chlorine dioxide/sodium chlorite. The data already called in through 

the post-RED GDCI and the ecological risk assessment planned during registration review will 

allow the Agency to determine potential acute and chronic risks to aquatic organisms exposed to 

chlorine dioxide/sodium chlorite that are transported from treatment sites into the aquatic 

environment. Such sites include recirculating and one-pass cooling water towers. The risk 

assessment also will allow the Agency to determine whether each use of the chlorine 

dioxide/sodium chlorite has 'no effect' or 'may affect' federally listed threatened or endangered 

species (listed species) or their designated critical habitats. When an assessment concludes that a 

pesticide’s use 'may affect' a listed species or its designated critical habitat, the Agency will 

consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the 

Services), as appropriate.

4.1 Environmental Fate Assessment

Chlorine dioxide

Since chlorine dioxide is an inorganic substance, the conventional fate studies outlined in Test 

Guidelines 835 cannot be used to generate fate data in the environmental media. Its degradation 

products in the environmental media of soil and water have been identified as chlorate, chlorite,

and chloride, depending on the pH of the medium. Perchlorate can be a contaminant from 

chlorine dioxide generators, but is unlikely to form under environmental conditions. Chlorine 

dioxide is known to hydrolyze at or above pH 10 into chlorite and chlorate ions. Chlorine 

dioxide is known to photolyze in aquatic medium in the presence of sunlight and the photolytic 

degradates are: chloride and chlorate ions. 

Chlorine dioxide is a free radical (has a single electron in its valence shell) and therefore is not a 

stable substance with short half-life in water, and it degrades into chlorite ions (EPA RED, 

2008).

Sodium chlorite

Sodium chlorite is a salt formed as a result of the degradation of chlorine dioxide in the presence 

of sodium which is ubiquitous in the environment. Since sodium chlorite is an inorganic 

compound, the conventional fate studies as outlined in Test Guidelines 835 cannot be used to 

generate fate data on sodium chlorite in environmental media. No data are available for the 

aquatic photolysis of chlorite ions.

There is one report of chlorite undergoing biodegradation in anaerobic conditions. 

Biodegradation of chlorite under anoxic conditions could result in the formation of chlorate or 

perchlorate in sediments and soils. However, sodium chlorite does not undergo ready 

biodegradation. No adsorption/desorption studies on chlorite have been reported. These species

are charged and are likely to be mobile in soils and sediments. The estimated log Kow for 

chlorite is -7.17. Chlorite is not likely to accumulate in aquatic species. (EPA RED, 2008)
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4.1.1 Water Quality

Chlorine dioxide was identified as a cause of impairment for San Antonio, Texas (ID# TX-1911-

09) water body in 2010 (one episode) and was listed as impaired under section 303 (d) of the 

Clean Water Act, based on the information provided at the Agency’s National Pesticides Cause 

of Impairment of Waters web site (searched on Feb.5, 2015). No source of the impairment was 

identified. In addition, no Total Maximum Daily Loads (TMDL) have been developed for 

chlorine dioxide based on the information provided at the Agency’s National Pesticides TMDL 

web site (searched on Feb.5, 2015). There are 175 TMDL/impaired water bodies (OW’s list 303 

(d)) for total residual chlorine (TRC) on a national level recorded from 2000-2007. TRC is 

defined as the “amount of remaining chlorine after contact time and is equal to available residual 

chlorine + free available chlorine.” Chlorine sources for TRC can be from chlorine and

chlorinated compounds used not only as pesticides, but also as industrial chemicals. More 

information on impaired water bodies and TMDL can be found at

http://water.epa.gov/lawsregs/lawsguidance/cwa/tmdl/index.cfm.

Sodium chlorite was not listed as a case of impairment under section 303 (d) of the Clean Water 

Act, based on the information provided at the Agency’s National Pesticides Cause of Impairment 

of Waters web site (searched on Feb.5, 2015). In addition, no Total Maximum Daily Loads 

(TMDL) are needed for sodium chlorite based on the information provided at the Agency’s 

National Pesticides TMDL web site (searched on Feb.5, 2015). However, there are 175 

TMDL/impaired water bodies (OW’s list 303 (d)) listed for total residual chlorine (TRC) on a 

national level recorded for 2000-2007. TRC is defined as the “amount of remaining chlorine 

after contact time and is equal to available residual chlorine + free available chlorine.” The 

source of TRC can be from chlorine and other chlorinated compounds including salts of chlorine 

compounds used not only as pesticides, but also as industrial chemicals. More information on 

impaired water bodies and TMDL can be found at 

http://water.epa.gov/lawsregs/lawsguidance/cwa/tmdl/index.cfm.

4.2 Conceptual Models for Environmental Exposure Pathways

Based on the summary of registered uses of chlorine dioxide and sodium chlorite presented in 

Table 5, physical/chemical properties and environmental fate data presented in Table 4 and 

Appendix B, under ambient environmental conditions, the experimentally-determined hydrolytic 

half-life of chlorine dioxide is between 30-35 minutes, if the container is kept open and no 

stabilizer is used to stabilize it in aqueous medium. Chlorite ions are highly water soluble.

The Agency has created conceptual models for potential routes of environmental exposure which 

are included in “Conceptual Models for Environmental Exposure Pathways of Antimicrobial 

Pesticides” (EPA-HQ-OPP-2014-0638-0002), found in the docket at www.regulations.gov, EPAHQ-OPP-2014-0638. For antimicrobial uses, all relevant pathways of exposure, including 

chlorine dioxide use as a disinfectant will be considered when the Agency performs a risk 

assessment for chlorine dioxide and sodium chlorite.
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4.3 Ecological Effects Assessment

The toxicity endpoints included in this registration review will be based on the results of sodium 

chlorite and chlorine dioxide toxicity studies submitted to EPA for review. Sodium chlorite is 

used as a precursor in the generation of chlorine dioxide. The antimicrobial registered uses of 

chlorine dioxide/sodium chlorite fall into several major categories including use in the treatment 

of human drinking water systems; in industrial process and water systems; as a materials 

preservative; and as a general disinfectant in medical, residential, agricultural, commercial and 

industrial settings. The once-through cooling tower use of chlorine dioxide/sodium chlorite was 

previously assessed in the RED using a screening level assessment, because this use is expected 

to have the most potential for environmental exposure. The modeling for this scenario will be 

updated to reflect current models. Acute risk to aquatic organisms was found to occur from the 

use of chlorine dioxide/sodium chlorite in once-through cooling towers. At the highest doses, the 

model showed risk to freshwater and marine/estuarine fish and invertebrates and aquatic plants, 

and at the lowest doses the model showed risk only to freshwater invertebrates. The 

environmental risk assessment for the registration review will be conducted using sodium 

chlorite endpoints because under environmental conditions, chlorine dioxide converts mostly 

into chlorite ions. Chronic risk to aquatic organisms could not be assessed in the RED due to the 

lack of chronic toxicity endpoints for fish and aquatic invertebrates. When the required aquatic 

chronic toxicity testing required in the post-RED GDCI are reviewed, chronic risk to these 

organisms will be assessed. Additional vascular aquatic plant (Lemna gibba), rice and aquatic 

plant testing (3 additional species: blue-green cyanobacteria (anabaena flos-aquae); freshwater 

diatom (Navicula pelliculosa) and marine diatom (Skeletonema costatum) as available will be 

considered in the risk assessment planned for registration review.

4.3.1 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aquatic and terrestrial organisms. All 

available ecotoxicity endpoints in the Agency’s files from chemical studies submitted by 

registrants or other interested parties, federal laboratory data, or from the public literature are 

tabulated in Appendix C along with the data gaps. The most sensitive values for each receptor 

group are used for the risk assessment. These selected endpoints will be updated during the risk 

assessment phase of registration review based on any additional submitted data or data found in 

the public literature. 

Table 18 – Ecological Effects Endpoints Selected for Sodium Chlorite/Chlorine Dioxide 

Receptor 

Group Surrogate Species Risk Scenario Toxicity Endpoint Reference

Freshwater fish Bluegill Sunfish Acute 96-h LC50 = 244 mg/L ACC# 254181

Bluegill Sunfish Chronic Data Gap

Freshwater 

invertebrates Daphnia magna Acute 48-h EC50 = 0.027 mg/L MRID# 146162

Chronic Data Gap

Estuarine/marine fish Sheepshead minnow Acute 96-h LC50 = 75 mg/L MRID# 

43259401

Chronic Not requiredA --

Estuarine/marine 

invertebrates Mollusk Acute 48-hr EC50 = 21.4 mg/L MRID# 43259403
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Receptor 

Group Surrogate Species Risk Scenario Toxicity Endpoint Reference

Shrimp Acute 96-hr LC50 = 0.576 mg/L MRID# 

43259402

Chronic Not requiredA --

Algae Green alga

Nonlisted 96-hr EC50 = 1.32 mg/L MRID# 

41880403

Listed NOAEC = <0.62 mg/L MRID# 

45862503

Aquatic Microphytes

Marine diatom, 

Freshwater diatom, 

Cyanobacteria species 

Acute Data GapA

Aquatic vascular 

plants Duckweed

Nonlisted Data GapA

Listed

Seedling Emergence Rice Nonlisted Data GapA

Listed

Vegetative vigor Rice Nonlisted Data GapA

Listed

Birds

Northern bobwhite 

quail Acute LD50 = 382 mg/kg ACC# 259373

Mallard duck Subacute 

dietary

LC50 = 31.25 mg/kg ACC# 254176

Chronic Not requiredB --

Mammals Acute NOAEL = 3 mg/kg/day Orme et.al. 1985

Chronic NOAEL = 3 mg/kg/day Orme et.al. 1985

Nontarget insects Honey bee Acute Not requiredB --

A Data was called in under reregistration.

B Not required for this use pattern.

4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available models will be used to determine the estimated environmental concentration (EECs) in 

the aquatic environment. Resulting exposure estimates will be compared to the toxicity endpoints 

to determine if levels of concern are exceeded for each receptor group. 

4.4.2 Screening Level Down-the-Drain Analysis

The Down-the-Drain (DtD) module of E-FAST (Exposure and Fate Assessment Screening Tool) 

is used to determine the potential for aquatic organisms downstream of domestic wastewater 

treatment plants (WWTPs) that receive discharges from application of a chemical and/or any 

degradates that form from the point of application to the point of discharge following wastewater 

treatment. The Agency does not anticipate the need for Down-the-Drain (DtD) assessment for 

the disinfectant, residential, and pool uses because chlorine dioxide is a very reactive chemical 

with a short half-life and is not stable in water. The aquatic releases for the once through cooling 

towers will be modeled for the revised risk assessment using current inputs and models.
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4.5 Effects Analysis Plan

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

database. The ECOTOX database will be searched during the risk assessment phase of chlorine 

dioxide and sodium chlorite and the data reviewed following the Agency’s policy for reviewing 

public literature for use in assessing risks from pesticides.

1 Those ecotoxicity values found in the 

public literature to be more sensitive than those currently in Table 18 and or which satisfy an 

existing data gap(s) will be used during the risk assessment phase of chlorine dioxide and sodium 

chlorite to update Table 18. ECOTOX was created and is maintained by the USEPA, Office of 

Research and Development, and the National Health and Environmental Effects Research 

Laboratory's Mid-Continent Ecology Division.

5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its reregistration decision for chlorine dioxide, EPA reviewed these 

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

existing hazard database. However, as required by FFDCA section 408(p), chlorine dioxide is 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 1

http://cfpub.epa.gov/ecotox/
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identified for EDSP screening was published on June 14, 20132 and includes some pesticides 

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

construed as a list of known or likely endocrine disruptors.

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

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

website.3

6 Label Changes

As stated in Sections 1.6.1 and 3.2.1, there is no tolerance or tolerance exemption for chlorine 

dioxide or sodium chlorite under 40 CFR 180.940(a) for public eating establishments, 

restaurants, etc. Although some public eating establishment labels allow active ingredient 

concentrations of up to 1,200 ppm, this concentration is greater than the currently established 

tolerance exemption of 200 ppm and will need to be addressed through label changes or a 

registrant submission of a petition to support these uses above the exemption. There are no listed 

tolerances for automobiles, RVs, boats, porta potties, shipping and storage containers, etc. These 

uses need to be removed from the labels or a tolerance exemption should be proposed or 

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

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

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

clarity.

7 Next Steps

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

section of this document. The Agency expects to issue the DCI by December 2016. 

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

chemicals. 3 http://www2.epa.gov/endocrine-disruption
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8 References 

ACGIH, 2001. Documentation of the Threshold Limit Value for Chlorine Dioxide, American 

Conference of Governmental Industrial Hygienists (ACGIH), 2001.

Dupont, 1955. Summary of Toxicological Evaluations of Chlorine Dioxide. Haskell Laboratory 

for Toxicology and Industrial Medicine, Haskell Lab Report No. 80-55, E.I. du Pont de 

Nemours and Company, Inc., Wilmington, DE.

NIOSH, 1994. Documentation for Immediately Dangerous to Life or Health Concentrations 

(IDLHs) for Chlorine Dioxide, Report #10049044. National Institute for Occupational Safety 

and Health (NIOSH).

NIOSH, 1997. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-

140, June 1997.

Speronello, Barry. 1998. Worst-Case Release Study for Automotive Deodorizing Products.

Engelhard Corporation, Iselin, NJ. Completed date March 12, 1998.

US EPA, 2006a. Reregistration Eligibility Decision (RED) for Chlorine Dioxide and Sodium 

Chlorite (Case 4023), EPA 738-R-06-007, U.S. Environmental Protection Agency, August

2006.

US EPA, 2006b. Chlorine Dioxide: Occupational and Residential Exposure Assessment Case 

4023, Timothy Leighton, Office of Pesticide Programs, Antimicrobials Division, U.S. 

Environmental Protection Agency, August 2, 2006.

US EPA, 2011a. Occupational and Residential Exposure Assessment for the Registration of the 

New Use of Chlorine Dioxide as Odor Rescue, D392885, Memorandum from Timothy C. 

Dole to Wanda Henson, September 12, 2011.

US EPA, 2011b. Human Health Risk Assessment of Chlorine Dioxide Exposures Resulting from 

the Existing Uses of NosGuard SG (87508-2) D394706, D395936, Memorandum from 

Timothy C. Dole to Wanda Henson, November 10, 2011.

Wood, Richard and Gallo, Vanessa. 1997. Aseptrol Automotive Field Testing: Chlorine Dioxide 

Air Levels inside Vehicle. Engelhard Corporation, Iselin, NJ. Completed date November 14, 

1997.
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Appendix A Toxicology Profile

Acute Toxicity 

The acute toxicity of chlorine dioxide (79% a.i.) is considered significant by the oral route (LD50 

= 292 mg/kg [males]; 340 mg/kg [females]; Toxicity Category II). The acute toxicity of sodium 

chlorite (80% a.i.) is considered moderate by the dermal route (LD50 > 2000 mg/kg; Toxicity 

Category III). For primary eye irritation, chlorine dioxide (2% a.i.) was a mild irritant (Toxicity 

Category III). No data were available for eye irritation potential of the 79% a.i. For primary 

dermal irritation, sodium chlorite (80% a.i.) was a primary irritant (Toxicity Category II). For 

dermal sensitization, there are no acceptable studies for chlorine dioxide or sodium chlorite.

Table A1 – Acute Toxicity Studies for Chlorine Dioxide/Sodium Chlorite

Guideline No./ Study Type MRID No. Results Toxicity 

Category

870.1100/ 

Acute oral toxicity 

(79% chlorine dioxide)

43558601 LD50 = 292 mg/kg (males)

LD50 = 340 mg/kg (females)

II

870.1200/ 

Acute dermal toxicity 

(80% sodium chlorite)

40168704 LD50 > 2000 mg/kg III

870.1300/ 

Acute inhalation toxicity

(80.6% sodium chlorite)

42484101 LC50 = 0.29 mg/L II

870.2400/ 

Acute eye irritation 

(2% chlorine dioxide)

43441903 Mild irritant III

870.2500/ 

Acute dermal irritation 

(80% sodium chlorite)

40168704 Primary irritant II

870.2600/ 

Skin sensitization No acceptable study is available. Unknown

N/A=Not available 

Subchronic Toxicity 

The subchronic toxicity database includes a 90-day oral toxicity study conducted by Daniel et al. 

(1990), a 14- and 90-day oral study by Harrington et al. (1995a) and inhalation toxicity studies of 

various durations (up to 60 days) conducted by Dalhamn (1957), Paulet and Desbrousses (1970, 

9172, and 1974), Akamatsu et al. (2012), and Ogata et al. (2013). Therefore, the database for 

subchronic toxicity via oral and inhalation route is considered complete.
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Daniel et al. (1990) exposed groups Sprague-Dawley rats (10/sex/dose) to chlorine dioxide in 

drinking water for 90 days at concentrations of 0, 25, 50, 100, or 200 mg/L (equivalent to 0, 2, 4, 

6, or 12 mg/kg-day chlorine dioxide for males and 0, 2, 5, 8, or 15 mg/kg-day chlorine dioxide 

for females, respectively). No exposure-related deaths were reported. Exposure to 200 mg/L 

resulted in significant reductions in terminal body weights and body weight gain (26%–29% 

lower than controls). Significant reductions in water consumption were observed in the males 

exposed to ≥ 50 mg/L and in females exposed to ≥ 25 mg/L; decreases in food consumption were 

also observed in the 200 mg/L males. Absolute liver weights were decreased in males at ≥ 50 

mg/L, and absolute spleen weights were decreased in females at ≥ 25 mg/L. No consistent 

alterations in hematology were observed. Serum lactate dehydrogenase and aspartate 

aminotransferase levels were decreased and serum creatinine levels were increased in the males 

exposed to 100 or 200 mg/L; no other alterations in serum chemistry parameters were 

consistently found. A significant increase in incidence of nasal lesions (goblet cell hyperplasia 

and inflammation of nasal turbinates) was found in males exposed to ≥ 25 mg/L and in females 

at ≥ 100 mg/L. The study authors postulated that these lesions were likely caused by inhalation 

of chlorine dioxide vapors at the drinking water sipper tube or from off-gassing of the vapors 

after drinking rather than ingestion of the drinking water. Thus, 25 mg/L (2 mg/kg-day) can be 

described as a lowest-observed-adverse-effect level (LOAEL), but the toxicological significance 

of the nasal lesions is not known. Respiratory tract pathologies have not been reported in other 

oral studies and the effect may possibly be an artifact of treatment. 

In a 14-day range-finding study (Harrington, et al., 1995), rats were administered gavage doses 

of sodium chlorite in the range of 25 to 200 mg/kg/day (equivalent to 18.6 to 149.2 mg 

chlorite/kg/day). One exposure-related death was observed in each sex in the 200 mg/kg/day 

group on treatment days 2 and 3. No treatment-related deaths occurred in the groups receiving 

chlorite doses ≤ 56 mg/kg/day. 

In the main study performed by Harrington et al. (1995a) Crl:CD (SD) BR rats (15/sex/group) 

were administered doses of 0, 10, 25, or 80 mg/kg-day sodium chlorite (equivalent to 0, 7.4, 19, 

or 60 mg chlorite/kg-day, respectively) via gavage for 13 weeks. In the 60 mg/kg-day group, four 

animals died during treatment and both sexes exhibited salivation, significantly decreased 

erythrocyte counts, and decreased total serum protein levels. The males receiving 60 mg/kg-day 

exhibited significantly decreased hematocrit and hemoglobin levels and increased 

methemoglobin and neutrophil levels, whereas in the females, methemoglobin levels were 

significantly decreased. Possible reasons for the decrease in methemoglobin in females, which is 

unexpected considering the known oxidative effects of sodium chlorite, were not discussed by 

the study authors. The following observations were also noted in the 60 mg/kg-day group: 

morphological changes in erythrocytes in some animals of both sexes, significant increases in 

relative adrenal and spleen weights in the males, increases in absolute and relative spleen and 

adrenal weight in females, and increases in relative liver and kidney weights in the females.

Body weight and food consumption were not affected by treatment. Histopathologic alterations 

in the 60 mg/kg-day group included squamous epithelial hyperplasia, hyperkeratosis, ulceration, 

chronic inflammation, and edema in the stomachs of seven males and eight females. At 19 

mg/kg-day, the following alterations were reported: occasional salivation in two males, 
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hematologic alterations in males (increased methemoglobin levels and neutrophil count, 

decreased lymphocyte count), increases in absolute and relative spleen and adrenal weights in 

females, and histologic alterations in the stomach of two males, similar to those seen in the highdose group. The increase in absolute spleen weight was attributed to morphological alterations in 

erythrocytes, but no explanation was provided for alterations in absolute adrenal weight. The 

NOAEL in this study is determined to be 7.4 mg/kg-day, and the LOAEL is 19 mg/kg-day for 

stomach lesions and increases in spleen and adrenal weights in rats subchronically treated with 

sodium chlorite. 

Dalhamn (1957) reported the results of several inhalation studies in laboratory animals. In one 

study, a single 2-hour inhalation exposure of four rats to a chlorine dioxide concentration of 260 

ppm (728 mg/m3

) resulted in pulmonary edema and nasal bleeding. In another study, rats were 

subject to 3-minute exposures to decreasing concentrations of airborne chlorine dioxide from 

3,400 to 800 ppm (from 9,520 to 2,240 mg/m3) once a week for 3 consecutive weeks.

Respiratory distress was reported in three rats subjected and bronchopneumonia was observed in 

two of these rats. In a third rat study, repeated exposure to approximately 10 ppm (28 mg/m3) of 

chlorine dioxide (4 hours/day for 9 days in a 13-day period) resulted in rhinorrhea, altered 

respiration, and respiratory infection. No indications of adverse effects were seen in rats exposed 

to approximately 0.1 ppm (0.28 mg/m3) of chlorine dioxide 5 hours /day for 10 weeks.

Paulet and Desbrousses (1970, 1972, and 1974) conducted a series of studies in which laboratory 

animals were exposed to atmospheres of chlorine dioxide. Nasal discharge and localized 

bronchopneumonia (with desquamation of alveolar epithelium) were noted in rats exposed to an 

airborne concentration of 10 ppm (28 mg/m3), 2 hours/day for 30 days. Another group of rats 

exposed to a concentration of 5 ppm (14 mg/m3) exhibited similar, but less severe, respiratory 

tract effects. Bronchial inflammation and alveolar congestion and hemorrhage were observed in 

rats exposed to 2.5 ppm (7 mg/m3), 7 hours/day for 30 days. Alveolar congestion and 

hemorrhage were also seen in rabbits following inhalation exposure to 2.5 ppm (7 mg/m3

), 4 

hours/day for 45 days. In a group of rats and rabbits sacrificed 15 days after exposure 

termination, recovery from the pulmonary lesions was apparent (Paulet and Desbrousses 1970). 

Vascular congestion and peribronchiolar edema were noted in the lungs of rats exposed to a 

concentration of 1 ppm (2.8 mg/m3

), 5 hours/day, and 5 days/week for 2 months (Paulet and 

Desbrousses 1972). A LOAEL of 1 ppm for respiratory effects was identified in this study.

In a 10-week inhalation toxicity study conducted by Ogata et al. (MRID 49660502), groups of 

male and female Wistar rats (8 rats/sex/dose) were exposed to chlorine dioxide gas at 

concentrations of 0 or 1.0 ppm for 5 hours per day, 5 days per week, for 10 weeks. One intent of 

this study was to reproduce the exposure protocol of Paulet and Desbrousses (19070, 1972, 

1974) to determine if adverse effects occur at this concentration and duration of chlorine dioxide 

exposure. During exposure, body weight of the rats was recorded twice per week and general 

condition of the rats was assessed visually during the study. At the end of exposure, rats were 

sacrificed for collection of blood and tissues, and bronchioalveolar lavage fluid obtained.

No mortality occurred in this study and there were no reported effects on body weight or signs of 

clinical toxicity. Examination of organs showed no significant changes. Hematological and 

biochemical analyses were reported to be within normal limits in chlorine dioxide exposed rats 

compared to control. No statistically significant differences were observed in bronchioalveolar 
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fluid between chlorine dioxide exposed rats and control. Histological examination of organs 

showed no abnormalities from chlorine dioxide exposure. The authors conclude that the 1.0 ppm 

concentration should be interpreted as a NOAEC, and not a LOAEC as reported by Paulet and 

Desbrousses.

This study only employed a concentrations of 1.0 ppm, and a dose-response for inhalation 

toxicity of chlorine dioxide was therefore not determined. However, the Agency, using a weight 

of evidence approach that considered the results of the Dalhamn, Paulet and Desbroussses, and 

Ogata et al. studies, is in agreement that the 1.0ppm concentration can be considered a NOAEC 

for chlorine dioxide inhalation exposure hazard and that the NOAEC of 1.0ppm is a more 

reliable point of departure for the chlorine dioxide occupational inhalation risk assessment.

This subchronic inhalation toxicity study in the rat is acceptable for quantitative use in inhalation 

risk assessment for chlorine dioxide, in accordance with the OPP document.

Guidance for Considering and Using Open Literature Toxicity Studies to Support Human Health 

Risk Assessment (US EPA, 2012). 

In a 6-month inhalation toxicity study (Akamatsu, 2012), groups of male and female SpragueDawley rats (approximately 5 weeks old, 16 rats/sex/concentration) were exposed to chlorine 

dioxide gas at concentrations of 0, 0.05, or 0.1 ppm for 24 hours per day, seven days per week, 

for 6 months. At the end of exposure, 10 rats/sex/concentration were sacrificed. The remaining 6 

rats/sex/concentration were subjected to an additional 2 weeks of exposure of air only, to 

measure recovery. Body weight, food and water consumption, hematology, clinical chemistry, 

and macroscpoic and microscopic examination of selected organs was performed. 

No mortality occurred in this study and there were no signs of clinical toxicity at either 

concentration of chlorine dioxide. Body weight, food consumption, and water consumption were 

unaffected at either concentration. Serum BUN in female rats was significantly increased at the 

0.1 ppm concentration. Eosinophil differential was significantly decreased at p < 0.05 at both the 

0.05 and 0.1 ppm concentrations for male rats, but not in a dose-related manner. Monocyte 

differential was decreased significantly in male rats at the 0.05 ppm concentration, but not at 0.1 

ppm. Migratory cell count (BC) in the bronchioalveolar lavage fluid was significantly elevated in 

female rats at the 0.05 ppm concentration, and also elevated (not significantly) at the 0.1 ppm 

concentration. No significant histopathological changes were observed in the nasal cavity, 

parhynx, trachea, and bronchus. 

The authors of this study conclude that exposure to chlorine dioxide gas up to 0.1 ppm for six 

months produced no significant toxicity in rats. A Lowest Adverse Effect Level (LOAEL) was 

not achieved in this study. The authors also acknowledge that “a higher dose(s) may have to be 

employed so as to define the LOAEL as well as NOAEL.” 

This study did not employ concentrations higher than 0.1 ppm, and a dose-response for 

inhalation toxicity of chlorine dioxide was therefore not determined. The lack of testing at higher 

concentrations does not support 0.1 ppm as a definitive NOAEL. Some effects reported in this 

study at 0.1 ppm might be considered as effects that would be adverse at higher concentrations 
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for chemicals like chlorine dioxide that generate oxygen radical species as the mode of toxic 

action. 

This subchronic inhalation toxicity study in the rat is acceptable for quantitative use in inhalation 

risk assessment for chlorine dioxide, in accordance with the OPP document 

Guidance for Considering and Using Open Literature Toxicity Studies to Support Human Health 

Risk Assessment (US EPA, 2012).

Developmental Toxicity 

Two developmental toxicity drinking water studies are included in the toxicity database for 

chlorine dioxide/ sodium chlorite. In one, chlorine dioxide was administered to (Orme et al., 

1985) while in the other study, rabbits were administered sodium chlorite. The database for 

developmental toxicity is considered complete.

In a study conducted by Orme et al. (1985) designed to assess toxicity of chlorine dioxide, 

female Sprague-Dawley rats (13-16/dose) were administered drinking water containing 0, 2, 20, 

or 100 mg/L (0, 1, 3, and 14 mg/kg/day estimated doses) chlorine dioxide from 2 weeks prior to 

mating until day 21 post-partum, and the effects on brain development in pups examined. There 

were no significant effects of chlorine dioxide on body weight of dams or pups at any dose level 

tested. Depression of serum thyroxin (T4) and increased serum triiodothyronine (T3) were 

observed in pups at weaning at the 100 mg/L (14 mg/kg/day) dose level. Neurobehavioral 

exploratory and locomotor activities were decreased in pups at the 14 mg/kg/day dose (p = 0.08).

These effects were not observed in pups at the 20 mg/L dose level (3 mg/kg). Pups administered 

chlorine dioxide by gavage at 14 mg/kg/day on post-natal days 5-20 showed a larger depression 

of serum T4 levels and greater delays in development of exploratory and locomotor behavior 

activity. There were no apparent effects in maternal animals up to the 14 mg/kg/day dose level.

The developmental toxicity NOAEL of 3 mg/kg/day was selected based on depression of serum 

T4 levels in pups from dosed maternal rats and delays in development of locomotor and 

exploratory behavior activity. 

In a developmental drinking water study (MRID 41715701), time-mated female New Zealand 

White rabbits (16-17/dose) were administered drinking water allowed free access to water 

containing 0, 200, 600, or 1200 ppm (calculated intake 0, 12.2-13.8, 30.1-38.3, or 32.0-60.1 

mg/kg/day) sodium chlorite (purity 80.58%) from gestation days 7 through 19. Mean intake of 

the test compound via the drinking water was consistent throughout the dosing period only at the 

lowest level, but was suppressed in a dose-related fashion at the highest levels, especially over 

the first few days of dosing. These variations in compound intake were considered to reflect 

problems in palatability of the preparations at high concentrations. There was no compoundrelated mortality, but two doses had to be sacrificed in extremis for other (incidental) reasons.

The sole treatment-related clinical effect was a dose-related increase in incidence of does with 

reduced fecal output during the dosing period, days 7 to 19, which was considered consistent 

with decreased food consumption. At necropsy, there were no abnormalities considered 

treatment-related in survivors. Among gross findings in scheduled sacrifices were: pitted kidneys 

in two mid-dose and one high-dose animal; alopecia in two low-dose, three mid-dose, and two 

high-dose does; and thoracic fluid in one low-dose animal. No significant differences from 
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control were observed in pregnancy rate, mean gavid uterine weight, or reproductive indices.

Mean fetal weights were comparable in all groups. External, visceral, and skeletal examinations 

of all live fetuses revealed no major abnormalities which could be considered related to sodium 

chlorite treatment. An increased incidence of minor skeletal variants was observed among 600 

and 1200 ppm fetuses, which was considered generally related to retardation and/or delayed 

ossification, rather than structural abnormalities. No evidence of embryolethality, fetotoxicity, or 

teratogenicity was found. There was a slight effect on embryonic growth of mid- and high-dose 

levels, but no clear dose-response was evident. The maternal toxicity NOAEL of 200 ppm (12-14 

mg/kg/day) and LOAEL of 600 ppm (36-42 ppm) were selected based on decreases in feces, 

food consumption, and water intake. The developmental toxicity NOAEL of 200 ppm (12-14 

mg/kg/day) and LOAEL of 600 ppm (36-42 mg/kg/day) were selected based on decreased fetal 

weight and skeletal retardation.

Reproductive Toxicity

A two-generation reproduction toxicity study (MRID 45358901) was conducted by the Chlorine 

Dioxide Panel of the Chemical Manufacturers Association (now called the American Chemistry 

Council) in 1996 and reviewed by the Agency’s Office of Water. The CMA (1996) study was 

conducted with sufficient numbers of animals of both sexes and examined numerous endpoints.

The study is acceptable and consistent with EPA testing guidelines that were in effect at the time 

of the study. The database for reproductive toxicity is considered complete

The Chemical Manufacturers Association (CMA) conducted a two-generation reproduction 

toxicity study (MRID 45358901) to examine reproductive, developmental neurotoxicity, and 

hematologic endpoints in rats exposed to sodium chlorite. Thirty male and 30 female SpragueDawley rats of the OFA(SD)IOPS-Caw strain (F0) generation received drinking water 

containing 35, 70, or 300 ppm sodium chlorite for 10 weeks and were then paired (1M:1F) for 

mating. A similar group received purified water and served as controls. Males were exposed 

throughout mating and then were sacrificed. Exposure for the females continued through mating, 

pregnancy, and lactation until necropsy following weaning of their litters. Sodium chlorite 

concentrations were adjusted downward during lactation to offset increases in the volume of 

water consumed so that a constant intake (mg/kg-day) could be maintained. Twenty-five males 

and females from each of the first 25 litters to be weaned in a treatment group were chosen to 

produce the F1 generation. The F1 pups were continued on the same treatment regimen as their 

parents. At approximately 14 weeks of age, they were mated to produce the F2a generation.

Because of a reduced number of litters in the 70 ppm F1-F2a generation, the F1 animals were remated following weaning of the F2a to produce the F2b generation. Pregnant F1 females were 

allowed to litter and rear the F2a and F2b generations until weaning at postnatal day 21. Doses 

for the F0 animals were 0, 3, 5.6, and 20 and 0, 3.8, 7.5, and 28.6 mg/kg-day chlorite for males 

and females, respectively. For the F1 animals, doses were 0, 2.9, 5.9, and 22.7 mg/kg-day 

chlorite for the males and 0, 3.8, 7.9, and 28.6 mg/kg-day chlorite for the females. Body weight, 

food and water consumption, estrus cycle in the F0 and F1 rats, and hematology and T3 and T4 

levels in the F1 rats (blood samples collected from 1 male and 1 female from the first 20 F1 

litters at age 25 days and another group at 13 weeks), gestation duration, litter size, pup sex, pup 

body weight, pup developmental landmarks, number alive/dead pups in the F1 and F2 

generations, total caudal sperm number and percent motile, morphology by computer-assisted 
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sperm motility analysis in the F0 and F1 rats, and organ weight and histopathology examination 

of the brain, pituitary gland, liver, adrenal gland, spleen, thymus, kidneys, and reproductive 

organs of all F0 and F1 controls and high-dose animals were measured. An additional group of 

F1 pups was chosen for neurohistopathology on postnatal day 11 (examination of the brain and 

spinal cord) or postnatal day 60 (sensory ganglia, dorsal and ventral nerve roots, and several 

peripheral nerves and muscles). Another group of F1 rats was examined for neurotoxicological 

endpoints (motor activity in a -Figure 8" Activity System and neuropathology on postnatal day 

60, auditory startle in the SR-Screening System, learning and memory retention in a water Emaze). A functional observational battery (FOB) was also conducted on the pups undergoing 

auditory and learning assessments. This group was composed of 2 males and 2 females from 20 

litters, and exposure was discontinued after weaning. Reevaluation of the auditory startle 

response was conducted in 20 males and 20 females in the F2a and F2b generations.

There were reductions in water consumption, food consumption, and body weight gain in both 

sexes in all generations at various times throughout the experiment (e.g., during pre-mating, 

pregnancy, gestation, post-weaning), primarily in the 70 and 300 ppm groups. The authors 

attributed these reductions to lack of palatability of the drinking water solution, but did not show 

data to support this contention. Significant alterations related to treatment at 300 ppm include 

reduced absolute and relative liver weight in F0 females and F1 males and females, reduced pup 

survival, and reduced body weight at birth and throughout lactation in F1 and F2 rats, lower 

thymus and spleen weight in both generations, lowered incidence of pups exhibiting normal 

righting reflex and with eyes open on postnatal day 15, alteration in clinical condition in F2 

animals chosen for neurotoxicity, decrease in absolute brain weight for F1 males and F2 females, 

delay in sexual development in males (preputial separation) and females (vaginal opening) in F1 

and F2 rats, and lower red blood cell parameters in F1 rats. The reported alterations in pup sexual 

maturation measures might be due to reduced pup body weight, but a definitive conclusion 

cannot be drawn. In the 70 ppm groups, reduced absolute and relative liver weight in F0 females 

and F1 males was observed. A significant decrease in maximum response to an auditory startle 

stimulus was noted in the 70 and 300 ppm groups on postnatal day 24, but not on postnatal day 

60. Analysis of the 21E-maze data by EPA personnel indicated possible alterations in learning 

behavior in the 70 ppm group, but the differences from the conclusions of the report could not be 

resolved.

The NOAEL for this study is 35 ppm (2.9 mg/kg-day chlorite) and the LOAEL is 70 ppm (5.9 

mg/kg-day chlorite) based on lowered auditory startle amplitude and altered liver weights in two 

generations.

Chronic Toxicity 

One chronic toxicity study, Haag (1949) is available for chlorine dioxide. The study was limited 

because an insufficient number of animals were tested per group, pathology was conducted on a 

small number of animals, and it did not provide adequate evaluations of more sensitive 

parameters, which would have been more useful in the overall assessment of chronic toxicity.

The database for chronic toxicity is considered incomplete.
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In a chronic study by Haag (1949), groups of rats (7/sex/group) were exposed to 0, 1, 2, 4, 8, 

100, or 1,000 mg/L chlorite in the drinking water (0, 0.09, 0.18, 0.35, 0.7, 9.3, or 81 mg/kg-day) 

for 2 years. Animals exposed to chlorite concentrations of 100 or 1,000 mg/L exhibited 

treatment-related renal pathology, characterized by distention of the glomerular capsule and 

appearance of a pale pinkish staining material in the renal tubules. These effects were also 

observed in a group of animals administered sodium chloride at a concentration equimolar to 

1,000 mg sodium chlorite/L. The study author concluded that the renal pathology was a 

nonspecific salt effect, but this observation does not alter the observation that concentrations of 

100 mg/L or higher led to adverse effects. Based on renal effects, this study identifies a NOAEL 

of 8 mg/L (0.7 mg/kg-day) and a LOAEL of 100 mg/L (9.3 mg/kg-day).

Carcinogenicity 

Studies that reported on carcinogenicity of chlorine dioxide and chlorite were reviewed from the 

open scientific literature and are summarized below. The database for carcinogenicity is 

considered incomplete.

In a study of the promoting and complete carcinogenic activities of some oxidizing chemicals

(MRID 40129401), sodium chlorite (20 mg/ml) was applied dermally to twenty (20) 4 week old 

female SENCAR mice in either a tumor promotion testing protocol or in a complete carcinogenic 

activity protocol. For the tumor promotion protocol, mice received a single dermal application of 

20nmol DMBA in 0.2ml acetone followed one week later by application of sodium chlorite 

(approximately 100 mg/kg per application) for 51 weeks. In the complete carcinogenic activity 

protocol, sodium chlorite only was administered dermally at the same dose (approx. 100 mg/kg) 

for 51 weeks. 

In mice subjected to the tumor promotion protocol, increased incidence of skin tumors was 

observed at weeks 26 (2/20), 38 (6/20), and 52 (6/20). Of the 6 mice observed with skin tumors, 

5 of these had squamous cell carcinoma. The increase was identified as not statistically 

significant over acetone control. 

In mice subjected to the complete carcinogenic activity protocol, there was no increase in the 

incidence of skin tumors was observed. 

Although no data were shown, it was stated that there were no significant differences in mean 

survival time and body weight of mice treated with sodium chlorite.

This carcinogenicity study in the mouse is unacceptable and does not satisfy the guideline 

requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice. This study was 

not submitted to fulfill a guideline requirement, but was reviewed to determine the available 

information in the study and its relevance to assessing carcinogenicity of chlorine 

dioxide/sodium chlorite. There are several deficiencies in this study, including: Only a single 

dose of sodium chlorite was tested in this study; the dose tested produced no systemic toxicity; 

several parameter measurements were not done as the 870.4200 guideline recommends.

In a carcinogenicity study (MRID 40943902), sodium chlorite (99.4%) was administered in 

drinking water ad libitum to groups of F344 rats or B6C3F1 mice (approximately 50/sex) at 
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doses of 0, 300 and 600ppm [rats] or 0, 250 and 500ppm [mice] for 104 and 78 (study 

termination at 85) weeks, respectively. Doses in mg/kg are approximately 18 and 32 mg/kg-day in 

male rats and 28 and 41 mg/kg-day in female rats. In mice, doses in mg/kg are approximately 0, 48, 

and 95 mg sodium chlorite/kg-day (0, 36, and 71 mg chlorite/kg-day), calculated by EPA (1994d).

The study in rats was terminated at 85 weeks due to widespread infection of the animals with the 

Sendai virus. Survival in males at 85 weeks was 68%, 60%, and 86% respectively at 0, 18, and 

32 mg/kg. Survival in females at 85 weeks was 94%, 88%, and 100% at 0, 28, and 41 mg/kg. 

Drinking water consumption was reported to be lower in treated animals vs control animals but 

no data were shown. Body weight gain appeared to be affected in a dose-related manner, but 

only graphical data were presented, and no statistical analysis was reported on body weight. 

In rats, there was no statistically significant effect of treatment with sodium chlorite in incidence 

of tumor-bearing animals in treated vs control rats. Incidence of several specific tumors was 

noted to be appreciable across dose groups, including C-cell adenoma of the thyroid, 

pheochromocytoma of the adrenal, and interstitial cell tumors of the testis (males), and 

chromophobic adenoma of the pituitary and endometrial polyps of the uterus (females). The 

incidence of these tumors was not related to the dose of sodium chlorite. 

In mice administered sodium chlorite, there were no significant changes in survival or body weight 

gain; increased mortality was observed in the male control group, which was attributed to severe 

fighting. In male mice, the incidence of hepatocellular carcinoma was significantly increased in the 

low- and high-dose groups relative to controls (3/35, 14/47, and 11/43 respectively). According to the 

report, the combined incidence of liver hyperplastic nodules and hepatocellular carcinoma was 

significantly increased in the low-dose group. Incidence of lung adenoma (0/35, 2/47, and 5/43, 

respectively) and combined incidence for lung adenoma and adenocarcinoma (0/35, 3/47, and 7/43, 

respectively) were significantly increased in the high-dose group compared with controls. The study 

authors considered these increases inconclusive, on the basis of (1) increased mortality in control 

males who were not included in the numbers for histopathologic evaluation; (2) the incidence of 

these tumors being within the historical control range of the data from the authors’ laboratory as well 

as the National Toxicology Programs’ historical control data.

It would appear that the body weight decrease at the 600ppm dose in males and reduced survival 

at this dose constitute an adverse effect of sodium chlorite; however, there is a lack of numerical 

data to conduct an analysis to determine the magnitude of the effect. Complicating the 

interpretation is the presence of the Sendai virus that caused premature termination of the study 

in rats. In mice, severe fighting in the control animals complicates interpretation of effects 

related to administration of sodium chlorite, including tumor incidence, due to reduced number 

of mice in the control. 

This carcinogenicity study in the rat and mouse is unacceptable using the criteria in the 

guidance document Guidance for Considering and Using Open Literature Toxicity Studies to 

Support Human Health Risk Assessment (Office of Pesticide Programs, 2012). It was not 

submitted to the Agency in fulfillment of any 870 series test guideline. Using the criteria in the 

above mentioned guidance document, there were several deficiencies that invalidate the study for 

quantitative use. However, the study may be used qualitatively in a weight of evidence 

determination for carcinogenicity of chlorine dioxide/sodium chlorite. 
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In a carcinogenicity study (MRID 40943903), sodium chlorite (99.4%) was administered in 

drinking water ad libitum to groups of B6C3F1 mice (50/sex) at doses of 0, 250 and 500 ppm for 

80 weeks. Doses in mg/kg are approximately 0, 48, and 95 mg sodium chlorite/kg/day (0, 36, and 

71 mg chlorite/kg/day), calculated by EPA (1994d). These data have also been presented in a 

publication by Kurokawa (Kurokawa et al., Long-term Carcinogenicity Tests of Potassium 

Bromate, Sodium Hypochlorite, and Sodium Chlorite Conducted in Japan. Env. Hlth. Perspec. 

69: 221-235. MRID 40943902). The present study was submitted by the Chemical 

Manufacturers’ Association (now known as the American Chemistry Council) with the intention 

of fulfilling the carcinogenicity data requirement for chlorine dioxide/chlorite. Note that this 

study was submitted prior to issuance of the RED for chlorine dioxide/chlorite, and is still 

relevant for data needed as part of the registration review. The document “Guidance for 

Considering and Using Open Literature Toxicity Studies to Support Human Health Risk 

Assessment” (Office of Pesticide Programs, 2012) was also used to determine the acceptability 

of this study under the 870.4200 guideline.

In mice administered sodium chlorite, there were no significant treatment-related changes in survival. 

Increased mortality was observed in the male control group, which was attributed to severe fighting 

after 34 weeks (survival of 70% in control, 94% in low-dose, and 86% in high-dose mice 

respectively). Body weight in male mice was stated to be decreased after week 65 of the study, but 

graphical representation showed no apparent difference in body weight among control or treated 

male mice. In female mice, body weight appeared decreased in low-and high-dose animals after 

week 60, but it is not known if the decrease was significant. Water consumption in male mice at the 

high-dose was stated to be slightly lower than other groups of male mice. There were no significant 

treatment-related changes in organ weights in male or female mice. 

Histologically, the incidence of lung adenoma in male mice was 0/35, 2/47, and 5/43, and combined 

incidence for lung adenoma and adenocarcinoma was 0/35, 3/47, and 7/43, in control, 250 ppm, and 

500 ppm male mice, respectively. The incidence of lung adenoma in the 500 ppm males was 

statistically higher vs. control according to the report (p < 0.05). However, the statistical difference 

could be partly due to the lower number of control male mice available (due to fighting after 34 

weeks) for histological analysis. In addition, the incidence of lung adenoma at 500 ppm in males 

(12%) was within historical control incidence (15.3%) for lung alveolar/bronchiolar adenoma from 

the NTP database. 

Liver histopathology was reported as hyperplastic nodules, hepatocellular carcinoma, and 

hemangioma. In male mice, the incidence of hyperplastic nodules in the liver was reported as 6/35 

(control), 14/47 (250 ppm), and 11/43 (500 ppm). The incidence of hepatocellular carcinoma in male 

mice was reported as 4/35 (control), 8/47 (250 ppm), and 6/43 (500 pm). According to the study 

report, these differences were not statistically significant. The report also stated that in a few cases, 

hepatocellular carcinoma had metastasized to the lung in one low-dose male and one high-dose male. 

However, data were not provided in the report to verify this observation. Historical incidence of 

hepatocellular carcinoma from the NTP database is 36.6% ± 11.44%, compared to the reported 

incidence of 14-17% for this lesion in the present study.
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The study authors concluded that it was not possible to make a conclusion on carcinogenicity of 

sodium chlorite, based on the absence of a dose-related increase in incidence of lung adenoma 

(which seems to conflict with the dose-response for lung adenoma in this paper) and a lack of an 

increase in lung adenocarcinoma. The reviewer is in agreement with the study authors’ overall 

conclusion. While there did appear to be an increase in lung adenoma in male mice administered 

sodium chlorite, the loss of control male mice for histological examination resulting in excess 

mortality confounds interpretation of study results since it does not provide complete information 

on dose-response. 

This carcinogenicity study in the mouse is unacceptable/guideline. It does not satisfy the 

guideline requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice.

Although the dose levels appear to be justified in this study, the excessive fighting reported in 

male mice after week 34 resulted in excessive mortality in the control group, complicating 

interpretation of the dose-response for benign tumors reported in this study. There were also 

deficiencies in data reporting of parameters required in the guideline, making a determination of 

non-cancer dose response not possible.

The study is also unacceptable using the criteria in the guidance document “Guidance for 

Considering and Using Open Literature Toxicity Studies to Support Human Health Risk 

Assessment” (Office of Pesticide Programs, 2012). For open literature studies, criteria for 

invalidation includes deficiencies in reporting of study data, and an insufficient number of 

animals tested. In the context of this study, an insufficient number of animals were available for 

histopathological examination in the control males, due to excessive mortality. In addition, 

several study parameters were not adequately reported (body weight) or were not reported at all 

(food consumption, hematology, clinical chemistry).

Mutagenicity 

Data on the mutagenicity of chlorine dioxide exist in the open scientific literature as well as 

within the Agency’s database of submitted studies. The following studies have been reviewed by 

the Agency and are considered acceptable: 

1) Miller et al. (1986) reported negative effects in Salmonella strains TA98 and TA100 

from a 400-fold drinking water concentrate of chlorine dioxide and positive effects in 

a 4000-fold concentrate to strain TA98 only in the absence of metabolic activation.

2) In L5178Y/TK cells, chlorine dioxide was positive for forward mutations under nonactivated conditions (dose-related from 3.2-24.3 μg/ml) and activation conditions 

(48.3 μg/mL) [Accession no. 265867].

3) Chlorine dioxide was positive for structural chromosome aberrations under nonactivated and activated conditions (10, 15, and 50 μg/ml) [Accession no. 265867].

4) Chlorine dioxide was negative for increased transformed foci up to cytotoxic levels 

[Accession no. 265867].
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5) In vivo micronucleus and bone marrow chromosomal aberration assays in Swiss CD1 mice administered 0.1–0.4 mg chlorine dioxide via gavage for 5 consecutive days 

were negative, as was a sperm-head abnormality assay in B6C3F1 mice administered 

0.1–0.4 mg via gavage for 5 consecutive days (0, 3.2, 8, and 16 mg/kg-day) (Meier et 

al., 1985).

Other Toxicological Effects 

Neurotoxicity of chlorine dioxide has been observed in the available toxicology database. In the 

two-generation reproduction toxicity study (CMA 1996), significant changes were observed in 

maximum response in startle amplitude and absolute brain weight in F1 rat pups at a dose of 3 

mg/kg/day. In the Orme et al. (1985) developmental toxicity study, neurobehavioral deficits in 

offspring were observed also at a dose of 14 mg/kg/day administered to maternal rats. These 

effects are noted from studies considered acceptable by the Agency and which are summarized 

under the reproductive toxicity and developmental toxicity sections above. 
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Toxicology References

265867 (Accession #): Mutagenicity Evaluation of Chlorine Dioxide in the Mouse Lymphoma 

Foreword Mutation Assay. Litton Bionetics, Kensington, MD, LBI Project No. 20989, 

March 1984.

40129401 (MRID#): Kurokawa,Yuji et al. (1984): Studies on the Promoting and Complete 

Carcinogenic Activities of Some Oxidizing Chemicals in Skin Carcinogenesis. Division 

of Pathology, National Institute of Hygienic Sciences, 1-18-1, Kamiyoga, Setagaya-ku, 

Tokyo 158 (Japan). Cancer Letters 24: 299-304 (1984).

40168704 (Accession #): Acute Dermal LD50 on Rabbit – Sodium Chlorite Powder, Lot 

#110984-15. Gibraltar Biological Lab, Inc. (Fairfield, NJ), Internaltional Dioxcide, Inc. 

Study Number GBL 024065, April 23, 1985.

40943903 (MRID#): Yokose, Y. et al. (1987): Studies of Carcinogenicity of Sodium Chlorite in 

B6C3F1 mice. Env. Hlth. Perspec. 76: 205-210.

41715701: Irvine, L. (1990) Sodium Chlorite: Rabbit Teratology Study (Drinking Water 

Administration): Lab Project Number: CMA/3/R. Unpublished study prepared by Toxicol 

Laboratories Ltd. 

42484101 (MRID #): Acute Inhalation Toxicity Evaluation in Rats. International Research and 

Development Corporation (IRDC), Mattawan, MI. Lab. Project No. 632-001, August 14, 

1992.

43441903 (MRID #): Primary Eye Irritation Study in Rabbits. Stillmeadow, Inc., Sugar Land, 

TX, Lab. Project No. 1441-94, October 11, 1994.

43558601 (MRID #): Abdel-Rahman, et al., “Toxicity of Alcide,” published in J. Appl. Toxicol. 

2(3): 160-164, 1982.

43558602 (MRID #): Dalhamn, T., “Chlorine Dioxide: Toxicity in Animal Experiments and 

Industrial Risks,” published in A.M.A. Arch. Indust. Hlth. 15(2): 101-107, 1957.

45358901: Sodium Chlorite: Drinking Water Rat Two-Generation Reproductive Toxicity Study. 

Chemical Manufacturers Association. Quintiles Report Ref. CMA/17/96.Abdel-Rahman, 

et al. (1984): The kinetics of chlorite and chlorate in the rat. J Am Coll Toxicol 3:261-

267.

49660502 (MRID#): Ogata, N. (2013): Ten-week Whole-body inhalation Toxicity Study of 

Chlorine Dioxide Gas in Rats. Drug Metabolism and Toxicology 4(2): pp. 1-5.

Akamatsu, A. (2012): Six-month low level chlorine dioxide gas inhalation toxicity study with 

two-week recovery period in rats. Journal of Occupational Medicine and Toxicology 

7(2): pp 1-8.
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Dalhamn, T. (1957): Chlorine Dioxide: Toxicity in Animal Experiments and Industrial Risks. 

Arch. Ind. Health 15: 101-107. 

Daniel, F.B., et al. (1990): Comparative subchronic toxicity studies of three disinfectants. J Am 

Water Works Assoc 82:61-69.

Haag, H.B. (1949): The effect on rats of chronic administration of sodium chlorite and chlorine 

dioxide in the drinking water. Report to the Mathieson Alkali Works from H.B. Haag of 

the Medical College of Virginia. February 7, 1949. 

Harrington, R.M., et al. (1995a): Subchronic toxicity of sodium chlorite in the rat. J Am Coll 

Toxicol 14:21-33.

Harrington, R.M., et al. (1995b) Developmental toxicity of sodium chlorite in the rabbit. J Am 

Coll Toxicol 14:109-118.

Kurokawa, Y. et al. (1986): Long-term Carcinogenicity Tests of Potassium Bromate, Sodium 

Hypochlorite, and Sodium Chlorite Conducted in Japan. Env. Hlth. Perspec. 69: 221-235. 

MRID 40943902.

Meier, J.R., et al. (1985): Evaluation of chemicals used for drinking water disinfection for 

production of chromosomal damage and sperm-head abnormalities in mice. Environ 

Mutagen 7:201-211. 

Miller, R.G. et al. (1986): Results of Toxicological Testing of Jefferson Parish Pilot Plant 

Samples. Env. Hlth. Perspec. 69: 129-139. 

Orme, J., et al. (1985): Effects of chlorine dioxide on thyroid function in neonatal rats. J Toxicol 

Environ Health 15:315-322.

Paulet G and S. Desbrousses (1970): On the action of ClO2 at low concentrations on laboratory 

animals. Arch Mal Prof 31:97-106.

Paulet G and S. Desbrousses (1972): On the toxicology of chlorine dioxide. Arch Mal Prof 

33:59-61.

Paulet G and S. Desbrousses (1974): Action of a discontinuous exposure to chlorine dioxide 

(ClO2) on the rat. Arch Mal Prof 35:797-804.

USEPA (2005): Chlorine Dioxide/ Sodium Chlorite - Report of the Hazard Identification 

Assessment Review Committee (HIARC) and the Antimicrobials Division Toxicity 

Endpoint Selection Committee (ADTC).
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Appendix B Environmental Fate

Environmental Fate and Transport Properties of Chlorine dioxide 

and Sodium chlorite 

Chlorine dioxide and sodium chlorite are inorganic compounds and the standard OCSPP 835 

series guideline studies do not provide useful fate information.

The pertinent fate characteristics are captured in the text in Section 4 of the FWP.
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Environmental Fate References

Chlorine Dioxide: Concise International Chemical Assessment Document 37, 2002; World

Health Organization. Geneva.

EPA RED of chlorine dioxide and Sodium Chlorite, 2008.

EPI Suite, version 4.1

MRID 41467601: Biehn, W (1989) Chlorine dioxide-Product Identity and composition

Certification of Ingredient Limits, Nominal Concentration, analytical methods, Physical, 

Chemical Properties : Lab Project#: IR-4/PR/NO/4042, Unpublished Study prepared by 

IR-4 Project, Rutgers University, pp 44

MRID 41467602: Biehn, W (1989) Chlorine Dioxide Safety Data in support of Petition 

Proposing an Exemption from Requirement of a tolerance for Chlorine Dioxide for Use 

in Mushroom Production: Lab Project #4042. Unpublished study prepared by IR-4, 

Rutgers Univ., p 145
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Appendix C Ecotoxicology Profile

Toxicity to Terrestrial Receptors

Birds

Acute oral toxicity studies using the technical grade of the active ingredient (TGAI) are available

to establish the toxicity of chlorine dioxide/sodium chlorite to birds. The preferred test species is 

either mallard duck (a waterfowl) or bobwhite quail (an upland game bird). The results of the 

toxicity studies are provided in the following table.

Table C1. Acute Oral Toxicity of Chlorine Dioxide and Sodium Chlorite to Birds

Substance/%

Active 

Ingredient

(AI)

Organism

Endpoints/Results

(95% conf. interval)

mg/kg

Reference Study 

Classification

Sodium 

Chlorite/80%

Northern bobwhite

(Colinus virginianus)

LD50 = 382 (300-520)

NOAEL = 175

Robaidek, 1985 

ACC # 259373 acceptable

Sodium 

Chlorite/80%

Northern bobwhite

(Colinus virginianus)

LD50 = 390 (310-490)

NOAEL = N.R.

Robaidek and

Johnson, 1985

ACC # 257341

acceptable

Sodium 

Chlorite/80%

Northern bobwhite

(Colinus virginianus)

LD50 = 395 (272-573)

NOAEL = N.R.

Fletcher, 1984

ACC # 253378 acceptable

Sodium 

Chlorite/83%

Northern bobwhite

(Colinus virginianus) LD50 = 660 (540-810) Fletcher, 1973MRID # 31610 acceptable

Sodium 

Chlorite/80%

Northern bobwhite

(Colinus virginianus) LD50 = 467 (372-585) Beavers, 1984ACC # 254177 acceptable

Sodium 

Chlorite/80%

Mallard Duck (Anas 

platyrhynchos) LD50 > 31.25 Beavers, 1984ACC # 254176 supplemental

Sodium 

Chlorite/25%

Northern bobwhite

(Colinus virginianus) LD50 = 797(420-2594)

NOAEL= 125

MBA 

Laboratories, 1984

ACC# 252854

acceptable

Note: LD50=Median Lethal Dose; NOAEL=No Observed Adverse Effect Level; N.R. = Not Reported
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These results indicate that chlorine dioxide/sodium chlorite range from slightly to highly toxic to 

birds on an acute oral basis. The guideline requirement (OPPTS 850.2100) is fulfilled.

Two subacute dietary studies using the technical grade of the active ingredient are conditionally 

required to establish the toxicity of a pesticide to birds. The preferred test species are mallard 

duck (a waterfowl) and bobwhite quail (an upland gamebird). Results of avian subacute dietary 

tests are tabulated below.

Table C2. Avian Subacute Dietary Toxicity of Chlorine Dioxide and Sodium Chlorite

Substance/

% AI Organism

LC50

(ppm)

(95 % c.i.)

NOAEC

(ppm) Reference Study 

Classification

Sodium 

Chlorite/80%

Mallard Duck (Anas 

platyrhynchos) >5000 5000 Johnson, 1984MRID # 94068008 acceptable

Sodium 

Chlorite/80%

Northern bobwhite 

(Colinus virginianus) > 5000 N.R. Fletcher, 1984ACC # 253378 acceptable

Sodium 

Chlorite/80%

Mallard Duck (Anas 

platyrhynchos) > 5000 N.R. Fletcher, 1984ACC # 253378 acceptable

Sodium 

Chlorite/80%

Northern bobwhite 

(Colinus virginianus) > 5000 N.R. Johnson, 1984MRID # 94068005 acceptable

Sodium 

Chlorite/80%

Mallard Duck (Anas 

platyrhynchos) > 5620 N.R. Beavers, 1984ACC # 254178 acceptable

Sodium 

Chlorite/80%

Northern bobwhite

(Colinus virginianus) > 5620 N.R. Beavers, 1984ACC # 254179 acceptable

Sodium 

Chlorite/80%

Northern bobwhite

(Colinus virginianus) >10,000 N.R. Fink, 1977MRID # 130649 acceptable

Sodium 

Chlorite/80%

Mallard Duck (Anas 

platyrhynchos) >10,000 N.R. Fink, 1977MRID # 130650 acceptable

Sodium 

Chlorite/25%

Mallard Duck (Anas 

platyrhynchos)

18686 (8186-

109184) N.R. MBA Laboratories, 1983ACC # 252854 acceptable

Sodium 

Chlorite/25%

Northern bobwhite 

(Colinus virginianus)

2031(1226-

3903) 417 MBA Laboratories, 1984ACC #252854 acceptable

Note: LC50=Median Lethal Concentration; NOAEC=No Observed Adverse Effect Concentration; N.R. = Not Reported
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These results indicate that chlorine dioxide/sodium chlorite range from slightly toxic to 

practically non-toxic to birds on a subacute dietary basis.

Toxicity to Aquatic Receptors

Freshwater Fish

Fish toxicity studies using the TGAI are available to establish the toxicity of a pesticide to 

freshwater fish. The preferred test species are rainbow trout (a cold water fish) or bluegill sunfish 

(a warm water fish). The results of studies submitted for sodium chlorite are provided in the 

following table.

Table C3. Acute Toxicity of Chlorine Dioxide and Sodium Chlorite to Freshwater Fish

Substance/ %

AI Organism

Endpoints/Results

(ppm)

(95% conf. interval)

Reference Study 

Classification

Sodium 

Chlorite/80%

Rainbow trout 

(Oncorhynchus mykiss)

LC50 = 360 (216-600)

NOAEC = 216

Barrows, 1984

MRID # 94068007 acceptable

Sodium 

Chlorite/80%

Bluegill

(Lepomis macrochirus)

LC50 = 244 (196-304)

NOAEC = 108

Larkin, 1984

ACC # 254181 acceptable

Sodium 

Chlorite/80%

Rainbow trout 

(Oncorhynchus mykiss)

LC50 = 360 (216-600)

NOAEC = 216

Larkin, 1984

ACC # 254180 acceptable

Sodium 

Chlorite/80.25%

Bluegill

(Lepomis macrochirus)

LC50 = 265 (231-309)

NOAEC = 130

EG&G Bionomics, 

1978

ACC # 69809

supplemental

Sodium 

Chlorite/79%

Bluegill

(Lepomis macrochirus)

LC50 = 208 (165-262)

NOAEC = N.R.

Sleight III, 1971

MRID # 131351 supplemental

Sodium 

Chlorite/79%

Rainbow trout 

(Oncorhynchus mykiss)

LC50 = 50.6 (38.8-

65.8)

NOAEC = N.R.

Sleight III, 1971

MRID # 131351 supplemental

Sodium 

Chlorite/80%

Rainbow trout 

(Oncorhynchus mykiss)

LC50 >100

NOAEC = N.R.

McMillen, 1985

ACC # 253743 supplemental
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Substance/ %

AI Organism

Endpoints/Results

(ppm)

(95% conf. interval)

Reference Study 

Classification

Sodium 

Chlorite/80%

Bluegill (Lepomis 

macrochirus)

LC50 >100

NOAEC = N.R.

McMillen, 1985

ACC # 253743 supplemental

Sodium 

Chlorite/25%

Rainbow trout 

(Oncorhynchus mykiss)

LC50 = 203 (175-236)

NOAEC = 100

MBA Laboratories, 

1984

ACC # 252854

acceptable

Sodium 

Chlorite/25%

Bluegill (Lepomis 

macrochirus)

LC50 = 222 (207-237)

NOAEC = 186

MBA Laboratories, 

1983

ACC # 252854

supplemental

Sodium 

Chlorite/81.5%

Bluegill (Lepomis 

macrochirus)

LC50 = 310 (270-350)

NOAEC = 220

Sousa, 1981

ACC # 245697 acceptable

Sodium 

Chlorite/80.25%

Rainbow trout 

(Oncorhynchus mykiss)

LC50 = 290 (250-340)

NOAEC = <70

EG&G Bionomics, 

1979

ACC # 69810

acceptable

Sodium 

Chlorite/80%

Rainbow trout 

(Oncorhynchus mykiss)

LC50 = 340 (220-600)

NOAEC = 130

Sousa and Surprenant, 

1984

ACC # 253379

acceptable

Sodium 

Chlorite/80%

Bluegill (Lepomis 

macrochirus)

LC50 = 420 (220-600)

NOAEC = 220

Sousa and Surprenant, 

1984

MRID # 94068006

acceptable

Note: LC50=Median Lethal Concentration; NOAEC=No Observed Adverse Effect Concentration; N.R. =Not Reported

These results indicate that chlorine dioxide/sodium chlorite range from slightly toxic to 

practically non-toxic to freshwater fish on an acute basis. The guideline requirement (OPPTS 

850.1075) is fulfilled.

Freshwater Fish, Chronic

A freshwater fish early life-stage test using the technical grade of the active ingredient is 

required for a pesticide when it may be applied directly to water or if the end-use product is 

expected to be transported to water from the intended use site, and any of the following 

conditions are met: (1) the pesticide is intended for use such that its presence in water is likely to 

be continuous or recurrent regardless of toxicity, (2) any aquatic acute LC50 or EC504 is less 

than 1 mg/l, (3) the EEC (estimated environmental concentration) in water is equal to or greater

than 0.01 of any acute LC50 or EC50 value, or (4) the actual or estimated environmental 

 4 EC50=Median Effective Concentration
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concentration in water resulting from use is less than 0.01 of any acute LC50 or EC50 value and 

any one of the following conditions exist: studies of other organisms indicate the reproductive 

physiology of fish may be affected, physicochemical properties indicate cumulative effects, or 

the pesticide is persistent in water (e.g., half-life greater than 4 days). The preferred test species 

is rainbow trout, but other species may be used. Freshwater fish early life-stage testing is 

required in the post-RED GDCI for chlorine dioxide and sodium chlorite in order to support 

once-through cooling tower uses. No data under this topic have been submitted; therefore 

Guideline OPPTS 850.1400 is not fulfilled.

Freshwater Invertebrates

A freshwater aquatic invertebrate toxicity test using the TGAI is required to establish the toxicity 

of chlorine dioxide and sodium chlorite to freshwater aquatic invertebrates. The preferred test 

species is Daphnia magna. Results of this test are tabulated below.

Table C4. Acute Toxicity of Chlorine Dioxide and Sodium Chlorite to Freshwater 

Invertebrates

Substance/%

Active Ingredient

(AI)

Organism Endpoints/Results

(ppm)

(95% conf. interval)

Reference Study 

Classification

Sodium 

Chlorite/80%

Daphnia magna EC50 = 0.027 (0.021-

0.031)

NOAEC = 0.003

Barrows, 1984

MRID # 146162

acceptable

Sodium 

Chlorite/80%

Daphnia magna EC50 = 0.39 (0.32-0.54)

NOAEC =N.R.

Hoberg and Surprenant, 

1984

MRID # 141149

acceptable

Sodium 

Chlorite/79%

Daphnia magna EC50 = 0.29

(0.25-0.33)

NOAEC = 0.10

Vilkas, 1976

MRID # 131350

acceptable

Daphnia magna acceptable
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Sodium 

Chlorite/80%

EC50 = 0.08

(0.06-0.10)

NOAEC = 0.06

Larkin, 1984

ACC # 254182

Sodium 

Chlorite/80%

Daphnia magna EC50 = 0.146 

(0.12 - 0.18)

NOAEC = 0.06

Nackord, 1984

MRID # 94068009

acceptable

Sodium 

Chlorite/25%

Daphnia magna EC50 = 1.4 (1.0-1.9 ) 

NOAEC = 0.4

MBA Laboratories, 

1984

ACC # 252854

supplemental

Note: EC50=Median Effective Concentration; NOAEC=No Observed Adverse Effect Concentration; N.R. =Not Reported

These studies indicate that chlorine dioxide and sodium chlorite range from very highly toxic for 

technical grade sodium chlorite a.i. to moderately toxic for the formulated product to aquatic 

invertebrates on an acute basis. The guideline requirement (OPPTS 850.1010) is fulfilled.

Freshwater Invertebrate, Chronic

A freshwater aquatic invertebrate life-cycle test using the technical grade of the active ingredient 

is required for a pesticide if the end-use product may be applied directly to water or expected to 

be transported to water from the intended use site, and any of the following conditions are met: 

(1) the pesticide is intended for use such that its presence in water is likely to be continuous or 

recurrent regardless of toxicity, (2) any aquatic acute LC50 or EC50 is less than 1 mg/l, (3) the 

EEC in water is equal to or greater than 0.01 of any acute EC50 or LC50 value, or (4) the actual 

or estimated environmental concentration in water resulting from use is less than 0.01 of any 

aquatic acute EC50 or LC50 value and any of the following conditions exist: studies of other 

organisms indicate the reproductive physiology of invertebrates may be affected, 

physicochemical properties indicate cumulative effects, or the pesticide is persistent in water 

(e.g., half-life greater than 4 days). The preferred test species is Daphnia magna. Freshwater 

aquatic invertebrate early life-stage testing is required in the RED GDCI for chlorine 

dioxide/sodium chlorite in order to support once-through cooling tower uses. No data under this 

topic have been submitted; therefore Guideline OPPTS 850.1300 is not fulfilled.

Estuarine/Marine Fish

Acute toxicity testing with estuarine/marine fish using the technical grade of the active 

ingredient is available for sodium chlorite, for when the end-use product is intended for direct 
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application to the marine/estuarine environment or the active ingredient is expected to reach this 

environment because of its use in coastal counties. The preferred test species is sheepshead 

minnow. Results of this test are tabulated below.

Table C5. Acute Toxicity of Chlorine Dioxide/Sodium Chlorite to Estuarine/Marine Fish

Substance/

% AI Organism

96 hr LC50 

mg/L (ppm) 

(95% conf. 

interval)

NOAEC 

mg/L 

(ppm)

Reference Study 

Classification

Sodium 

Chlorite/79%

Sheepshead minnow

(Cyprinodon 

variegatus)

75 (62.6-89.8) 13.9 Yurk and Overman, 1994

MRID # 43259401 acceptable

Note: LC50=Median Lethal Concentration; NOAEC=No Observed Adverse Effect Concentration

The results indicate that chlorine dioxide/sodium chlorite are slightly toxic to estuarine/marine 

fish on an acute basis. The guideline requirement (OPPTS 850.1025) is fulfilled.

Estuarine and Marine Fish, Chronic

Estuarine/marine fish early life-stage testing is not anticipated to be required for the currently 

registered uses of chlorine dioxide and sodium chlorite. Since freshwater and estuarine/marine 

fish are comparably sensitive to sodium chlorite on an acute basis, the freshwater early life-stage 

endpoints will suffice for assessing risk to estuarine/marine fish species. However, as noted 

above, the data requirement for freshwater fish early life-stage testing (850.1400) has not been 

fulfilled.

Estuarine/Marine Invertebrates

Acute toxicity testing with estuarine/marine invertebrates using the technical grade of the active 

ingredient is available for sodium chlorite, for when the end-use product is intended for direct 

application to the marine/estuarine environment or the active ingredient is expected to reach this 

environment because of its use in coastal counties. The preferred test species are the mysid 

shrimp and eastern oyster. Results of these tests are tabulated below.

Table C6. Acute Toxicity of Chlorine Dioxide and Sodium Chlorite to Estuarine/Marine 

Invertebrates
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Substance/

% AI Organism

96-hour

EC50 mg/L (ppm)

(95% conf. 

interval)

Reference Study 

Classification

Sodium 

Chlorite/79%

Eastern oyster 

(Crassostrea virginica)

21.4 (14.3-27.1)

NOAEC = 14.3

Yurk and Overman, 1994

MRID # 43259403 acceptable

Sodium 

Chlorite/79%

Mysid

(Mysidopsis bahia)

0.576 (0.44-0.75)

NOAEC= N.R. Yurk and Overman, 1994

MRID # 43259402

acceptable

Note: EC50=Median Effective Concentration; NOAEC=No Observed Adverse Effect Concentration

The results indicate that chlorine dioxide/sodium chlorite range from highly toxic to slightly 

toxic to estuarine/marine invertebrates on an acute basis. The guideline requirements (OPPTS 

850.1035 and 850.1045) are fulfilled. 

Estuarine and Marine Invertebrate, Chronic

An estuarine/marine invertebrate life-cycle toxicity test is required for a pesticide if the end-use 

product may be applied directly to estuarine or marine waters, or is expected to be transported to 

these waters from the intended use site, and any of the following conditions are met: (1) the 

pesticide is intended for use such that its presence in water is likely to be continuous or recurrent 

regardless of toxicity, (2) any aquatic acute LC50 or EC50 is less than 1 mg/l, (3) the EEC in 

water is equal to or greater than 0.01 of any acute EC50 or LC50 value, or (4) the actual or 

estimated environmental concentration in water resulting from use is less than 0.01 of any 

aquatic acute EC50 or LC50 value and any of the following conditions exist: studies of other 

organisms indicate the reproductive physiology of invertebrates may be affected, 

physicochemical properties indicate cumulative effects, or the pesticide is persistent in water 

(e.g., half-life greater than 4 days). Due to the high acute toxicity of sodium chlorite to 

estuarine/marine invertebrates, life-cycle testing is necessary; however, freshwater invertebrates 

tend to be more sensitive than estuarine/marine invertebrates to sodium chlorite on an acute 

basis, and, therefore, freshwater life-cycle endpoints will suffice for assessing risk to 

estuarine/marine invertebrate species. As noted above, freshwater invertebrate life-cycle testing 

(850.1300) has not been submitted.

Aquatic Plants

Microphytes and Floating Vascular Macrophytes

The once-through cooling tower use of chlorine dioxide/sodium chlorite requires that 5 aquatic 

plant tests be conducted due to the algaecidal nature of the chemical and the likelihood of 

exposure to aquatic plants in surface waters receiving industrial facility outfall from the cooling 

system. Guideline OPPTS 850.4400 and 850.4500, 850.4550, Vascular Aquatic Plant and 
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Algal dose-response toxicity testing (4 species), is not fulfilled because only one study (1 

species) under this topic has been submitted and 5 were required in the post-RED GDCI. The 

results of this test are tabulated below. The following aquatic plant studies are still required: 

blue-green cyanobacteria (Anabaena flos-aquae), freshwater diatom (Navicula pelliculosa), 

marine diatom (Skeletonema costatum) and floating macrophyte (Lemna gibba). These studies 

have been submitted to the Agency and are currently under review.

Table C7. Toxicity of Chlorine Dioxide/Sodium Chlorite to Aquatic Plants

Substance/

% AI Organism 96 hr EC50 (ppm)(95% conf. interval) Reference Study Classification

Sodium 

Chlorite/80%

Green algae (Selenastrum 

capricornutum)

1.32 (1.18-1.47)

NOAEC = <0.62

Ward and Boeri, 1991

MRID # 41880403 supplemental

Note: EC50=Median Effective Concentration; NOAEC=No Observed Adverse Effect Concentration

The results indicate that chlorine dioxide/sodium chlorite are moderately toxic to green algae.

Aquatic Emergent Rooted Plants

Currently, terrestrial plant testing is not required for pesticides other than herbicides except on a 

case-by-case basis (e.g., labeling bears phytotoxicity warnings, incidents of plant damage have 

been reported, or literature indicating phytotoxicity is available). The once-through cooling 

tower use of chlorine dioxide/sodium chlorite requires such testing, due to the algaecidal nature 

of the chemical and the likelihood of exposure to semi-aquatic plants along surface waters 

receiving industrial facility outfall from the cooling system. Results of these tests are tabulated 

below.

Table C8. Toxicity of Chlorine Dioxide/Sodium Chlorite to Terrestrial/Semi-aquatic Plants

Substance/% AI Organism EC25

(ppm) Reference Study Classification

Sodium Chlorite/80% Monocots & Dicots (10 

Species) >3.5 Backus et al., 1990MRID # 41843101 acceptable

Sodium Chlorite/80% Monocots & Dicots (9 Species) >3.5 Backus et al., 1990

MRID # 41843102 acceptable

Sodium Chlorite/80% Buckwheat (Polygonum 

convolvulus) <3.5 Backus et al., 1990MRID # 41843102 acceptable
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Note: EC25=Effective Concentration (25th Percentile)

The results indicate that chlorine dioxide/sodium chlorite are moderately toxic to terrestrial 

plants. However, since the once-through cooling use of chlorine dioxide/sodium chlorite would 

result in aquatic exposure, it is necessary to conduct Tier II testing with rice. Guideline OPPTS 

850.4225 and 850.4250, Seedling Emergence and Vegetative Vigor testing with Rice (Oryza 

sativa) is not fulfilled. 

Ecotoxicology References

ACC 245697. Sousa, J.V. 1981. Acute Toxicity of Sodium Chlorite to Bluegill (Lepomis 

macrochirus). Unpublished Data. Conducted by EG&G, Bionomics for Olin Chemicals.

ACC 252854. 1984. 96-Hour LC50 in Juvenile Rainbow Trout. Unpublished Data. Conducted by 

Microbiological and Biochemical Assay Laboratories for Magna Corporation.

ACC 252854. 1983. 96-Hour LC50 in Bluegill Perch. Unpublished Data. Conducted by 

Microbiological and Biochemical Assay Laboratories for Magna Corporation.

ACC 252854. 1984. 48-Hour LC50 in Daphnia magna. Unpublished Data. Conducted by 

Microbiological and Biochemical Assay Laboratories for Magna Corporation.

ACC 252854. 1984. Avian Dietary LC50 in Bob White Quail. Unpublished Data. Conducted by 

Microbiological and Biochemical Assay Laboratories for Magna Corporation.

ACC 252854. 1983. Avian Dietary LC50 in Mallard Ducks. Unpublished Data. Conducted by 

Microbiological and Biochemical Assay Laboratories for Magna Corporation.

ACC 252854. 1984. Avian Single-Dose Oral LD50 in Bobwhite Quail. Unpublished Data.

Conducted by Microbiological and Biochemical Assay Laboratories for Magna 

Corporation.

ACC 253378. Fletcher, D. 1984. 8-Day Dietary LC50 Study with Sodium Chlorite in Mallard 

Ducklings. Unpublished Data. Conducted by Bio-Life Associates, Ltd. for Calgon 

Corporation.

ACC 253378. Fletcher, D. 1984. 8-Day Dietary LC50 Study with Sodium Chlorite in Bobwhite 

Quail. Unpublished Data. Conducted by Bio-Life Associates, Ltd. for Calgon 

Corporation.
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Page 64 of 78

ACC 253378. Fletcher, D. 1984. Acute Oral Toxicity Study with Sodium Chlorite in Bobwhite 

Quail. Unpublished Data. Conducted by Bio-Life Associates, Ltd. for Calgon 

Corporation.

ACC 253379. Sousa, J.V. and D.C. Surprenant. 1984. Acute Toxicity of AC-66 to Rainbow 

Trout (Salmo gairdneri). Unpublished Data. Conducted by Springborn Bionomics, Inc. 

for Calgon Corporation.

ACC 253743. McMillen, C. 1984. Static Bioassay on Sodium Chlorite to Rainbow Trout and 

Bluegill Sunfish. Unpublished Data. Conducted by Environmental Research Group, Inc. 

for Rio Linda Chemical Company, Inc.

ACC 254176. Beavers, 1984. An Acute Oral Toxicity Study in the Mallard with Sodium 

Chlorite. Unpublished Data. Conducted by Wildlife International, Ltd. for TR America 

Chemicals, Inc.

ACC 254177. Beavers, 1984. An Acute Oral Toxicity Study in the Bobwhite with Sodium 

Chlorite. Unpublished Data. Conducted by Wildlife International, Ltd. for TR America 

Chemicals, Inc.

ACC 254178. Beavers, 1984. A Dietary LC50 Study in the Mallard Duck with Sodium Chlorite.

Unpublished Data. Conducted by Wildlife International, Ltd. for TR America Chemicals, 

Inc.

ACC 254179. Beavers, 1984. A Dietary LC50 Study in the Bobwhite with Sodium Chlorite.

Unpublished Data. Conducted by Wildlife International, Ltd. for TR America Chemicals, 

Inc.

ACC 254180. Larkin, J. 1984. The Acute Toxicity of Sodium Chlorite to Rainbow Trout (Salmo 

gairdneri). Unpublished Data. Conducted by Biospherics Incorporated for TR America 

Chemicals, Inc.

ACC 254181. Larkin, J. 1984. The Acute Toxicity of Sodium Chlorite to Bluegill Sunfish 

(Lepomis macrochirus). Unpublished Data. Conducted by Biospherics Incorporated for 

TR America Chemicals, Inc.

ACC 254182. Larkin, J. 1984. Acute Toxicity of Sodium Chlorite to Daphnia magna Strauss.

Unpublished Data. Conducted by Biospherics Incorporated for TR America Chemicals, 

Inc.

ACC 257341. Robaidek and Johnson, 1985. Avian Single-dose Oral LD50: Bob White Quail 

(Colinus virginianus). Unpublished Data. Conducted by Hazleton Laboratories America, 

Inc. for Rio Linda Chemical Company.
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Page 65 of 78

ACC 259373. Robaidek, E. 1985. Avian Single-Dose Oral LD50 Bobwhite Quail. Unpublished 

Data. Conducted by Hazleton Laboratories America, Inc. for Degussa Corporation.

ACC 69809. 1978. Acute Toxicity of Sodium Chlorite to Bluegill (Lepomis macrochirus).

Unpublished Data. Conducted by EG&G, Bionomics, Aquatic Toxicology Laboratory for 

Olin Chemicals.

ACC 69810. 1979. Acute Toxicity of Sodium Chlorite to Rainbow Trout (Salmo gairdneri).

Unpublished Data. Conducted by EG&G, Bionomics, Aquatic Toxicology Laboratory for 

Olin Chemicals.

MRID 130649. Fink, R. 1977. Eight-day Dietary LC50 - Bobwhite Quail – Sodium Chlorite.

Unpublished Data. Conducted by Wildlife International, Ltd. for Olin Corporation.

MRID 130650. Fink, R. 1977. Eight-day Dietary LC50 – Mallard Duck – Sodium Chlorite.

Unpublished Data. Conducted by Wildlife International, Ltd. for Olin Corporation.

MRID 131350. Vilkas, A.G. 1976. Acute Toxicity of Textone to the Water Flea Daphnia magna 

Strauss. Unpublished Data. Conducted by Aquatic Environmental Sciences for Olin 

Corporation.

MRID 131351. Sleight III, B.H. 1971. Acute Toxicity of Sodium Chlorite to Bluegill (Lepomis 

macrochirus) and Rainbow Trout (Salmo gairdneri). Unpublished Data. Conducted by 

Bionomics, Inc.

MRID 141149. Hoberg, J.R. and D.C. Surprenant. 1984. Acute Toxicity of AC-66 to Daphnids 

(Daphnia magna). Unpublished Data. Conducted by Springborn Bionomics, Inc. for 

Calgon Corporation.

MRID 146162. Barrows, 1984. The Acute Toxicity of Sodium Chlorite Technical to the Water 

Flea, Daphnia magna in a Static Test System. Unpublished Data. Conducted by 

Biospherics Incorporated for Degussa Corporation.

MRID 31610. Fletcher, D. 1973. Acute Oral Toxicity Study with Sodium Chlorite in Bobwhite 

Quail. Unpublished Data. Conducted by Industrial BIO-TEST Laboratories, Inc. for Olin 

Corporation.

MRID 41843101. Backus, P., K.E. Crosby and L.J. Powers. 1990. Effect of Sodium Chlorite on 

Vegetative Vigor of Plants (Tier I). Unpublished Data. Conducted by Ricerca, Inc. for the 

Sodium Chlorite Reregistration Task Force.
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MRID 41843102. Backus, P., K.E. Crosby and L.J. Powers. 1990. Effect of Sodium Chlorite on 

Seed Germination/Seedling Emergence (Tier I). Unpublished Data. Conducted by 

Ricerca, Inc. for the Sodium Chlorite Reregistration Task Force.

MRID 41880403. Ward, T.J. and R.L. Boeri. 1991. Static Acute Toxicity of Sodium Chlorite to 

the Freshwater Alga, Selenastrum capricornutum. Unpublished Data. Conducted by 

EnviroSystems Division, Resource Analysis, Inc. for the Sodium Chlorite Reregistration 

Task Force.

MRID 43259401. Yurk, J.J. and M.A. Overman. 1994. Acute Toxicity of Sodium Chlorite to the 

Sheepshead Minnow (Cyprinodon variegatus). Conducted by Environmental Science & 

Engineering, Inc. for the Chemical Manufacturers Association.

MRID 43259402. Yurk, J.J. and M.A. Overman. 1994. Acute Toxicity of Sodium Chlorite to 

Mysid Shrimp. Conducted by Environmental Science & Engineering, Inc. for the 

Chemical Manufacturers Association.

MRID 43259403. Yurk, J.J. and M.A. Overman. 1994. Effect of Sodium Chlorite on New Shell 

Growth in Eastern Oyster (Crassostrea virginica). Conducted by Environmental Science 

& Engineering, Inc. for the Chemical Manufacturers Association.

MRID 94068005. Johnson, G. 1984. Avian Dietary LC50 Bobwhite Quail (Colinus virginianus).

Unpublished Data. Conducted by Hazleton Laboratories America, Inc. for Degussa 

Corporation.

MRID 94068006. Sousa and Surprenant, 1984. Acute Toxicity of A-66 (Technical Sodium 

Chlorite) to Bluegill (Lepomis macrochirus). Unpublished Data. Conducted by 

Springborn Binomics, Inc for Calgon Corporation.

MRID 94068007. Barrows, B. 1984. The Acute Toxicity of Sodium Chlorite Technical to the 

Rainbow Trout, Salmo gairdneri, in a Static Test System. Unpublished Data. Conducted 

by Biospherics Incorporated for Degussa Corporation.

MRID 94068008. Johnson, G. 1984. Avian Dietary LC50 Mallard Duck (Anas platyrhynchos).

Unpublished Data. Conducted by Hazleton Laboratories America, Inc. for Degussa 

Corporation.

MRID 94068009. Nachrord, S. 1984. Daphnia LC50 Bioassay. Unpublished Data. Conducted by 

Anater Tesconi Circle for Rio Linda Chemical Company, Inc.

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide 

Programs U.S. Environmental Protection Agency - Endangered and Threatened Species 

Effects Determinations, 1/23/04.
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Appendix D Product Chemistry

Chlorine dioxide and sodium chlorite product chemistry information is summarized in Table D1 

(source: MRIDs 41467601, and 41467602 and EPI Suite v4.1).

Table D1 – Product Chemistry of Chlorine dioxide and Sodium chlorite

Guideline

Numbers Chlorine dioxide Sodium chlorite Source

830.1550

Product identity and composition

Refer to Table 3 of this 

document

Refer to Table 3 of this 

document

MRID 41467601, 

and 41467602

830.6302

Color Greenish Yellow White powder RED

830.6303

Physical State Gas Solid RED

830.6304

Odor Chlorine like Odorless RED

830.6313

Stability

Half- life 30-35 minutes in 

open container Stable RED

830.6314

Oxidation/Reduction Oxidizing agent Oxidizing agent RED

830.6315

Flammability Not flammable Not flammable RED

830.6316

Explodability

Explodes if kept in a closed 

container without a stabilizer Not explosive RED

830.7000

pH at25 °C 6-7 7 Don Gates, 1998

830.7050

UV/Visible Absorption Does not absorb in uv-visible Does not absorb MRID 41467601

830.7200

Melting point (°C) -59 C About 200o

C Don Gates, 1998

830.7220

Boiling point (°C) 11 C NA Don Gates, 1998

830.7300

Density (g/cm3) 1.64 g/ml 2.468 g/ml MRID 41467601

830.7370

Dissociation Constant pKa(s) NA NA

830.7520

Particle size, fiber length, &

diameter distribution

NA NA

830.7550

Log Kow -3.2 -7.17 EPI Suite (version 4.1)

830.7840

Solubility in water (mg/L) at 25 oC

Miscible in water: up to 

60,000 mg/L 608,000 mg/L MRID 41467601
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Guideline

Numbers Chlorine dioxide Sodium chlorite Source

830.7860

Solubility in organic solvents NA NA

830.7950

Vapor pressure (mm Hg) at 25 °C

490 mm Hg at 0 C

760 mm Hg at 25o C

It is high melting solid, 

vapor pressure not 

measureable

MRID 41467602

A Confidential business information

Product Chemistry References

EPI Suite, Version 4.1

Manual on Chlorine dioxide by Don Gates (1998).

MRID 41467601. Biehn, W. (1989) Chlorine Dioxide--Product Identity and Composition 

Certification of Ingredient Limits, Nominal Concentration, Analytical Methods, Physical 

and Chemical Properties: Lab Project Number: IR-4/PR/NO/4042. Unpublished study 

prepared by IR-4 Project, Rutgers Univ. 44 p.

MRID 41467602. Biehn, W. (1989) Chlorine Dioxide Safety Data in Support of Petition Proposing 

an Exemption from the Requirement of a Tolerance for Chlorine Dioxide for Use in 

Mushroom Production: Lab Project number: 4042. Unpublished study prepared by IR-4, 

Rutgers Univ. 145 p.
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Appendix E Comments Received 

Concerning the Preliminary Work Plan

On June 25, 2015 EPA opened a 60-day public comment period on the preliminary work plan 

(PWP) for the registration review of chlorine dioxide and sodium chlorite. The comment period 

ended on September 24, 2015. The comments received did not result in a modification to the 

anticipated data needs detailed in the chlorine dioxide and sodium chlorite PWP.

The Agency received a comment submission from the Center for Biological Diversity (Center) 

during the public comment period on the initial docket. The Center’s comment sought to confirm 

the Agency’s coordination with the U.S. Fish and Wildlife Service and the National Marine 

Fisheries under Section 7 of the Endangered Species Act (ESA) to ensure that chlorine dioxide 

and sodium chlorite does not jeopardize the continued existence of any listed species or result in 

adverse modification or destruction of critical habitat. EPA received a second comment from the 

American Chemistry Council Sodium Chlorite/Chlorine Dioxide Panel (referred to as “The 

Panel”), which is also summarized and responded to here.

1. Comment: EPA should consider sodium chlorate in the chlorine dioxide/sodium 

chlorite registration review. The Panel suggested that registration review should include the 

sodium chlorate registrants. Sodium chlorate registrants should also be responsible for the 

same data requirements as the sodium chlorite registrants.

Agency Response: EPA chose to assess sodium chlorate separately from chlorine 

dioxide/sodium chlorite during reregistration and has decided to do the same for 

registration review pursuant to 40 CFR 155.42. Sodium chlorate, which also has 

conventional uses, will be assessed through the inorganic chlorates registration 

review case and is subject to a set of data requirements unique to its own case. The 

public will have an opportunity to comment on the work plan and anticipated data 

needs for inorganic chlorates when the docket opens, which is anticipated in 2016.

2. Comment: Corrections to the Physical, Chemical and Fate Properties for Chlorine 

Dioxide/Sodium Chlorite. Corrections should be made to Table 4 and Table D1 sodium 

chlorite for accuracy, consistency, and typographical errors.
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Agency Response: The Agency thanks the submitter for the information and has adjusted the 

tables to accurately reflect the physical properties and made the necessary corrections.

3. Comment: Summary of Registered Uses in section 1.4.2 should be clarified. The Panel

asked that the work plan revise section 1.4.2 and remove the large scale computer controlled 

gas generation systems (used to control biological weapons) due to infrequent use.

Agency Response: The Agency is considering all labeled application types, even if they are 

infrequent, during registration review.

4. Comment: The Panel expressed concerns over the wide range of application rates for 

Chlorine Dioxide. The submitter requests that the information used to determine application 

rates be provided.

Agency Response: The Agency provided LUIS Reports to the submitter and has posted 

these materials to the docket.

5. Comment: EPA may not have engaged all parties in the collection of Post-RED GDCI 

and Registration Review. The Panel feels that new product registrations for Chlorine 

Dioxide/Sodium Chlorite appear to be based on unregistered imported active ingredients that 

are not subject to the DCI.

Agency Response: The Post-RED generic DCI was issued to all registrants with both 

technical and end-use products at the time. Registrants of products registered since 

the post-RED Generic DCI were issued registrations that are subject to the data 

requirements in the DCI.

6. Comment: The Panel feels that submitted CMA 2-generation studies (MRID # 45358901)

should be adequate for acute and subchronic neurotoxicity data requirements.

Agency Response: The panels request is currently under review. If accepted, the Agency 

will amend the FWP to remove these data requirements for the acute and subchronic 

neurotoxicity studies for chlorine dioxide/sodium chlorite.

7. Comment: The Panel requests neurotoxicity requirements timeframes be adjusted from 3 

months to 12 or 24 months in accordance with Agency guidelines. 

Agency Response: Thank you for pointing out this error. The Agency has adjusted the 

timeframe to accurately reflect the timeframes for these data requirements.

8. Comment: Table 11 incorrectly lists several studies as “outstanding”. The following studies 

have been submitted by the Panel to EPA in response to the Post RED GDCI:
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GLN Study Name MRID #

850.1300 Daphnid chronic toxicity 49270201

850.4225 Seedling emergence, Tier 49270202

850.4250 Vegetative Vigor, Tier II 49270203

Agency Response: The Agency agrees that it has received the studies and has updated the 

information listed in Table 11.

9. Comment: The work plan includes several discrepancies in the occupational inhalation 

endpoint. The Panel requested the Agency to re-consider the value selected for the 

occupational RfC for chlorine dioxide, based on publication of new information on the doseresponse from inhalation toxicity studies in experimental animals, and the current difficulty 

in meeting the selected occupational RfC value.

Agency Response: The Agency has accepted The Panel’s submission of additional data in 

support of revision to the occupational RfC for chlorine dioxide. The Agency

concludes that, based on the weight of evidence, that the NOAEC of 1.0 ppm 

identified by Ogata et al. is a more reliable point of departure for the chlorine dioxide 

inhalation risk assessment. This point of departure can be used for revision of the 

occupational RfC for chlorine dioxide. 

10. Comment: The dietary risk assessment for chlorine dioxide/sodium chlorite should be 

expanded and revised. The Panel expressed concern that the Agency needs to identify the 

product(s) that have residential indirect food uses. 

Agency Response: The Agency appreciates the Panel’s comments regarding the dietary uses 

of chlorine dioxide and sodium chlorite. The Agency has conducted a thorough label 

review to identify both residential and commercial indirect dietary uses during the 

Registration Review process. Additionally, the Agency will identify labels that fall 

under 40 C.F.R. 180.940(a). Appropriate assessments (risk estimates and total 

estimate daily dietary intake (TEDDI)) will be conducted based on the currently 

registered use patterns during Registration Review.
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11. Comment: There is no discussion or assessment of previously submitted residue studies and 

regulatory Agency (FDA) evaluations of the direct food contact uses for sodium chlorite and 

chlorine dioxide.

Agency Response: The Agency will review all appropriate studies and available residue data 

during Registration Review. This will include analyzing previously-submitted data as 

well as any information available from FDA. The Agency encourages registrants to 

send information submitted to the FDA. 

12. Comment: The Occupational Post Application assessment planned by the Agency relies on 

ClO2 exposure data gathered by OSHA which may include non-pesticidal applications.

Agency Response: The Agency thanks the submitter for the inquiry. The existing OSHA 

surveillance monitoring data will be reviewed based on similar use scenarios if 

available.

13. Comment: The Panel noted that Table A1 does not include references to two recent studies 

that have been accepted and reviewed by the Agency and should be included in the acute 

toxicity profile table for chlorine dioxide.

Agency Response: The chlorine dioxide RED and PWP cited an acute inhalation toxicity 

with 79% a.i. (MRID 42484101) which resulted in a Toxicity Category II for acute 

inhalation hazard of chlorine dioxide. The Panel has cited a more recent acute 

inhalation toxicity study (MRID 49386301) that tested a 37% a.i. and resulted in a 

Toxicity Category III for acute inhalation hazard. 

The chlorine dioxide RED and PWP stated that there was no acceptable dermal 

sensitization study for chlorine dioxide. The Panel has cited a recent dermal 

sensitization study (MRID 48450701) submitted to and reviewed by the Agency, 

conducted with 31% chlorine dioxide. This study showed chlorine dioxide not to be a 

dermal sensitizer. 

In the risk assessment for chlorine dioxide (and as with all pesticide active ingredient 

risk assessments), the Agency bases the toxicity categories for acute toxicity on 

testing of the technical grade of the active ingredient. In the case of chlorine dioxide, 

the technical grade is 80%. Testing of formulations with lower concentrations would 

typically result in lower, less hazardous acute toxicity categories, as is demonstrated 

by the result of the acute inhalation toxicity study with 37% chlorine dioxide that 

resulted in a Toxicity Category III. For the acute toxicity profile for the technical 

grade active ingredient, the Agency is not changing the current Category II 

determination for acute inhalation toxicity.
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In the chlorine dioxide RED, a dermal sensitization study was identified as a data gap. 

The Panel has cited a submitted study (MRID 48450701) conducted with 31%

chlorine dioxide in which no dermal sensitization was observed, using the 

maximization test. 

As with all acute toxicity testing on the technical active ingredient, the Agency also 

characterizes dermal sensitization potential of a pesticide active ingredient from 

testing of the technical grade of the active ingredient. In the case of chlorine dioxide, 

testing of a 31% a.i. does not represent the technical grade of the active ingredient. 

Further, this study was not submitted to address the data gap identified in the chlorine 

dioxide RED. The Registrants should either submit a dermal sensitization study 

conducted with the technical grade active ingredient (~80% a.i.), or a valid waiver 

request for not conducting the study. 

14. Comment: The reference to the Chemical Manufacturers Association’s (CMA) 2-generation 

reproduction study should be corrected to include the assigned MRID # 45358901 for this 

study.

Agency Response: The MRID# 45358901 number for the CMA 2-generation reproduction 

toxicity study has been added to the document.

15. Comment: The Panel would like the EPA to review their evaluation and position on Other 

Toxicological Effects section of Appendix A. The Panel felt it is important to point out that 

no such effects were noted at the 3 mg/kg/day dose level in the CMA (1996) study. 

Agency Response: With regard to the interpretation of the NOAEL and LOAEL in the CMA 

study, the IRIS Toxicological review notes (page 34):

“Alterations in multiple endpoints define the LOAELNOAEL boundary in the CMA 

study. Effects observed included statistically significant decreases in pup body weight, 

absolute brain weight, liver weight, and lowered startle amplitude at the 28.6 mg/kg-day 

dose. Statistically significant decreases in auditory startle amplitude (F1 and F2 

generations) and absolute and relative liver weights (F0 and F1) occurred at 6 mg/kg-day. 

Although different responses were found for auditory startle (as indicated by measures of 

amplitude, latency, and habituation), this is not unexpected given that these measures 

examine different aspects of nervous system function and thus can be differently affected. 

Transient alterations in neuro-functional (or neurochemical) measures, such as in the 

auditory startle response, can occur without neuropathological changes and are 

considered of neurotoxic concern (U.S. EPA, 1998a). Some of effects observed at 6 

mg/kg-day and 28.6 mg/kg-day occurred in both sexes and in more than one generation. 

These effects are considered toxicologically significant, which is consistent with EPA 
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guidelines for reproductive, developmental, and neurotoxicity risk assessment (U.S. EPA, 

1991, 1996b, 1998a). The NOAEL for this study is 3 mg/kg-day chlorite and the LOAEL 

is 6 mg/kg-day chlorite based on lowered auditory startle amplitude and decreased liver 

weight.”

The selection of the NOAEL value of 3 mg/kg/day and the LOAEL value of 6 mg/kg/day 

is also consistent with the 1998 Federal Register summary by EPA’s Office of Water. 

The Agency does not intend to re-evaluate the CMA 2-generation toxicity study.

16. Comment: The Panel would like the Agency to consider the data from carcinogenicity 

studies submitted to the Agency.

Agency Response: The Panel has raised the issue of whether cancer studies are required in two 

species (rat and mouse) for chlorine dioxide. The Panel first cites open literature data 

summarized in the chlorine dioxide PWP and suggests that the evidence is equivocal 

regarding carcinogenic potential of chlorine dioxide/sodium chlorite. The Panel goes on 

to state that a” single definitive carcinogenicity study (most likely in rats) would suffice 

to fulfill the data requirements for this compound.” The Panel cites language in the Final 

Rule for Data Requirements for Antimicrobial Pesticides in which it is stated that “OPP is 

currently conducting a comprehensive analysis of its rodent chronic bioassay database to 

document the utility of the mouse bioassay for both cancer risk assessment and Reference 

Dose (RfD) derivation for non-cancer endpoints.”

The OPP rodent chronic bioassay analysis has not been completed. The Agency still 

requires carcinogenicity testing in two species when such data are required or 

conditionally required. Registrants may provide a waiver request to the DCI with a valid 

scientific rationale..

17. Comment: The Panel has raised the issue of the Agency’s interpretation of the effects in the 

CMA 2-generation reproduction toxicity study and the use of the published study by Orme at 

al. (1985).

Agency Response: The Panel claims that the Orme et al. study was “conducted in an 

unaccredited college laboratory, without any quality assurance, analytical data, validated 

test methods, or recognized protocol. The published study, Orme (1985), lacks significant 

data and fails to adequately describe the methodology and results of the study. Their 

equipment was not validated and the results are at best unreliable. If this is reviewed in 

accordance with the Guidance for Considering and Using Open Literature Toxicity 

Studies to Support Human Health Risk Assessment (Office of Pesticide Programs, 2012), 

it is likely that it would not meet the minimum requirements.”
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The Agency (including OPP and NCEA/IRIS) has used the study of Orme et al. (1985) as 

well as the CMA 2-generation reproduction toxicity study in characterizing the 

neurotoxicity of chlorine dioxide. NCEA has also cited the study of Orme et al. (1985) in 

its Toxicological review of Chlorine Dioxide and Chlorite, where a NOAEL of 3 

mg/kg/day and LOAEL of 14 mg/kg/day was determined, based on neurobehavioral 

effects. This conclusion is consistent with the summary provided in the chlorine dioxide 

PWP. The Agency does not intend to remove the Orme et al. study from the hazard 

characterization as the study was subject to external peer review and generated for the 

Office of Water. The NOAEL from this study is supportive of the NOAEL of 6 

mg/kg/day observed in the CMA 2-generation reproduction toxicity study. 

The Panel also questions the NOAEL and LOAEL values determined by the Agency for 

the CMA 2-generation reproduction toxicity study. The Panel states that the NOAEL and 

LOAEL values, “conflicts directly with the data and the conclusions of the authors who 

conclude that the highest dose tested (approximately 30-39/mg/kg/day) was a NOAEL 

for neurotoxicological endpoints. The effects at the mid and high dose levels were barely 

significant, observed only at one time point, and were the only significant finding in the 

entire battery of tests, observations, and pathological testing.”

The CMA 2-generation reproduction toxicity study was subject to external peer review. 

The NOAEL from this study was used in a weight of evidence determination to derive 

the Maximum Contaminant Level Goal (MCLG) for chlorite in water (Federal Register 

Vol. 63, No. 241, December 16, 1998). The Agency does not intend to re-evaluate the 

CMA 2-generation toxicity study.

18. Comment: The Panel noted that post RED GDCI submitted studies have not been reviewed 

and were not included in Appendix C Ecotoxicology Profile for Freshwater Invertebrate, 

Chronic, Toxicity of Chlorine Dioxide/Sodium Chlorite to Aquatic Plants, and Tier II 

Testing. 

Agency Response: The Post RED GDCI studies are currently under review.

19. Submitter: The Center for Biological Diversity (Center)

Comment: The Center’s comment focuses on the EPA’s duty to consult with the U.S. 

Fish and Wildlife Service and the National Marine Fisheries Service (the Services) on the 

registration review of chlorine dioxide and sodium chlorite in accordance with the ESA. 

The Center mentions various aspects of the risk assessment process, including use of the 

best available data to develop endangered species risk assessments, sources of data 

available to conduct an effects determination, and evaluation of effects on endangered 
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and threatened species and their designated critical habitat. The Center also expressed 

concern regarding the rigor of the Agency’s preliminary determinations regarding the 

effects of chlorine dioxide and sodium chlorite on endangered and threatened (listed) 

species and their designated critical habitat for the chlorine dioxide and sodium chlorite 

registration review.

Agency Response: EPA has reviewed the comments from the Center on the registration review 

docket opening for chlorine dioxide and sodium chlorite and plans to address many of the 

concerns raised by the Center as part of the implementation plan for assessing the risks of 

pesticides to listed species based on the recommendations of the April 2013 National 

Academy of Sciences (NAS) report (also cited by the Center). EPA will address concerns 

specific to chlorine dioxide and sodium chlorite in connection with the development of its 

final registration review decision for this pesticide. 

In November 2013, EPA, along with the Services and USDA, released a summary of 

their joint interim approaches for assessing risks to endangered and threatened (listed) 

species from pesticides. The interim approaches were developed jointly by the agencies 

in response to the NAS recommendations and reflect a common approach to risk 

assessment shared by the agencies as a way of addressing scientific differences between 

the EPA and the Services. The NAS report1 outlines recommendations on specific 

scientific and technical issues related to the development of pesticide risk assessments 

that EPA and the Services must conduct in connection with their obligations under the 

ESA and FIFRA. 

The joint interim approaches were released prior to a stakeholder workshop held on 

November 15, 2013. In addition, the EPA presented the joint interim approaches at the 

December 2013 Pesticide Program Dialogue Committee (PPDC) and State-FIFRA Issues 

Research and Evaluation Group (SFIREG) meetings. The agencies also held stakeholder 

workshops in April and October 2014, allowing additional opportunities for stakeholders 

to comment on the interim approaches. Additional workshops are planned to enhance 

stakeholder involvement. As part of a phased, iterative process for developing the interim 

approaches, the agencies will also consider public comments on the interim approaches in 

connection with the development of upcoming registration review decisions. The details 

of the joint interim approaches are contained in the white paper, Interim Approaches for 

National-Level Pesticide Endangered Species Act Assessments Based on the 

Recommendations of the National Academy of Sciences April 2013 Report2 dated 

November 1, 2013. [2]

 

1. http://www.nap.edu/catalog.php?record_id=18344

2. http://www.epa.gov/espp/2013/nas.html
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Given that the agencies are continuing to develop and work toward implementation of the 

interim approaches to assess the potential risks of pesticides to listed species and their 

designated critical habitat, this FWP for chlorine dioxide and sodium chlorite does not 

describe the specific ESA analysis, including effects determinations for specific listed 

species or designated critical habitat, to be conducted during registration review. Once 

the agencies have fully developed and implemented the scientific methods necessary to 

complete risk assessments for endangered and threatened (listed) species and their 

designated critical habitats, these methods will be applied to subsequent analyses for 

chlorine dioxide and sodium chlorite as part of completing this registration review.