Docket Number EPA

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Page 2 of 78 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 RossDocket Number EPA

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Page 3 of 78 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

- m 3 /mole atmospheric pressure

- cubic meter per mole BCF bioconcentration factor °C degrees Celsius CAS Chemical Abstracts Service CFR Code of Federal Regulations ClO 2 c hlorine d ioxide CMA Chemical Manufacturers Association CO 2 carbon dioxide COC concentration

- of

- concern cPAD chronic population adjusted dose DCI data call

- in EC 50 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 e nd

- u se p roduct 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 guideli ne 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 coeffici ent Kd soil

- water partition coefficient Kow octanol

- water partition coefficient LC 50 median (or 50 percent) l ethal concentration LD 50 median (or 50 percent) l ethal dose LOAEC lowest

- observed

- adverse

- effect

- concentration LOC level of c oncern LOD limit of detection LOEC lowest

- observed

- effect

- concentration LOAEL lowest

- observed

- adverse

- effect

- level Log K ow logarithm of the octanol

- water partition coefficient
μg microgramDocket Number EPA

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Page 4 of 78 ml/g milliliter per gram mg/kg milligram per kilogram mg/kg/day milligram per k ilogram 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 o f 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 r eady

- t o

- u se SAR stru cture 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 plantsDocket Number EPA

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Page 5 of 78 

### 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 He alth

................................ ................................ ................................ ......... 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 Steps 36 8 References

................................ ................................ ................................ ............................. 37Docket Number EPA

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Page 6 of 78 Appendix A T oxicology 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 (ClO 2 ) 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 R egulations 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 D ioxide

................................ . 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

......... 33Docket Number EPA

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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 Agenc y 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 i ntends, 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 Ac t (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 e nvironment 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 standa rd 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 s ure 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 reg istration 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 CF R 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is th e 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 NeedsDocket Number EPA

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Page 8 of 78 • Updated Table 5 to revise application rates for drinking water, metal wo rking 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 l abel recommendations in Section 6

.

• Updated Section 7, “Next Steps.”

• Added Appendix E, which includes the A gency’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 th ese comment s

.

The comment s received result ed 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 , 20 15, and the 60

- day comment period ended on September 2 4 , 2015. The Agency received
two submission s . Documents associated with this registration review case can be viewed at http://www.regulations.gov in docket EPA

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- 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 . Rev iew : 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 detail s) *

Dietary (food) Yes 2006 Updated Immunotoxicity Acute Neurotoxicity Subchronic Neurotoxicity Residue Chemistry Data Crop Field TrialsDocket Number EPA

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Page 9 of 78 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 detail s) *

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 ) , refe r 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 Preli minary 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 20 18

- 12

Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 202 0

- 06

Close Public Comment Period 202 0

- 0 7
Phase 3: Registration Review Decision and ImplementationDocket Number EPA

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Page 10 of 78 Open 60

- Day Public Comment Period for Proposed Decision 20 20

- 12

Close Public Comment Period 202 1

- 0 2

Issue Final Decision 202 1

- 06

Begin Post

- Decision Follow

- up 202 1
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 s odium 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

, usin g 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 i mmediate conversion is to ch lorite ion

. The chlorite ion may also be used to generate chlorine dioxide under appropriate acidic conditions

.

Table 3

– Chemical Identification of Chlorine Dioxide / Sodium C hlorite

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 ClO 2 Na ClO 2 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 , C hemical and Fate Properties for Chlorine Dioxide / Sodium Chlorite

GLN No. Parameter Chlorine dioxide S odium chlorite Source
830.7200 Melting point ( o C)

- 59 C About 200 o C Gates, Don, 1998
830.7220 Boiling point ( o C) 11 C NA Gates, Don, 1998Docket Number EPA

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Page 11 of 78 GLN No. Parameter Chlorine dioxide S odium 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 o C (Log K ow ) - 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 25 o 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 c hlorine dioxide hydrolyzes into chlorate and chloride ions Inorganic ionic substance, no data EPA RED

835.3110 1 Ready biodegradation Not Applicable Not Applicable

atm

- m 3 /mol = atmosphere cubic meter per mole; o C = 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 a ctive 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 7 5 EUPs that contain sodium chlorite as an a.i. The percent a.i. for sodium chlorite ranges from 0.63 percent to 80 percen t, and the formulation s include soluble concentrate, RTU solution, impregnated material, dust, pelleted/tableted, solid , granular, and wet t able 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 applic ation 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 anthra x, 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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Page 12 of 78 Table 5

– Chlorine Dioxide (ClO 2 ) and Sodium Chlorite Registered Uses

Use Application Rate (PPM ClO 2 ) 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 2 00 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 Potatoes 1 20 to 520 20 208 to 2000 20 to 1000 2000 200 t o 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 Applicable 2 Open PourDocket Number EPA

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Page 13 of 78 Use Application Rate (PPM ClO 2 ) 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 3 000 Fumigation Mop, Spray, Fog

Residential and Public Access Premises

HVAC Ductwork and Filters A nthrax 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 Unknown 3 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 d i oxide. 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 t o 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 U sage 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 non

pesticidal bleaching use in the pulp and paper industry (US EPA, 2006 a )

.


## 1.6 Regulatory Histor y EPA first registered the aqueous form of chlorine dioxide for use as a disi nfectant 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 add ed 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 ( G DCI) 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 chlo rine 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 conce ntration 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 s upport 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 liste d 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 (C AS 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, 2011Docket Number EPA

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Page 15 of 78 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, In corporated 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

– FD A 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 ppmDocket Number EPA

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Page 16 of 78 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 proces sed 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 follo wed 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 c hlorite

, t he Agency determined that chlorine dioxide and sodium chlorite were eligible for re registration

. A dditional data were required to support this decision and r isk mitigation measures were outlined in the RED. The generic data requirements are listed in Tab le 11

. The mitigation measures and label amendments are listed in Table 9

. The reregistration process is ongoing for these products , and a product

- specific post

RED 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 Handler s applying chloride dioxide in an occupational setting must wear gloves.Docket Number EPA

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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 tre atments; 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 chl orite 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 HC l 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 tre ated 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.Docket Number EPA

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Page 18 of 78 6. Sensor malfunction in dosing system at tomato processing plant caused excessive application of product. 7. Malfunction in tomato plant dosing system caused excessive applic ation 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 trea t 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 t he family felt that it burned their throats.



### 1.7.2 Ecologic al

No incidents have been reported in the OPP Incident Data System (IDS) for c hlorine 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 A nticipated Data Needs

The RED published for c hlorine 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 followin g studies as listed in Table 10 are expected to be needed for the registration review of c hlorine dioxide and sodium chlorite. Table 11 outlines the data requirements required by the post

- RED GDCI s issued for both chemic als 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 c hlorine dioxide

.Docket Number EPA

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Page 19 of 78 Table 10

– Studies Anticipated as Needed for the Reg istration 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

- r esidue 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)

860.1500 1 , 2 Crop Field Trials TEP 24 months Dietary Direct Food Treatment Dietary (food)

None 2 Nature of residue on surfaces TGAI 24 months Dietary Hard Surface Disinfection Dietary (food)

None 2 Migration studies TEP 24 months Dietary Hard Surface Disinfection Dietary (food)

870.6200 2, 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

875.2300 4 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 Deodorizers 5 Inhalation Exposures

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

- use product 1. C rop field trials are required for the fruit and ve getable 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 stud ies 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 D CI 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 reviewDocket Number EPA

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Page 20 of 78 850.1400 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

850.4225 1 Seedling emergence, Tier II Chlorine dioxide Sodium chlorite Ecological risk assessment Recirculating and one

- pass Cooling Water Towers Down

- the

- drain Under review

850.4250 2 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

850.5400 3 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 AEATF 4

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

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. 2 In a Federal Register Notice dated June 27, 2012, test guidelines 850.4150 and 850.4250 were merged and har monized into OCSPP 850.4150. See “Final Test Guidelines; OCSPP 850 Series; Notice of Availability” 77 FR 38282, June 27, 2012. http://www.regulations.gov/#!do cumentDetail;D=EPA

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. 3 In a Federal Register Notice dated June 27, 2012, EPA split the Public Draft OPPTS 850.5400 test guideline into two test guid elines: OCSPP 850.4500 and OCSPP 850.4550. See “Final Test Guidelines; OCSPP 850 Serie s; Notice of Availability” 77 FR 38282, June 27, 2012. http://www.regulations.gov/#!documentDetail;D=EPA

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Page 21 of 78 

## 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 c hlorine dioxide and sodium chlorite was conducted in 2006 for the reregistration eligibility decision (RED), and posted to www.regulations.gov under docket number EPA

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- 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 i mmunotoxicity 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 c hlorine dioxide and sodium chlorite.



## 3.1 Existing Toxicological Endpoints

Table 12 presents the existing toxicological endpoints used in the Agency ’s most recent risk
assessment s for c hlorine 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 c hlorine dioxide and sodium chlorite

. A ppendix A contains a detailed description of the toxicity studi es.

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 inter

species 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 inter

species 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 intermediate

term 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 abso lute brain and liver weight, and lowered auditory startle amplitude at LOAEL of 6 mg/kg/day.
Short

- Term Dermal A NOAEL= 3 mg/kg/day MOE = 100 See summary for dietary assessmentDocket Number EPA

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Page 22 of 78 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)
Intermediate

term 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’

= 0.0 9 mg/m 3 (0. 03 ppm) B

Homeowner short

term ‘RfC’ = 0.14 mg/m 3 (0.05 ppm) B MOE (occupational) = 30

MOE (homeowner short

term)

- 300 Inhalation toxicity studies

- Rat homeowner short

- term: Dalhamn, 1957 [LOAEL of 28 mg/m3 (10 ppm)]

O ccupational 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/m 3 (USEPA, 2000) Paulet and Debrousses, 1970, 1972) selected as co

critical 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/m 3 x 24.45)/ MW. For chlorine dioxide 1 ppm = 2.8 mg/m 3



### 3.1.1 Comparison to Other Endpoints

Because of the non

- FIFRA regulated uses of c hlorine dioxide as an industrial chemical,
t oxicological endpoints for occupational inhalation exposure to c hlorine dioxide have been established by other government agencies such as the Occupational Safety and Health Ad ministration (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 a nd 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 TLV s
The OSHA permissible exposure limit (PEL) for c hlorine 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 AEGLDocket Number EPA

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Page 23 of 78 The immediately hazardous to lif e and health (IDLH) value established by N IOSH 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 dela yed 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
resp iratory 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 N RC for

c hlorine 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 D ioxide (ppm)

Classification 10 Minute 30 Minute 1 hour 4 hour 8 hour End Point

AEGL

- 1 (Non

disabling) 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 c hlorine dioxide and the endpoint of 0.1 ppm established by OSHA f

or regulating industrial exposures to c hlorine 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 submit ted and review ed by the A gency. 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 an d 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 chlorit e 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 poul try chiller water sanitizer; and (5) as a slimicide in paper production.Docket Number EPA

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Page 24 of 78 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 t he 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 c hlorine dioxide w ill 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 ingred ient 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 all ow 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 tole rance 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 surf ace area of 2000 cm 2 , 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. H owever, 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

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Page 25 of 78 In commerci al 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 cm 2 , 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 ye ars 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 result s in risks above the Agency’s level of concern for some population subgroups. Additionally, the total daily dietary intake for acute exp osures 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 resident ial and commercial scenarios greater than 200 ppb t riggers 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

. Thes e 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 ) , a nd two non

- guideline studies ( nature of the residues on surfaces, and residue mi gration 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 vege tables, residue data are anticipated to be required to support these uses as listed in Table 10 (guideline 860.1500). For t he 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 b e 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 upd ated information on occurrence of chlorine dioxide/chlorite in drinking water that is obtained from the EPA’s Office of Water

. The Office ofDocket Number EPA

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Page 26 of 78 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 c hlorine dioxide were asse ssed in the ORE assessment for the RED (US EPA, 2006 b ) 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 (U S 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 reasse ss 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 D ioxide

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 methodDocket Number EPA

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Page 27 of 78 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 du ring 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 al lowed entry when the c hlorine 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 expo sures 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 c hlorine 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 wit hout 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 Fat e 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 re view.

Table 15

– Residential Handler Exposure Scenarios for Chlorine D ioxide

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 applicatio n 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 andDocket Number EPA

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Page 28 of 78 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 restricte d 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 measu red c hlorine dioxide air concentrations in automobiles (Wood and Gallo 1997, and Speronello 1998).

Wood and Gallo (1997) measured c hlorine dioxide in a total of 16 automobiles (8 cars parked outside and 8 cars parked inside a garage). Th e study author indicated that “ approximately half the c hlorine 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 c hlorine dioxide Analyzer was used to measure c hlorine 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 re ading values of c hlorine 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 i nhalation 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, th e data indicate d that the concentration of

c hlorine dioxide remains below the STEL and the average of the single measurements does not exceed the RfC of 0.05 ppm. However, a more approp riate 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 D ioxide Measurements in Automobiles

Chlorine di oxide 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

* R epresents the average where non

- detects (LOD = 0.01 ppm) are counted as zero.
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Page 29 of 78 (problems were encountered with the 3 rd 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 c hlorine 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 applicati on rate indicated a maximum c hlorine 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 meas urements, 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 c hlorine dioxide air concentration data that was submitted by each registrant.

In the assessm ent of Odor Rescue ( US EPA, 2011a ) c hlorine 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 p pm 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 c hlorine 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 ), c hlorine dioxide levels were measured inside an unventilated room and in an automobile. The room test results indicate that c hlorine 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 th at 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 c hlorine 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 b elow 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 c hlorine dioxide levels inside a subcompact car reached a maximum of 0.30 to 0.35 ppm within 15 to 20 minutes of activating the treatmentDocket Number EPA

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Page 30 of 78 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 don e 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 c hlorine dioxide as it was released.

Exposure s to be A sse s sed during Registration Review

Because t he 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 product s 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 D ioxide

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, u nlike other pestic ides 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 c hlorine 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 effec ts from substances found to have a common mechanism on EPA’s website at http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/guidance

cumulative

- 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/s odium chlorite

. The data already called in through the post

- RED GDCI and the ecological risk assessment planned during registration r eview will allow the Agency to determine potential acute and chronic risks to aquatic organisms exposed to chlorine dioxide/s odium chlorite that are transported from treatment sites into the aquatic environment. Such sites include recirculating and one

- pas s cooling water towers

. The risk assessment also will allow the Agency to determine whether each use of the chlorine dioxide/s odium chlorite has 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or their designa ted 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 Serv ices), as appropriate.



## 4.1 Environmental Fate Assessment

Chlorine dioxide

Since c hlorine dioxide is an inorganic substance, the conventional fate studies outli ned in Test Guidelines 835 can not 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 chlora te ions. Chlorine dioxide is known to photolyz e in aquatic medium in the presence of sunlight and the photolytic degradates are: chloride and chl orate 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 chlo rite is a salt formed as a result of the degradation of chlorine dioxide in the presence of s odium which is ubiquitous in the environment

. Since sodium chlorite is an inorganic compound

, the conventional fate studies as outlined in Test Gu idelines 835 can n ot 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 c hlorite underg o ing biodegradation in anaerobic conditions. Biodegradation of chlorite und er 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

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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 chl orine + free available chlorine. ” Chlorine sources for TRC can b e 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 chl orite 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.” T he 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/l awsguidance/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 u s ed to stabilize it in aqueous medium. C hlorite io ns 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

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- 0002), found in the docket at www.regulations.gov , EPA

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- 0638. For antimicrobial uses, a ll 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 syste ms; 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 scre ening 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 inve rtebrates. 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 organism s 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 Sodiu m Chlorite/Chlorine Dioxide

Receptor

Group Surrogate Species Risk Scenario Toxicity Endpoi nt Reference

Freshwater fish Bluegill Sunfish Acute 96

- h LC 50 = 244 mg/L ACC# 254181 Bluegill Sunfish Chronic Data Gap
Freshwater invertebrates Daphnia magna Acute 48

- h EC 50 = 0.027 mg/L MRID# 146162 Chronic Data Gap

Estuarine/marine fish Sheepshead minnow Acute 96

- h LC 50 = 75 mg/L MRID# 43259401 Chronic Not required A

-- Estuarine/marine

invertebrates Mollusk Acute 48

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Group Surrogate Species Risk Scenario Toxicity Endpoi nt Reference

Shrimp Acute 96

- hr LC 50 = 0.576 mg/L MRID# 43259402 Chronic Not required A

--

Algae Green alga Nonlisted 96

- hr EC 50 = 1.32 mg/L MRID# 41880403

Listed NOAEC = <0.62 mg/L MRID# 45862503

Aquatic Microphytes Marine diatom, Freshwater diatom, Cyanobacteria species Acute Data Gap A

Aquatic vascular plants Duckweed Nonlisted Data Gap A
Listed
Seedling Emergence Rice Nonlisted Data Gap A Listed
Vegetative vigor Rice Nonlisted Data Gap A Listed

Birds Northern bobwhite quail Acute LD 50 = 382 mg/kg ACC# 259373

Mallard duck Subacute dietary LC 50 = 31.25 mg/kg ACC# 254176

Chronic Not required B

--
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 required B

--

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 d etermine 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) data base. 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 pesticide s

. 1 Those ecoto xicity 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 D ivision.


## 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 histopathol ogy, 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 repr oductive effects in different taxonomic groups. As part of its reregistration decision for c hlorine 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), c hlorine dioxide is subject to the endocrine screening part of the En docrine 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 estro gen, 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 effe ct.

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 in gredients. A second list of chemicals

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. Neither of these lists should be construed as a list of known o r 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 i n Section s 1. 6 .1 and 3.2.1 , t here 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 ingr edient 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 t he 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 imp rove 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 201 6

.

2 See http://www.regulations.gov/#!documentDetail;D=EPA

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- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

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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 Com pany, 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, 2006 b . 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 Ti mothy 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.Docket Number EPA

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# Appendix A T oxicology Profile

Acute Toxicity

The acute toxicity of chlorine dioxide (79% a

. i.) is considered significant by the oral route (LD 50 = 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 (LD 50 > 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/S odium Chlorite

Guideline No./ Study Type MRID No. Results Toxicity Category
870.1100/ Acute oral toxicity (79% chlorine dioxide) 43558601 LD 50 = 292 mg/kg (males) LD 50 = 340 mg/kg (females) II

870.1200/ Acute dermal toxicity (80% sodium chlorite) 40168704 LD 50 > 2000 mg/kg III

870.1300/ Acute inhalation toxicity (80.6% sodium chlorite) 42484101 LC 50 = 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 stud y 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. (2 012), and Ogata et al. (2013). The refore, the database for subchronic toxicity via oral a n d inhalation route is considered complete.Docket Number EPA

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Page 39 of 78 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 lactat e 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 i ncidence 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 diox ide 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 admi nistered 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 se rum 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 r easons 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: morphologica l 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,Docket Number EPA

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Page 40 of 78 hematologic alterations in males (increased methemoglobin levels and neutrophil count, decreased lymphocyte count), increases in ab solute and relative spleen and adrenal weights in females, and histologic alterations in the stomach of two males, similar to those seen in the high

dose group. The increase in absolute spleen weight was attributed to morphological alterations in erythrocy tes, 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/m 3 ) resulted in p ulmonary 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/m 3 ) once a week for 3 consecutive weeks. Respiratory distre ss 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/m 3 ) of chlorine dioxide (4 hours/day for 9 days in a 13

- day period) resulted in rhinorrhe a, altered respiration, and respiratory infection. No indications of adverse effects were seen in rats exposed to approximately 0.1 ppm (0.28 mg/m 3 ) of chlorine dioxide 5 hours /day for 10 weeks.

Paulet and Desbrousses (1970, 1972, and 1974) conducted a se ries 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/ m 3 ), 2 hours/day for 30 days. Another group of rats exposed to a concentration of 5 ppm (14 mg/m 3 ) 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/m 3 ), 4 hours/day for 45 days. In a group of rats and rabbits sacrificed 15 days after exposure terminat ion, 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/m 3 ), 5 hours/day, and 5 days/week for 2 months (P aulet 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 a t 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 a nd 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 an d 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 bronchioalveolarDocket Number EPA

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Page 41 of 78 fluid between chlorine dioxide exposed rats and control. Histological examina tion 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 Sprague

Dawley rats (approximately 5 weeks old, 16 rats/sex/concentration) were exposed to chlorine dioxide gas at concentrati ons 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, t o 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 significa ntly 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 aut hors 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 n ot 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 concentrationsDocket Number EPA

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Page 42 of 78 for chemicals like chlo rine 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 triiodoth yronine (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 appare nt 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 be havior 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 compound

related m ortality, 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 fromDocket Number EPA

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Page 43 of 78 control were observed in pregnancy rate, mean gavid uterine weight, or reproductive indices. Mean fetal weights were compar able 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

a nd 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 bo th 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 Sprague

Dawley 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 throug hout 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 continue d 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 re

mated 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

an d 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 he matology 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 landmark s, number alive/dead pups in the F1 and F2 generations, total caudal sperm number and percent motile, morphology by computer

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Page 44 of 78 sperm motility analysis in the F0 and F1 rats, and organ weight and histopathology examination of the brain, pituitary gla nd, 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
sp inal 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 neuropat hology on postnatal day 60, auditory startle in the SR

- Screening System, learning and memory retention in a water E

maze). 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 consumptio n, 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 reduct ions 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, alt eration 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 female s 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 possib le 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 low ered 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 grou p, 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 conside red incomplete.Docket Number EPA

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Page 45 of 78 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 a nimals 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 10 0 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 ch l orine 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 wee k 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 ap plication 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 signi ficant 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 m ean 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

no t 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) atDocket Number EPA

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Page 46 of 78 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 chlo rite/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 fe males 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 g raphical 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

r eport, 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 adenocarc inoma (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. Complicatin g 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 t umor 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.Docket Number EPA

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Page 47 of 78 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), calcu lated 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. MRI D 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 Ri sk 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 6 5 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 lun g 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 statistic ally 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 ma le 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). Acco rding 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.Docket Number EPA

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Page 48 of 78 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 interpre tation 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 u sing 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 d eficiencies 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 addi tion, 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 non

activated 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 non

activated and activated conditions (10, 15, and 50 μg/ml) [Accession no. 265867].

4) C hlorine dioxide was negative for increased transformed foci up to cytotoxic levels [Accession no. 265867].Docket Number EPA

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Page 49 of 78 5) In vivo micronucleus and bone marrow chromosomal aberration assays in Swiss CD

1 mice administered 0.1

– 0.4 mg chlorine dioxide via gavage for 5 cons ecutive 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/d ay. 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.Docket Number EPA

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Page 50 of 78 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 Diox cide, 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 inhalatio n toxicity study with
two

- week recovery period in rats. Journal of Occupational Medicine and Toxicology 7(2): pp 1

- 8.Docket Number EPA

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Page 51 of 78 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 A ssoc 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.

Harring ton, 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 c hemicals 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 ClO 2 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 dio xide (ClO 2 ) 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).Docket Number EPA

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Page 52 of 78 

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of Chlorine dioxide and S odium 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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Page 53 of 78 Environmental Fate References

Chlorine Dioxide: C oncise International Chemical Assessment Document 37, 2002; World Health Organization. Geneva

.

EPA RED o f 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 Propertie s : 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

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Page 54 of 78 

# Appendix C Ecotoxicology Profile

Toxicity to Terrestrial Receptors

Birds

Acute oral toxicity stud ies 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 C 1. 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

- 81 0) Fletcher, 1973 MRID # 31610 acceptable

Sodium Chlorite/80% Northern bobwhite ( Colinus virginianus ) LD50 = 467 (372

- 585) Beavers, 1984 ACC # 254177 acceptable

Sodium Chlorite/80% Mallard Duck ( Anas platyrhynchos ) LD50 > 31.25 Beavers, 1984 ACC # 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 ReportedDocket Number EPA

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Page 55 of 78 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 ingred ient 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 C 2. Avi an 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, 1984 MRID # 94068008 acceptable

Sodium Chlorite/80% Northern bobwhite ( Colinus virginianus ) > 5000 N.R. Fletcher, 1984 ACC # 253378 acceptable

Sodium Chlorite/80% Mallard Duck ( Anas platyrhynchos ) > 5000 N.R. Fletcher, 1984 ACC # 253378 acceptable

Sodium Chlorite/80% Northern bobwhite ( Colinus virginianus ) > 5000 N.R. Johnson, 1984 MRID # 94068005 acceptable

Sodium Chlorite/80% Mallard Duck ( Anas platyrhynchos ) > 5620 N.R. Beavers, 1984 ACC # 254178 acceptable

Sodium Chlorite/80% Northern bobwhite ( Colinus virginianus ) > 5620 N.R. Beavers, 1984 ACC # 254179 acceptable

Sodium Chlorite/80% Northern bobwhite ( Colinus virginianus ) >10,000 N.R. Fink, 1977 MRID # 130649 acceptable

Sodium Chlorite/80% Mallard Duck ( Anas platyrhynchos ) >10,000 N.R. Fink, 1977 MRID # 130650 acceptable

Sodium Chlorite/25% Mallard Duck ( Anas platyrhynchos ) 18686 (8186

- 109184) N.R

. MBA Laboratories, 1983 ACC # 252854 acceptable

Sodium Chlorite/25% Northern bobwhite ( Colinus virginianus ) 2031(1226

- 3903) 417 MBA Laboratories, 1984 ACC #252854 acceptable

Note: LC50=Median Lethal Concentration; NOAEC=No Observed Adverse Effect Concentration; N.R. = Not ReportedDocket Number EPA

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Page 56 of 78 These results indicate that chlorine dioxide/sodium chlorite range from slightly toxic to practically non

- toxic to birds on a su bacute dietary basis.



## Toxicity to Aquatic Receptors

Freshwater Fish

F ish toxicity stud ies 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 blueg ill sunfish (a warm water fish). The results of studies submitted for sodium chlorite are provided in the following table.

Table C 3. 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% B luegill ( 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 supplementalDocket Number EPA

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Page 57 of 78 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 EC50 4 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

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Page 58 of 78 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 i ndicate 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 speci es 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 OPP TS 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
spec ies 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 acceptableDocket Number EPA

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Page 59 of 78

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 tox ic 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 i ts 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 estimat ed 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 th e 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 850.1 3 00 is not fulfilled.

Estuarine/Marine Fish

Acute toxicity testing with es tuarine/marine fish using the technical grade of the active ingredient is available for sodium chlorite , for when the end

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Page 60 of 78 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 C 5. 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 c hlorite 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 (850.1 4 00) has not been fulfil led.

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 marin e/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 T oxicity of Chlorine Dioxide and Sodium Chlorite to Estuarine/Marine InvertebratesDocket Number EPA

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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 ful filled.

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 i s 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 greate r 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 a cute 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 (850.1 3 00) has not been submitted.

Aquatic Plants

Microphytes a nd 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 andDocket Number EPA

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Page 62 of 78 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 ( Navicu la 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

Substanc e/ % A I 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 pesticid es 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 tabula ted 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 ., 1990 MRID # 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 ., 1990 MRID # 41843102 acceptableDocket Number EPA

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Page 63 of 78 Note: EC25=Effective Concentration (25 th 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 n ecessary 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 R eferences

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 Laboratorie s 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. Fletch er, D. 1984. 8

- Day Dietary LC50 Study with Sodium Chlorite in Bobwhite Quail. Unpublished Data. Conducted by Bio

- Life Associates, Ltd. for Calgon Corporation.Docket Number EPA

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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 Ca lgon 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. Unpublis hed 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 Chemical s, 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 R ainbow 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. Robaide k 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.Docket Number EPA

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Page 65 of 78 ACC 259373. Robaidek, E. 1985. Avian Single

- Dose Oral LD 50 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 Labo ratory 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. B ackus, 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.Docket Number EPA

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Page 66 of 78 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 T oxicity 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 LC 50 Bobwhite Quail ( Colinus virginianus ). Unpublished Data. Conducted by Hazleton L aboratories 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 Corporati on.

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 LC 50 Mallard Duck ( Anas platyrhynchos ). Unpublished Data. Conducted by Hazleton Laboratories America, Inc. for Degussa Corporation.

MRID 94068009. Nachrord, S. 1984. Daphnia LC 50 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.Docket Number EPA

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Page 68 of 78 

# Appendix D Product Chemistry

Chlorine dioxide and sodium chlorite product chemistry information is summarized in Table D 1 (source: MRIDs 41467601, and 41467602 and EPI Suite v4.1).

Table D 1

– 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 200 o C Don Gates, 1998

830.7220 Boiling point (°C) 11 C NA Don Gates, 1998

830.7300 Density (g/cm 3 ) 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 o C Miscible in water: up to 60,000 mg/L 608,000 mg/L MRID 41467601Docket Number EPA

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Page 69 of 78 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 25 o 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

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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 d ioxide 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 mod ification 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 c hlorate registrants should also be responsible for the same data requ irements 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. So dium 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.Docket Number EPA

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Page 71 of 78 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 se ction 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 gener ation systems ( used to control biological weapons ) due to infrequent use

. Agency Response: The Agency is consider ing 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 the se materials to the docket.

5. Comment: EPA may not have engaged all parties in the collection of Post

- R ED GDCI and Registration Review. The Panel feels that new product registrations for Chlorine Dioxide/Sodium Chlorite appear to be based on unregistered impo rted 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 i ssued registrations that are subject to the data requirements in the DCI.

6. Comment: The Panel feels that submitted CMA 2

- g e neration 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 the se data requirement s 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 tim eframes for these data requirements.

8. Comment: Table 11 incorrectly lists several studies as “outstanding”. The following studies have been submitted by the P anel to EPA in response to the Post RED G DCI:Docket Number EPA

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Page 72 of 78 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 o ccupational 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 dose

r esponse 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 th e 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 conduct ed 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.Docket Number EPA

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Page 73 of 78 11. Comment: There is no discussion or assessment of previously submitted residue studies and regula tory 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 O ccupational P ost A pplication assessment planned by the Agency relies on ClO2 exposure data g athered 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 3 7% 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% chlori ne 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, le ss 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, th e Agency is not changing the current Category II determination for acute inhalation toxicity

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Page 74 of 78 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 ingred ient 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 identif ied 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 Che mical Ma nufacturers 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 Toxicologica l 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 (pag e 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 do se. 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 measure s 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, su ch 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 generatio n. These effects are considered toxicologically significant, which is consistent with EPADocket Number EPA

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Page 75 of 78 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 O ffice 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 c arcinogenicity 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 carcin ogenic 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 a nd Reference Dose (RfD) derivation for non

- cancer endpoints.”

T h e 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. Registra nts 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 a dequately 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.”Docket Number EPA

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Page 76 of 78 The Agency (including OPP and NCEA/IRIS) has used the study of Orme et al. (1985) as well as the CMA 2

- generation reproducti on 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 determin ed, 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 NOA EL 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.”

T he C MA 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, N o. 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 review ed 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 ES A. 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 enda ngeredDocket Number EPA

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Page 77 of 78 and threatened species and their designated critical habitat. The Center also expressed concern regarding the rigor of the A gency’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 sod ium 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 USD A, 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 co mmon approach to risk assessment shared by the agencies as a way of addressing scientific differences between the EPA and the Services. The NAS report 1 outlines recommendations on specific scientific and technical issues related to the development of pesti cide 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 presente d 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 additio nal 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 publ ic 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 Spe cies Act Assessments Based on the Recommendations of the National Academy of Sciences April 2013 Report 2 dated November 1, 2013. [2]

1. http://www.nap.edu/catalog.php?record_id=183 44 2. http://www.epa.gov/espp/2013/nas.htmlDocket Number EPA

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Page 78 of 78 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.