Page 2 of 53 Azadioxabicyclooctane Re gistration Review Team

Human Health & Environmental Effects Nate Mottl William Hazel (now retired) Donald Wilbur Michelle Centra Siroos Mostaghimi Srini Gowda Najm Shamim David Bays

Risk Management Sandra O’Neill Elizabeth Watkins James Parker

Office of General Counsel Philip RossPage 3 of 53 TERMS, ABBREVIATIONS AND SYMBOLS

–CH 2 O Formaldehyde moiety group –CH 2 –OH Hydroxy methyl group AD Antimicrobials Division 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 CHO Chinese hamster ovary –CH 2 O formaldehyde moiety CMA Chemical Manufacturers Association CO 2 carbon dioxide COC concentration-of-concern cPAD chronic population adjusted dose DCI data call-in DtD down-the-drain EC 50 median (or 50 percent) effect concentration EC 05 5 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 °F degrees Fahrenheit FDA Food and Drug Administration FFDCA Federal Food, Dr ug, and Cosmetic Act FGD flue-gas desulfurization FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FWP Final Work Plan g/mol grams per mole GLN guideline number HPV high production volume IDS Incident Data System ISP International Specialty Products Koc organic carbon normalized soil-water partition coefficient Kd soil-water partition coefficient Kow octanol-water partition coefficient LC 50 median (or 50 percent) lethal concentration LD 50 median (or 50 percent) lethal dose LOAEC lowest-observed-adverse-effect-concentration LOEC lowest-observed-effect-concentration LOAEL lowest-observed-adverse-effect-level Log K ow logarithm of the octanol-water partition coefficient μg microgramPage 4 of 53 ml/g milliliter per gram mg/kg milligram per kilogram mg/kg/day milligram per kilogram per day mg/L milligram per liter mm Hg millimeter of mercury MOE margin of exposure MRID Master Record Identification Number MRL maximum residue limit MSDS material safety data sheet NA not available N/A not applicable
nm nanometers NOAEC no-observed-adverse-effect-concentration NOAEL no-observed-adverse-effect-level OCSPP Office of Chemical Safety and Pollution Prevention OECD Organization for Economic Co-operation and Development OPP Office of Pesticide Programs PAD population adjusted dose PAI pure active ingredient PDM Probabilistic Dilution Model % percent PC Code Pesticide Chemical Code PCF pounds per cubic foot pH power of hydrogen or power of the concentration of the hydrogen ion PHED Pesticide Handler’s Exposure Data PIS primary irritation score pKa power of the acid dissociation constant or negative base-10 logarithm of the acid dissociation constant of a solution ppb parts per billion ppm parts per million PWP Preliminary Work Plan QSAR quantitative structure-activity relationship RED Reregistration Eligibility Decision SAR structure activity relationship SDF stream dilution factor SF safety factor SSTS Section Seven Tracking System TEP typical end-use product TGAI technical grade active ingredient TMDL total maximum daily loads UF uncertainty factor UV/VIS ultraviolet/visible light absorption % w/w percent weight per weight. WP wettable powder WWTPs wastewater treatment plantsPage 5 of 53 

### Table of Contents
1 Introduction .................................................................................................................. ........... 7 1.1 Statutory and Regulatory Authority ................................................................................. 7 1.2 Updates to the Workplan .................................................................................................. 8 1.3 Case Overview ............................................................................................................... 1 0 1.4 Chemical Identification and Properties .......................................................................... 10 1.5 Use/Usage Description ................................................................................................... 14 1.5.1 Registrations ........................................................................................................... 14 1.5.2 Summary of Regist ered Uses .................................................................................. 14 1.5.3 Usage Information .................................................................................................. 14 1.6 Regulatory History ......................................................................................................... 15 1.6.1 Tolerance Information ............................................................................................ 15 1.7 Incidents ..................................................................................................................... .... 16 1.7.1 Human Health ......................................................................................................... 16 1.7.2 Ecological ............................................................................................................... 16 2 Anticipated Data Needs ........................................................................................................ 16 3 Human Health Risk Assessment ........................................................................................... 21 3.1 Existing Toxicological Endpoints .................................................................................. 21 3.2 Dietary Exposure ............................................................................................................ 2 4 3.2.1 Food ........................................................................................................................ 2 4 3.2.2 Drinking Water ....................................................................................................... 24 3.3 Occupational and Residential Exposures ....................................................................... 25 3.3.1 Occupational Handler Exposure ............................................................................. 25 3.3.2 Occupational Post-Application Exposures ............................................................. 26 3.3.3 Residential Handler Exposures ............................................................................... 26 3.3.4 Residential Post-Applic ation Exposures ................................................................. 26 3.4 Aggregate and Cumulative Exposure ............................................................................. 27 3.4.1 Aggregate Exposures .............................................................................................. 27 3.4.2 Cumulative Exposures ............................................................................................ 27 4 Environmental Risk Assessment........................................................................................... 27 4.1 Environmental Fate Assessment .................................................................................... 28 4.1.1 Leaching from Paint, Adhesives, Caulks, Textiles ................................................. 28 4.1.2 Water and Sediment ................................................................................................ 28 4.1.3 Soil .......................................................................................................................... 28 4.1.4 Air ........................................................................................................................... 28 4.1.5 Wastewater Treatment Plant (WWTP) ................................................................... 28 4.1.6 Water Quality .......................................................................................................... 29 4.2 Conceptual Models for Envir onmental Exposure Pathways .......................................... 29 4.3 Ecological Effects Assessment ....................................................................................... 29 4.3.1 Mode of Action ....................................................................................................... 30 4.3.2 Measures of Effect (Ecotoxicology Endpoints) ...................................................... 30 4.4 Exposure Analysis Plan .................................................................................................. 31 4.5 Effects Analysis Plan ..................................................................................................... ..... 32 5 Endocrine Disruptor Screen ing Program (EDSP) ................................................................. 32 6 Optional Label Changes ........................................................................................................ 33 7 Next Steps .................................................................................................................... ......... 33Page 6 of 53 8 References .................................................................................................................... ......... 34

Appendix A Toxicology Profile ............................................................................................... 37 Appendix B Environmental Fate ............................................................................................. 42 Appendix C Ecotoxicology Profile .......................................................................................... 45 Appendix D Product Chemistry ............................................................................................... 52

List of Tables Table 1 – Summary of Anticipated Risk Assessments and Data Needs for Registration Review: 9 Table 2 – Anticipated Regist ration Review Schedule .................................................................. 10 Table 3 – Chemical Identificati on of Azadioxabicyclooctane ...................................................... 11 Table 4 – Physical-Chemical and Environmental Fate Properties for Azadioxabicyclooctane ... 12 Table 5 – Summary of Azadioxabicy clooctane Registered Uses ................................................. 14 Table 6 – Studies Anticipated as Needed for th e Registration Review of Azadioxabicyclooctane

............................................................................................................................... ........................ 17 Table 7 – Data Needs Required by the Data Ca ll-In for the Azadioxabicyclooctane RED ......... 20 Table 8 – Existing Toxicological Endpoints ................................................................................. 22 Table 9 – Occupational Handler Exposure Scenarios for Azadioxabicyclooctane ...................... 25 Table 10 – Residential Handler Exposure Scenarios for Azadioxabicyclooctane ........................ 26 Table 11 – Residential Post-App lication Exposure Scenarios for Formaldehyde Released from Azadioxabicyclooctane Treated Paint ........................................................................................... 26 Table 12 – Selected Ecological Effects Endpoints for Risk Assessment of Azadioxabicyclooctane ......................................................................................................... ........ 31Page 7 of 53 

## 1 Introduction

This document is the United States Environmen tal Protection Agency’s (USEPA, EPA or “the agency”) Final Work Plan (FWP) for azadi oxabicyclooctane. Azadi oxabicyclooctane was evaluated in the 2005 Registration Eligibility De cision (RED) for azadioxabicyclooctane as an active ingredient (a.i.) consisti ng of an equilibrium mixture of three chemicals: (component I) 5- hydroxymethoxymethyl-1-aza-3,7- dioxabicyclo(3,3,0)octane (PC Code 107001); (component II) 5-hydroxymethyl-1-aza-3,7-dioxabi cyclo(3,3,0)octane (PC Code 107002); and (component III): 1H,3H,5H,-Oxazolo(3,4-c)oxazole, poly(oxym ethylene) derivative (PC Code 107003).

The FWP document explains what EPA's O ffice of Pesticide Programs (OPP) knows about azadioxabicyclooctane, highlighting anticipated data and assessment needs, identifying the types of information that would be especially usef ul to the agency in conducting the review, and providing an anticipated timeline for comp leting azadioxabicyclooctane’s review.

Azadioxabicyclooctane is a formaldehyde releaser . This registration revi ew case only addresses potential exposure to formaldehyde in the occ upational and residential post-application risk assessments, resulting from the volatilization of formaldehyde from indoor exposure to surfaces painted with products containing azadioxabicyclooctane. This regi stration review case does not address possible risks from form aldehyde derived from azadioxabicyclooctane for the other areas identified for risk assessment listed in Table 1. When the formaldehyde registration review case is at the stage in which a risk assessment is conducted, any other risks identified in Table 1 from formaldehyde derived from the uses of azadioxabi cyclooctane will be considered at that time. The agency issued a Reregistration Eligibility Decision (RED) document for formaldehyde in 2008 to address potential risks a ssociated with formaldehyde. The formaldehyde RED did not include potential exposure to formaldehyde re sulting from the use of products containing azadioxabicyclooctane as an active ingredient.

The registration review process was designed to include a publi c participation component to solicit input from interested stak eholders. The agency intends, by sh aring this information in the docket, to inform the public of what it knows about azadioxabicyclooctane and what types of new data or other information w ould be helpful for the agency to receive as it moves toward a decision on azadioxabicyclooctane.



## 1.1 Statutory and Regu latory Authority
The Food Quality Protection Act (FQPA) of 1996 mandated a regi stration review program. All pesticides distributed or sold in the United St ates generally must be registered by the USEPA based on scientific data showing that they will not cause unreasonable risk s to human health or the environment when used as directed on produc t labeling. The registra tion review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects to human health or the environm ent. Changes in scien ce, public policy, and pesticide use practices will occur over time. Th rough the registration review program, the agency periodically reevaluates pesticides to make sure that as change occurs, products in thePage 8 of 53 marketplace can be used safely. Inform ation on this program is provided at http://www.epa.gov/oppsrr d1/registration_review/

. The agency is implementing the registration revi ew 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 th e FIFRA standard for registration. The regulations governing registra tion review begin at 40 CFR 155.40. The agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the agency’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are need ed to make a registra tion review decision. The Azadioxabicyclooctane Preliminary Work Plan (PWP) was published on March 28, 2014 and the 60-day comment period ended on May 27, 2014.

No public comments were received concerning the PWP, documents associated with this registration review can be viewed at http://www.regulations.gov in docket EPA-HQ-OPP-2013- 0604. Tables 1-2 below summarize the issues relevant to this regi stration review case and the anticipated registration review schedule.



## 1.2 Updates to the Workplan
Since the publication of the PWP, the agency has made the following updates:

 Corrected formatting and typographical errors.

 Updated Table 7 to reflect th e carcinogenicity study is no longer needed due to label

mitigation specified in the 2005 RED.

 Tables 1, 6 and Appendix C updated to reflect OPPTS 850.5400 Algal Toxicity

guideline was split into two separate guidelines and renumbe red with the cyanobacteria species separated into OCSPP 850.4550 and the other three species under OCSPP 850.4500.

 Table 6 and Appendix B updated to reflect addition of degradat es as test substances for

environmental fate studies.

 The agency reviewed the need for the follo wing data requirements and determined they

are no longer necessary. Updated Tables 1 and 6.

o Leaching-adsorption-desorption study (GLN 835.1240)

o Product use study (GLN 875.2700)

 Re-ordered references listed in Section 8.

The agency did not receive any comments concer ning the PWP. Modifications to the anticipated data needs detailed in the Azadioxabicycloo ctane PWP are listed above. This document makes final the work plan for the azadioxabicycl ooctane registration review process.Page 9 of 53 Table 1 – Summary of Anticipated Risk Asse ssments and Data Needs for Registration Review:

Risk Assessment Assessment Necessary to

Support Registration Review Date of Most Recent Assessment Type of Assessment

Required (New/Updated) Data Anticipated as Needed (See Table 6 for details)

Dietary (food) Yes July, 2005 Updated Reproduction and fertility effects Immunotoxicity Dietary (drinking water) No (see 3.2.2) July, 2005 None None

Occupational Handler Yes July, 2005 Updated Reproduction and fertility effects Immunotoxicity OccupationalPost-ApplicationInhalation Yes July, 2005 New Inhalation Exposure (volatilization of formaldehyde)

Residential Handler Yes July, 2005 Updated Reproduction and fertility effects Immunotoxicity

Residential Post Application - Inhalation Yes July, 2005 New Inhalation Exposure (volatilization of formaldehyde)

Aggregate Yes July, 2005 Updated Reproduction and fertility effects Immunotoxicity

Cumulative No (see 3.4.2) July, 2005 None None

Tolerance Review No (see 1.6.1) N/A None None

Ecological Yes May, 2005 Updated Adsorption – desorption (Batch equilibrium) Hydrolysis Aqueous photolysis Ready biodegradability or one of three biodegradation in activated sludge simulation tests Aerobic soil metabolism Anaerobic soil metabolism Aqueous aerobic metabolism Aquatic invertebrate life-cycle Fish early life stage Algal toxicity Tier II (marine diatom, freshwater diatom, green algae, cyanobacteria) Activated sludge, respiration inhibition
test Special Leaching Study Table 1 is a summary of the anticipated risk assessments and data needs for registration review. For data called in through the post-RED DCI, see Table 7.Page 10 of 53 Table 2 – Anticipated Regi stration Review Schedule
Anticipated Activity Target Date* Completion Date Phase 1: Openin g the Docket Open Docket and 60-Day Comment Period for Preliminary Work Plan 2014-03 2014-03-28 Close Public Comment Period 2014-05 2014-05-27 Phase 2: Case Development Issue Final Work Plan 2014-09 2014-09-30 Issue Data Call-In (DCI) 2015-09 Receive Data to be Considered in Risk Assessment 2019-09 Open 30-Day Public Comment Period for Preliminary Risk Assessment(s) 2021-03 Close Public Comment Period 2021-04 Phase 3: Registration Review Decision and Implementation Open 60-Day Public Comment Period for Proposed Decision 2021-09 Close Public Comment Period 2021-11 Issue Final Decision 2022-03 Begin Post-Decision Follow-up 2022 Total (years) 8 *The anticipated schedule will be revised as necessary ( e.g ., needed schedule adjustments aris ing from data requirements in the formaldehyde registration review or under the Endocrine Disruptor Screening Prog ram with respect to the active ingredients in this case).



## 1.3 Case Overview
The docket for azadioxabicyclooctane ( case 3023) has been established at http://www.regulations.gov in docket number EPA-HQ-OPP-2013-0604.



## 1.4 Chemical Identification and Properties

As described in the Section 1 Introduction, azad ioxabicyclooctane is a formaldehyde releaser consisting of a mixture of three chemicals in equilibrium in the product. Each chemical component has an individual OPP Pesticide Chemical Code (PC Code) and is listed on the label as a separate active ingredient, ev en though they occur as part of a mixture. Table 3 presents the three components in the azadioxabicyclooctane ch emical mixture to be assessed in Case 3023: 5- Hydroxymethoxymethyl-1- aza-3,7-dioxabicyclo(3,3,0)octane (PC Code 107001); 5- Hydroxymethyl-1-aza-3,7-di oxabicyclo(3.3.0)octane (PC Code 107002); and 1H,3H,5H,- Oxazolo(3,4-c)oxazole, poly(oxymethylene) deri vative (PC Code 107003). For more information on the azadioxabicyclooctane product chemistry, see Appendix D.

The degradates from the three azadioxabicycl ooctane compounds without the formaldehyde (- CH 2 O) moiety are as follows:

 Component I minus the formaldehyde (–CH 2 O) moiety becomes Component II,

 Component II minus the –CH 2 O becomes degradate IIa.

 All of the potential degradates of Component III are unknown and information on degradates formed is anticipated as needed (see below).

Component III is a polymer with repeating–CH 2 O units. The distribution of the number of units (noted as “n” in Table 3) of formaldehyde presen t has not been found in the records. The agencyPage 11 of 53 anticipates needing information about the polyme r n distribution as well as about the rate of release for use in determining appropriate equiva lent formaldehyde release levels and exposure concentrations.

Table 3 – Chemical Identification of Azadioxabicyclooctane

Constituent of mixture Component I Component II (also a degradate of Component I) Component III

Chemical

Name 5-Hydroxymetho xymethyl-1-aza3,7-dioxabicyclo(3,3,0)octane 5-Hydroxymethyl-1-aza-3,7- dioxabicyclo (3,3,0)octane 1H,3H,5H,-Oxazolo(3,4- c)oxazole, poly(oxymethylene) derivative Chemical Classification Bicyclic Oxazolidine Bicyclic Oxazolidine Bicyclic Oxazolidine

PC Code 107001 107002 107003
CAS Number 59720-42-2 6542-37-6 56709-13-8 Molecular Formula C 7 H 13 NO 4 C 6 H 11 NO 3 (CH 2 O)n C 6 H 11 NO 3 n = Data gap Molecular Weight (grams/mole) 175.08 145.07 (30.03)n + 145.07 n = Data gap
Proportion in a 50% technical product 16% 28.8% 5.2%

Molecular Structure

Moles of formaldehyde per mole of component 2 moles 1 mole n = Data gap (n = 5 for the representative CAS Number)
n = number of repeating formaldehyde units in the polymer.
International Specialty Products (ISP) is the so le producer of azadioxabicyclooctane under the name Nuosept 95 (Kline, 2004). The azadioxabicyclooctane product chemistry information (MRIDs 42734301, 42740801, 41671601, 41671602, 41671603, 48691701, and material safety data sheet (MSDS) for Nuosept 95 Technical) rele vant to risk assessment and environmental fate properties are summarized in Table 4. Data about individual components ar e anticipated as being needed for exposure modeling and risk assessment.Page 12 of 53 Table 4 – Physical-Chemical and Environmental Fate Properties for Azadioxabicyclooctane

Guideline No. Parameter Equilibrium Mixture of 3 inseparable components in Nuosept 95 Technical:50% TGAI; EPA Reg. No. 1529-49 1 5- Hydroxymethoxy methyl-1-aza-3,7- dioxabicyclo (3,3,0)octane

(PC code107001) 5-Hydroxymethyl-1- aza-3,7- dioxabicyclo(3,3,0)oc
tane

(PC code107002) 1H,3H,5H,- Oxazolo(3,4- c)oxazole, poly(oxymethyl ene) deriv

(PC code107003)

Physical/Chemical Properties

830.7000 pH 6.0 - 7.5 at 25 °C Not Available (NA) NA NA

830.7050 UV/Visible Absorption Not reported NA NA NA

830.7200 Melting point Not applicable for liquids.

Freezing poin t: -2.2 °F NA NA NA

830.7220 Boiling point 100 °C NA NA NA

830.7300 Density 1.145 g/ml at 25 °C NA NA NA

830.7370 Dissociatio
n constant (pKa) Not reported NA NA NA

830.7550 Octanolwater partition coefficient at 25 o C (Log K ow ) Log K ow : <1 NA NA NA

830.7840 Solubility in water (mg/L) Miscible with water in all proportions NA NA NA

830.7860 Solubility in organic solvents Miscible with methanol, ethanol, chloroform, ethylene glycol and acetone in all proportions. NA NA NA

830.7950 Vapor
pressure (mmHg) ~23mm Hg at 25°C (high vapor pressure is due to 50% water in the formulation) NA NA NAPage 13 of 53 Guideline No. Parameter Equilibrium Mixture of 3 inseparable components in Nuosept 95 Technical:50% TGAI; EPA Reg. No. 1529-49 1 5- Hydroxymethoxy methyl-1-aza-3,7- dioxabicyclo (3,3,0)octane

(PC code107001) 5-Hydroxymethyl-1- aza-3,7- dioxabicyclo(3,3,0)oc
tane

(PC code107002) 1H,3H,5H,- Oxazolo(3,4- c)oxazole, poly(oxymethyl ene) deriv

(PC code107003)

Environmental Fate Properties

Henry's law
constant at 25 o C (atmm 3 /mol) The HLC varied for the three components from values 1.88 x 10 -11 – 5.67 x 10 -11 (EPI Suite, version 4.1) NA NA NA

Octanol-air partition coefficient at 25 o C (Log K OA ) Log K ow : <1 for the parent NA NA NA

Mobility

Organic Carbon Partitioning Coefficient (K oc ) The values of log K oc for the three components varied from - 0.5903 to 1.00 which indicates that the isomers are mobile on soil surfaces NA NA NA

Persistence in Water (half-life)

Hydrolysis at 25 o C: pH 5, 7 &9 (days) The mixture of the three components does not undergo a typical hydrolysis in the presence of 0.1% formalin (dissolved formaldehyde) but converts into component I. However in the absence of formalin, and in buffered media at pH5, 7, and 9 the mixture degrades (see Appendix B). The mixture is hydrolytically not stable. NA NA NA

Persistence in WWTP (% removed)

Ready biodegradat ion Does not undergo ready biodegradability (EPI Suite, version 4.1) NA NA NA

atm-m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; o F = degrees Fahrenheit; mg/L = milligrams per liter; mmHg = millimeters of mercury.Page 14 of 53 NA = Not Available



## 1.5 Use/Usage Description

1.5.1 Registrations There are currently two products registered with azadioxabicyclooc tane as the active ingredient; one is a manufacturing use product, EPA Reg. N o. 1529-49, and one is an end-use-product, EPA Reg. No. 1529-28. Both products cont ain 5-Hydroxymethoxymethyl-1-aza-3,7- dioxabicyclo(3,3,0)octane; 5-Hydroxymethyl-1 -aza-3,7-dioxabicyclo(3,3,0)octane; and 1H,3H,5H,-Oxazolo(3,4-c)oxazole, poly(oxymethylene) derivative as the active ingredient. The percent a.i., as shown on the label, fo r both is as follows: 28.8 percent for 5- Hydroxymethoxymethyl-1-aza-3,7- dioxabicyclo(3,3,0)octane, 16 pe rcent for 5-Hydroxymethyl1-aza-3,7-dioxabicyclo(3,3,0)octane, and 5.2 pe rcent for 1H,3H,5H,-Oxazolo(3,4-c)oxazole, poly(oxymethylene) derivative.


### 1.5.2 Summary of Registered Uses

Table 5 presents a summary of the registered uses of azadioxabicyclooctane that will be assessed in this registration review. A zadioxabicyclooctane can be app lied by the following application methods: open pour, brush/roller , and airless sprayer.

Table 5 – Summary of Azadioxab icyclooctane Registered Uses

Use Application Method Application Rate

Material Preservatives
Industrial Adhesives, Caulks, Inks, Sealants, Paper Coatings 1 Open pour 0.5 ppm

Latex Paints Open pour, brush/roller, and airless sprayer 0.4 ppm Latex Emulsions, Pigment Dispersion Open pour 0.3 ppm Metalworking Fluids 2 Fully Enclosed Systems 0.2 ppm

Textile Fiber Finish 3 Open pour 0.1 ppm Industrial Processes and Water Systems Drilling Muds Open pour 0.2 ppm Flooding Fluids Open pour 0.1 ppm

1 Must be limited to contact with dry foods.

2 Only for use on enclosed metalworking systems.

3 Only for use on fibers that are not for direct use on skin.



### 1.5.3 Usage Information Azadioxabicyclooctane is register ed for use to control slime form ing bacteria and fungi at the following use sites: oil recovery drilling muds and packer fl uids; industrial adhesives and coatings; resin/latex/polymer emulsions; metalworking cutting fluids; latex paints; paper/paper products; and for industrial processing chemicals. EPA did not find any specific distribution of usage or market data in the 2005 Kline Report for azadioxabicyclooctane.Page 15 of 53 

## 1.6 Regulatory History
Azadioxabicyclooctane

The first pesticide product containing azadioxa bicyclooctane was registered in October 1975. The registration and all data to support reregistration were tran sferred from Tenneco Chemicals on December 22, 1982 to Nuodex Inc. The Nuosep t 95 product was purchased by International Specialty Products on March 26, 2002. The agency completed a RED for azadioxabicyclooctane in 2005. Three post-RED Generic Data Call-Ins ( GDCIs) were issued for azadioxabicyclooctane in 2008, they are the following: GDCI-107001-27848, GDCI-107002-27890, and GDCI-107003- 27849. Of seven studies identified in the GDCIs, two have been satisfied: 1.) EPA guideline 870.2600, a skin sensitization study; and 2.) EPA guideline 870.3465, a 90 day inhalation toxicity study. For more information on the st atus of data requir ements, see Table 7.

Formaldehyde

EPA prepared a separate formaldehyde RED to address potential risk s associated with nonazadioxabicyclooctane uses of formaldehyde. This document is available in the formaldehyde public docket at http://www.regulations.gov in docket number EPA-HQ-OPP-2008-0121. Though the formaldehyde registration review data requirements will be handled separately, background regulatory history info rmation is provided here for the reader’s convenience. The first product containing formaldehyde was register ed in the United States in 1967, for use as a fumigant. Formaldehyde is registered for use as a fumigant in, among other sites, agricultural premises such as poultry and swine farms and proce ssing plants as well as in citrus packing and mushroom houses. It is also registered for us e as a hard surface disinfectant in commercial premises, industrial premises and veterinary cl inics. Formaldehyde is also registered as a materials preservative for consumer products such as laundry dete rgents, general purpose cleaners and wall paper adhesives.

The agency identified the following confirmato ry data requirements in the 2008 formaldehyde RED and anticipates issuing a post-RED DC I: 90 Day Dermal Toxicity (GLN 870.3250), Developmental Toxicity in N on-Rodents (GLN 870.37000), and Acute Daphnia magna using formaldehyde (GLN 850.1010).



### 1.6.1 Tolerance Information For the active ingredient, the EPA has no established tolerances or exemptions from tolerances in raw agricultural commodities or processed f ood and feed products under the Federal Food, Drug and Cosmetic Act (FFDCA) Section 408 for azadioxabicyclooctane. A zadioxabicyclooctane has been cleared as a food additive by the US Food and Drug Administration (US FDA) under FFDCA Section 409 for use as an antibacterial preservative in paper and paperboard products (that are limited to dry food contact only) in 21CFR 176.180 and is also a component in paper adhesives in 21CFR 175.105.Page 16 of 53 

## 1.7 Incidents

1.7.1 Human Health

No azadioxabicyclooctane human poisoning incidents have been reported in OPP’s Incident Data System (IDS) for the time period spanning 2005 to 2013.



### 1.7.2 Ecological

No azadioxabicyclooctane ecological incidents have been reported in the agency’s Ecological Incident Information System (EISS) for the time period spanning 2005 to 2013.


## 2 Anticipated Data Needs

Table 6 presents a summary of the data anticipate d as being needed to su pport this registration review. Table 7 outlines the data requiremen ts required by the post-RED GDCIs issued on August 11, 2008. 1 The agency anticipates reviewing any data received in response to the postRED DCIs as well as data that are required for this registration review prior to conducting the registration review risk assessm ents for azadioxabicyclooctane.

1 See Section 1.5 for a list of the GDCIs.Docket Number EPA-HQ-OPP-2013-0604www.regulations.govPage17of53Table 6 – Studies Anticipated as Needed for theRegistration Review of AzadioxabicyclooctaneGLNStudy NameTest SubstanceTime Frame(Measuredin monthsfrom DCIReceipt)RiskAssessment(s)Data Will SupportUse Site(s)TriggeringAnticipated DataRequirementApplicable ExposureScenarioStudies Anticipated to be Required through the Registration Review DCI835.12301Adsorption-desorption(Batch equilibrium)TGAI, Degr 24Fate and persistenceassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesRelease into water835.21201Hydrolysis TGAI, Degr 12Fate and persistenceassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesRelease into water835.22401, 10Aqueous photolysisTGAI, Degr 12Fate and persistenceassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesRelease into water835.31103, 4835.3220835.3240835.3280Ready biodegradability orone of three biodegradationin activated sludgesimulation testsTGAI, Degr 24Fate and persistencein WWTPs Downthe drainassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesToxicity to WWTPorganisms835.41001Aerobic Soil metabolismTGAI 24Fate and persistenceassessmentPaints, MaterialPreservatives,TextilesRelease into water835.42001, 5Anaerobic soil metabolismTGAI 12Fate and persistenceassessmentPaints, MaterialPreservatives,TextilesRelease into water835.43001Aqueous AerobicmetabolismTGAI 12Fate and persistenceassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesRelease into waterPage18of53850.1300Aquatic invertebrate life-cycleTGAI, Degr 24EcologicalassessmentPaints, MaterialPreservatives,Drilling Muds, andFlooding FluidsRelease into water850.1400 Fish early life stage TGAI, Degr 24EcologicalassessmentPaints, MaterialPreservatives,Drilling Muds, andFlooding FluidsRelease into water850.4400Aquatic plant growth(aquatic vascular plant) TierII-dose response TGAI, Degr 12EcologicalassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesRelease into water850.45008Algal toxicity Tier II(marine diatom, freshwaterdiatom, green algae)TGAI, Degr 12EcologicalassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesRelease into water850.45508Algal toxicity Tier II(cyanobacteria)TGAI, Degr 12EcologicalassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesRelease into water850.33003,6orOECD 209Activated sludge, respirationinhibition testTGAI, Degr 24Fate and persistencein WWTPs Downthe drainassessmentPaints, MaterialPreservatives,Drilling Muds andFlooding Fluids,TextilesToxicity to WWTPorganisms870.3800Reproduction and fertilityeffectsTGAI 48Human HealthAssessmentAll use sites All exposure scenarios870.7800 Immunotoxicity TGAI 12Human HealthAssessmentAll use sites9All exposure scenarios875.1700 Product Use TEP 12OccupationalHandlerPaints, MaterialPreservatives,Drilling Muds andFlooding FluidsPour liquidsBrush/RollerAirless Sprayer875.25002Inhalation Exposure TEP 24Occupational andResidential PostApplicationPaints PaintsPage19of53*Degradates for Table 6 are defined here as well asin Section 1.3: Component I minus formaldehyde (–CH2O) becomes or Component II, Component II minus (–CH2O) becomes degradate IIa, Component III degradates are unknown and are considered data gaps.Degr = DegradatesTEP = Typical end-use productTGAI = Technical grade of the active ingredient1The half-life of all major degradates also needs to be determined, e.g., Component II, degradate IIa, unknown degradates for Component III.2A small chamber study is anticipated to be needed. Post-application inhalation data are anticipated as needed to assess the exposures of formaldehyde in paint.3The anticipated data requirement for degradates could be waivedin cases where the degradates are less toxic than the parent compound.4The results of the ASRI test will determine which of these fourbiodegradation tests is/are anticipated to be required. If theASRI test EC50is less than or equal to20 mg/L, then either the (i)Biodegradation in Activated SludgeStudy or (ii) Simulation Test – Aerobic Sewage Treatment: A. Activated Sludge Units or (iii) thePorous Pot Test is expected to be required. If the ASRI test EC50is greater than 20 mg/L, then the registrant would likely be required to conduct either: (i) ReadyBiodegradability or (ii) a) Biodegradation in Activated Sludge orb) Simulation Test – Aerobic Sewage Treatment: A. Activated Sludge Units or c) thePorous Pot Test. If the Ready Biodegradability study is conducted and passes, then no further testing would be expected to be required. If, however, theantimicrobial fails the Ready Biodegradability study, then the a) Biodegradation in Activated Sludge or b) Simulation Test – Aerobic Sewage Treatment: A.Activated Sludge Units, or c) the Porous Pot study would likely be required.5Data will be tiered: data are expected tobe required based on a weight-of-evidenceevaluation of the results of the hydrolysis, photodegradation in water,biodegradability, and activated sludge, respiration inhibition tests.6For degradates, the agency anticipatesrequiring data only for degradate IIa.EPA published draft guidance under guideline 850.6800 and has since publishedfinal guidance for this study under guideline 850.3300:http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0154-0021. OECD Test Guideline209 can also be used as guidance for this study, available online athttp://www.oecd-ilibrary.org/content/book/9789264070080-en.7The anticipated DCI will provide that the study must include measure of formaldehyde released.8For industrial processes and water systems, Tier II (dose response) studies areanticipated to be required for (i) the freshwater green alga, Selenastrumcapricornutum, (ii) the freshwater diatom, Navicula pelliculosa,(iii) the marine diatom, Skeletonema costatum, and (iv) the cyanobacteria species Anabaena flosaquae. Final 850 guidelines for the algal testing were posted inJune 2012. The Public Draft OPPTS 850.5400 Algal Toxicity guideline was split into two separateguidelines and renumbered with the cyanobacteria species separated into OCSPP 850.4550 and the other threespecies under OCSPP850.4500. .9All use sites listed in Table 5.10To be conducted at PH 9.Special Study3,7Leaching from Paint,Adhesives, Caulks, TextilesDegr 24 Down the DrainPaints, Adhesives,Caulks, TextilesRelease into waterPage20of53Table 7 – Data Needs Required by the DataCall-In for the Azadioxabicyclooctane REDGLNStudy NameTest SubstanceTime Frame(Measuredin monthsfrom DCIReceipt)RiskAssessment(s)Data Will SupportUse Site(s)TriggeringAnticipated DataRequirementApplicable ExposureScenario870.2600 Skin sensitization Data requirement is satisfied.870.3465 90 Day Inhalation Toxicity Data requirement is satisfied.870.4200 CarcinogenictyThe 2005 RED specified that this data requirement would not be necessary if the metalworkingfluid use is limited to enclosed systems; all labelshave this specification; therefore, this datarequirement is no longer needed.875.12001,2Indoor Dermal Exposure TGAI 24Occupational andResidential HandlerAll usesPour liquidsBrush/RollerAirless Sprayer875.14001, 2Indoor Inhalation Exposure TGAI 24Occupational andResidential HandlerAll usesPour liquidsBrush/RollerAirless Sprayer875.16002Application exposuremonitoring data reportingTGAI 24OccupationalHandlerPaintsPour liquidsBrush/RollerAirless Sprayer875.28002Description of HumanActivityTGAI 24 Post-application Paints Metal working FluidsTGAI= technical grade of the active ingredient.1It may be possible to use proprietary surrogate exposure data if data compensation issues are appropriately and adequately addressed.2According to the existing data call-in, the registrant is a memberof the Antimicrobial Exposure Assessment Task Force II (AEATF). AEATF will be conductingexposure studies for liquid pour, brush/roller, and airless sprayer applications, as well as numerous other application methods, and these data will be submitted asrequired under the DCI.Docket Number EPA-HQ-OPP-2013-0604 www.regulations.gov

Page 21 of 53 

## 3 Human Health Risk Assessment

Azadioxabicyclooctane is a formaldehyde releaser . This registration revi ew case only addresses potential exposure to formaldehyde in the occ upational and residential post-application risk assessments, resulting from the volatilization of formaldehyde from indoor exposure to surfaces painted with products containing azadioxabicyclooctane. This regi stration review case does not address possible risks from form aldehyde derived from azadioxabicyclooctane for the other areas identified for risk assessment listed in Table 1. When the formaldehyde registration review case is at the stage in which a risk assessment is conducted, any other risks identified in Table 1 from formaldehyde derived from the uses of azadioxabi cyclooctane will be considered at that time.

The agency anticipates the need to c onduct a human health risk assessment for azadioxabicyclooctane. The agency anticipates new exposure data from the RED data call-in and expects to require additional exposure da ta to conduct new assessments for registration review to assess the vo latilization of formaldehyde from i ndoor exposure to painted surfaces. Additionally, the agency anticipates the need to require a dditional toxicology data (reproduction and fertility effects, and immunotoxicity studies) to support the human health risk assessment for all use patterns of antimicrobial pesticide chem icals, as further described in Appendix A.

Table 8 presents the endpoints used in EPA’s most recent human health risk assessment in support of the 2005 RED. All available inform ation including new and existing toxicology studies, valid scientific literature, and the studies that are expected to be required for registration review will be considered in es tablishing the endpoints to be used in the registration review risk assessment. A detailed description of the to xicity studies is pr ovided in Appendix A .



## 3.1 Existing Toxicological Endpoints

The Antimicrobials Division’s Toxicity Endpoint Selection Committee (ADTC) reviewed the available toxicology data for azadioxabicyclooc tane and selected endpoints to conduct occupational and residential risk assessments for the registration eligibility decision (RED, 2005). In addition, increased sensitivity of infants and children potentially exposed to azadioxabicyclooctane was assessed by the Co mmittee in order to meet the statutory requirements of the Food Quality Protection Act (FQPA) of 1996.

Although there was no evidence of special sens itivity to infants and children, the ADTC recommended that the special 10x hazard-based sa fety factor under the FQPA be retained (10x) for azadioxabicyclooctane. There is a limited de velopmental and reproductive toxicology data base for azadioxabicyclooctane: one prenatal dermal developmenta l toxicity study in rats and no reproduction and fertility effects study or inform ation. While the only available developmental toxicity study showed no evidence of susceptibility of fetuses to this chemical, the timing of the administration of test substance was not adjusted for the dermal route. Consequently, the 10x FQPA hazard-based safety factor was utilized in the human hea lth risk assessment conducted for the 2005 azadioxabicyclooctane RED to account for th is uncertainty as well as the absence of a reproductive toxicity study (US EPA, 2005 b). A reproductive and fertility effects study is anticipated to be required in registration re view. Following issuance of the post-RED DCI,Page 22 of 53 several toxicity studies identified as data gaps for azadioxabicyclooctane were submitted to the agency; a skin sensitization assay (870.2600) and a subchroni c inhalation toxicity study (870.3465). These data have been reviewed and cl assified as acceptable for regulatory purposes (US EPA 2012a and 2012b). The addition of a route specific inhalation study to the azadioxabicyclooctane database may provide a new dose and toxicity endpoint that can be used in place of the oral endpoint cu rrently selected for inhalation ri sk assessments. Under registration review, a re-evaluation of sel ected toxicological dose, endpoint and uncertainty factors for inhalation risk assessment is required (Table 8).

Table 8 – Existing Toxicological Endpoints

Table 8. Summary of Toxicological Dose/Endp oint Selection for Azadioxabicyclooctane
Exposure

Scenario Dose Used in Risk Assessment UF, Target MOE and FQPA SF for Risk Assessment Study and Toxicological Effects

Acute Dietary (general population) NOAEL = 10.6 mg/kg/day UF = 100 (10x interspecies extrapolation, 10x intra-species variation) FQPA SF = 10x

Acute RfD = NOAEL ÷ UF = 10.6 ÷ 100 = 0.106 mg/kg/day

aPAD = acute RfD ÷ FQPA SF = 0.106 ÷ 10 = 0.01 mg/kg/day 90-Day Oral Toxicity in Rats (MRID 41641606)

LOAEL = 56.5 mg/kg/day based

on decreased water consumption in males.

Acute Dietary (females 13+) NOAEL = 10.6 mg/kg/day UF = 100 (10x interspecies extrapolation, 10x intra-species variation) FQPA SF = 10x

Acute RfD = NOAEL ÷ UF = 10.6 ÷ 100 = 0.106 mg/kg/day

aPAD = acute RfD ÷ FQPA SF = 0.106 ÷ 10 = 0.01 mg/kg/day 90-Day Oral Toxicity in Rats (MRID 41641606)

LOAEL = 56.5 mg/kg/day based

on decreased water consumption at in males.Page 23 of 53 Table 8. Summary of Toxicological Dose/Endp oint Selection for Azadioxabicyclooctane
Exposure

Scenario Dose Used in Risk Assessment UF, Target MOE and FQPA SF for Risk Assessment Study and Toxicological Effects

Chronic Dietary (All populations) NOAEL = 10.6 mg/kg/day UF = 300 (10x interspecies extrapolation, 10x intra-species variation, 3x lack of a chronic endpoint) FQPA SF = 10x

Chronic RfD = NOAEL ÷ UF = 10.6 ÷ 300 = 0.03 mg/kg/day

cPAD = chronic RfD ÷ FQPA SF = 0.03 ÷ 10 = 0.003 mg/kg/day 90-Day Oral Toxicity in Rats (MRID 41641606)

LOAEL = 56.5 mg/kg/day based

on decreased water consumption at in males.

Incidental Oral Short-Term,IntermediateTerm (1-30 days, 30 days-6 months) No endpoint is required based on the use pa tterns for pesticide products containing azadioxabicyclooctane.

Dermal (all durations) Short-Term,IntermediateTerm, LongTerm (1-30 days, 30 days-6 months, > 6 months) LOAEL(dermal) = 100 mg/kg/day Target MOE (ST/IT occupational) = 300 (10x inter-speciesextrapolation, 10x intraspecies variation, 3x lack of a NOAEL)

Target MOE (LT occupational) = 3000 (10x inter-speciesextrapolation, 10x intraspecies variation, 10x extrapolation from an oral endpoint, 3x lack of a NOAEL) Co-critical studies: 21-Day Dermal Toxicity in Rats (MRID 41641605)

LOAEL = 100 mg/kg/day (severe dermal effects)

Developmental Toxicity in Rats (MRID 41699001)

LOAEL = 100 mg/kg/day (severe dermal effects)Page 24 of 53 Table 8. Summary of Toxicological Dose/Endp oint Selection for Azadioxabicyclooctane
Exposure

Scenario Dose Used in Risk Assessment UF, Target MOE and FQPA SF for Risk Assessment Study and Toxicological Effects

Inhalation a (all durations) Short-Term,IntermediateTerm, LongTerm (1-30 days, 30 days-6 months, > 6 months) NOAEL = 10.6 mg/kg/day

(inhalation absorption rate = 100%) Target MOE (ST/IT/LT occupational) = 3000 (10x inter-speciesextrapolation, 10x intraspecies variation, 10x extrapolation from an oral endpoint, 3x lack of a histopathology data) 90-Day Oral Toxicity in Rats (MRID 41641606)

LOAEL = 56.5 mg/kg/day based

on decreased water consumption at in males.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic), RfD = reference dose, MOE = margin of exposure, LO C = level of concern, NA = not applicable

a The availability of an acceptable route- specific inhalation toxicity study fo r azadioxabicyclooctane requires a reevaluation of toxicological dose, endpoint and uncertainty factors for inhalation risk assessments.



## 3.2 Dietary Exposure

3.2.1 Food The only approved uses of azadioxabicyclooctane that may result in residues in food are as antibacterial preservatives of food-contact adhesives and paper coatings in contact with dry foods. Acute and chronic dietary risks associated with these FDA uses of azadioxabicyclooctane were summarized in the 2005 RED. The treatmen t rate was 2500 ppm activ e ingredient in the adhesive and the coating which remains the maximum label rate in each preserved material. The aPAD and cPAD were 0.01 mg/kg/day and 0.003 mg/ kg/day, respectively, both from a 90-day rat oral toxicity study. Combined (adhesives plus coatings) acute dietary risks were 5.1% of the aPAD in adults and 12% of the aPAD in children. Combined chronic dietary risks were 17% of the cPAD in adults and 40% of the cPAD in childre n. Dietary risks may need to be reassessed if there is a change in the acute or chronic dietary e ndpoint and/or if aggregate risks exceed the agency’s levels of concern. No residue chemistry da ta are expected to be needed at this time to characterize residues of azadi oxabicyclooctane in food.



### 3.2.2 Drinking Water A drinking water assessment has not been condu cted for azadioxabicyclooctane in the past. There are no direct aquatic uses of azadioxabicyclooctane. Howeve r, several approved uses as a material preservative are likely to result in azadioxabicyclooctane being discharged in waste water or leached from preserved materials a nd subsequently running off into surface water. These are uses as a preservative of drilling muds, flooding fluids, late x paints, sealants, and metalworking fluids. Since the resi dues of concern in drinking water have yet to be determined (i.e., azadioxabicyclooctane and/or its biotic or abiotic products) , the magnitude of the potential residues in drinking water, their mammalian toxic ities, how persistent they will be, and if they are likely to pass through a wa stewater treatment plant (WWT P) is unknown. Therefore, the agency anticipates needing certain environmental fa te data listed in Section 4 of this PWP. ThesePage 25 of 53 data will be useful to determine whether, and to what extent, residues of azadioxabicyclooctane pass through a WWTP. These data will be used du ring the risk assessment stage to determine the potential for discharged or leached residues of azadioxabicycl ooctane to result in human dietary exposure via drinking water which may trigge r a drinking water assessment. No residue chemistry data are expected to be needed at this time to characterize residues of azadioxabicyclooctane in drinking water.



## 3.3 Occupational and Re sidential Exposures

The agency anticipates the need to revise the occupational and resident ial assessments conducted in support of the 2005 RED based on receipt of new exposure and toxicity data. Uses of azadioxabicyclooctane that may result in occupati onal and residential scenarios are identified in Tables 9 and 10 below.



### 3.3.1 Occupational Handler Exposure EPA anticipates the need to revise the occupa tional handler assessment conducted in support of the 2005 RED. Occupational handler dermal and inhalation exposures to azadioxabicyclooctane were assessed in the 2005 RED for applicati ons using brush/roller , and airless sprayer applications and mixing /loading via the liquid pu mp and pour liquid scenario for the registered uses specified in Table 5. Th ese exposures were assessed usin g unit exposure data from the Pesticide Handler Exposure Database (PHED) a nd Chemical Manufacture r’s Association (CMA) data. For the occupational handler dermal and inhalation risk assessment, the short- and intermediate-term risks calculated were above the target MOEs for all scenarios (i.e., dermal and inhalation >300). However, the inhalation MOE for the airless sprayer paint scenario falls below the MOE target of 1,000, when the additional 10X route- to-route extrapolation uncertainty factor is applied. The need for additional exposure data was confirmed by the EPA’s Scientific Advisory Board (SAP) in 2007. The occupational data requirements may be fulfilled by completed or planned Antimicrobial Exposure Assessment Task Force (AEATF) studies.

All of the handler scenar ios listed in Table 9 will need to be revised during re gistration review upon receipt of the new unit exposure data. The ag ency will also need to address occupational post-application exposures to th e release of formaldehyde described in the next section.

Table 9 – Occupational Handler Exposure Scenarios for Azadioxabicyclooctane

Scenario Exposure Route(s) Duration Occupational Exposures 1 Liquid Pour During Manufacturing of Latex Paints 3 Dermal and Inhalation Short and Intermediate-Term Liquid Pour for Drilling Muds and Flooding Fluids 3 Dermal and Inhalation Short and Intermediate-Term Liquid Pour for a Material Preservative Slurries 2, 3 Dermal and Inhalation Short and Intermediate-Term Applying Paint Using an Airless Sprayer Dermal Inhalation Short and Intermediate Term Applying Paint Using a Brush/Roller Dermal Inhalation Short and Intermediate Term

1 The Antimicrobial Division will not be assessing pump liquid scen arios in registration review. Th e paper coating scenario whic h was specified in the RED as a metered pump system will not be assessed. In addition metalworking systems are specified in the labels as an en closed system, an occupational handler risk assessment is also not required for this scenario.

2 Includes adhesives (natural-based or synthetic), caulks, latex emulsions, wax em ulsions, inks, pigment dispersions, pigment slurries, sealants, and textile fiber finishes.

3 If the labels are restricted to closed loading and transfer , then the liquid pour data and a ssessments will not be needed.Page 26 of 53 

### 3.3.2 Occupational Post-Application Exposures

The 2005 RED assessed the dermal and inhalati on exposure when a worker handles treated metalworking fluids. This route of exposure occurs after the chemical has been incorporated into the metalworking fluid and a machinist is using/ handling this treated end-product. The agency does not anticipate the need to conduct another assessment since the metalworking fluid uses are fully enclosed; therefore, no exposure is expected to occur as a result of this use. The updated mitigation language for the metalworking fluids are currently reflected on the existing labels.

The agency anticipates the need to conduct a pos t-application inhalation assessment to examine the potential formaldehyde vapor exposures for professional painters inhaling formaldehyde vapors. As such, formaldehyde monitoring data ar e anticipated as needed to assess this postapplication exposure scenario (e.g., small air chamber tests).


### 3.3.3 Residential Handler Exposures

EPA conducted a residential pain ter assessment for the RED in 2005. The calculated risks for the brush/roller application were not at a level of concern. However the calculated risks (e.g., dermal MOE=236) for the airless sprayer were at a potential risk of c oncern because they were below the target MOE of 300. As a result, the RED speci fied that the maximum diluted concentrations of active ingredient in paint should be reduced to 0.4% a.i. These redu ced rates are currently reflected on the existing labels. An additional assessment is needed due to the expected submission of new dermal and inhalation exposure su rrogate data for paint, required by the postRED DCI (see Table 7). The residential handler exposure scenarios are listed in Table 10.

Table 10 – Residential Handler Exposure Scenarios for Azadioxabicyclooctane

Scenario Exposure Route(s) Duration Residential Exposures Applying paints with brush/roller Dermal/Inhalation Short and Intermediate Term Applying paints with airless spray Dermal/Inhalation Short and Intermediate Term



### 3.3.4 Residential Post-Application Exposures

EPA anticipates the need to revise the reside ntial post-application a ssessment conducted in support of the 2005 RED. Residential post-applic ation exposures could result when bystanders (adults and children) inhale volatilized formalde hyde released from treat ed paint (e.g., treated hard surfaces/walls). Table 11 li sts the residential post-applic ation scenarios. The agency anticipates the need to require additional inhalation exposure data.

Table 11 – Residential Post-Application Expo sure Scenarios for Formaldehyde Released from Azadioxabicyclooctane Treated Paint

Scenario Exposure Route(s) Duration Residential Exposures Post application exposure to formaldehyde vapors released from treated paint Inhalation Short and Intermediate TermPage 27 of 53 

## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures In examining aggregate exposure for azadioxa bicyclooctane, EPA takes into account the available and reliable information concerning exposures to pesticide residues in food and drinking water, as well as non-occupational pesticide exposures. The agency will determine the need for a new aggregate assessment once the ag ency has identified the toxicological endpoints for each route of exposure. If the toxicological endpoints change, the agency will develop a new aggregate exposure assessment. In addition, the agency may need to conduct a new aggregate risk assessment if the agency de termines the need for a new dr inking water exposure assessment. If drinking water exposure is added then the agency would need to consider aggregating drinking water with the existing food exposure from indi rect dietary exposures from residue found in paper coatings and adhesives. The agency does no t anticipate the need to aggregate residential exposures (handler or post-applic ation exposures to paint) with dietary and/or drinking water exposures since the toxicological endpoints and effects for the de rmal and inhalation routes of exposure are anticipated to be differe nt from the oral exposure route.



### 3.4.2 Cumulative Exposures

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a cumulative risk approach based on a common me chanism of toxicity, EPA has not made a common mechanism of toxicity finding as to a zadioxabicyclooctane and any other substances. For the purposes of this registration revi ew, therefore, EPA has not assumed that azadioxabicyclooctane has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determ ine which chemicals have a common mechanism of toxicity and to evaluate the cumu lative effects of such chemicals, see http://www.epa.gov/pesticides/cumulative/

. 

## 4 Environmental Risk Assessment

This registration review case does not addres s possible risks from formaldehyde for the environmental risk assessment. When the formalde hyde registration review case is at the stage in which a risk assessment is conducted, the agency will include formaldehyde and degradates of formaldehyde derived from the uses of azadioxabicyclooctane.

The agency has not previously conducted a risk assessment that supports a complete endangered species determination for azadioxabicyclooctane. An ecological hazard and environmental risk assessment chapter for the RED was completed in May, 2005. At the time, most uses of azadioxabicyclooctane were considered indoor and were considered to have little chance of exposure to the environment. An assessment of the industrial uses and processes will be conducted during the future risk assessment of azadioxabicyclooctane. This would include modeling of exposure scenarios that were not considered when the or iginal assessment was conducted. The ecological risk assessment pla nned during registration review will allow the agency to determine potential acute and chr onic risks to aquatic organisms exposed to azadioxabicyclooctane that are transported from tr eatment sites into the aquatic environment.Page 28 of 53 Aquatic organisms could be exposed to azadioxabicyclooctane. Exposure from industrial uses, such as drilling muds, textile manufacturing and metal working fluids, will need to be assessed during the risk assessment. The agency will determine if these uses result in parent chemical and/or degradate releases. The risk assessment also will allow the agency to determine whether each use of the azadioxabicyclooctane has 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or their desi gnated critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a liste d species or its designated critical habitat, the agency will consult with the U.S. Fish and Wild life Service and/or National Marine Fisheries Services (the Services), as appropriate.



## 4.1 Environmental Fate Assessment
The unique mixture of three compone nts in this mixture is not sepa rable, and the exposure from this active in various environmental media are due to the three components. The agency has no environmental fate data on the degradates; plea se refer to Table 6 for the anticipated data requirements and Appendix B for additional information on environmental fate.



### 4.1.1 Leaching from Paint, Adhesives, Caulks, Textiles No leaching studies for in-service use of treated commodities such as paint, textiles, adhesives, and caulks were conducted. However, a dow n the drain screen was conducted for azadioxabicyclooctane. The results indicate that if everything leached out of consumer products (e.g., paint, textiles, etc) and went down-the-drain, there would be no risk. Still, the agency anticipates the need to require leaching data fo r the azadioxabicyclooctane degradates as there are no data for the degradates.



### 4.1.2 Water and Sediment The three components are highly water soluble (misci ble in all proportions with water). Since the log K oc is 1.00 and the agency considers values of log K oc from 1 to 10 as showing high mobility in soils, azadioxabicyclooctane is mobile in soil medium and easily partitions into aqueous medium. The components are not expected to partition from wa ter into sediments.



### 4.1.3 Soil The three components are highly water soluble (mis cible in all proportions with water). The log K oc for the components is a maximum of 1.00, and thus these are highly mobile in aqueous medium. The three components are not expected to partition from water into soils.



### 4.1.4 Air The half lives in air for the three components vary from 1 to 1.5 hours (EPI Suite, version 4.1), and these are not persiste nt in the atmosphere.



### 4.1.5 Wastewater Treatment Plant (WWTP) There are not enough data for assessment of azadioxa bicyclooctane and its degradates. For a list of anticipated and already imposed data requirements, see Tables 6 and 7.Page 29 of 53 

### 4.1.6 Water Quality Azadioxabicyclooctane is not identified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act. 2 In addition, no Total Maximum Daily Loads (TMDL) have been developed for the mixture of these azadioxabicyclooctane compounds. 3 More information on impaired water bodies and TMDLs can be found at EPA’s website. 4



## 4.2 Conceptual Models for Enviro nmental Exposure Pathways
Based on the summary of registered uses of azadioxabicyclooctane as materials preservatives for adhesives, caulks, paints, textiles, metalworking fluids and drilling muds, residues may enter the aquatic environment via both municipal and indust rial wastewater treatm ent plants. Aquatic organisms in surface water downstream of both direct and indirect sources of azadioxabicyclooctane could be expected to be exposed to azadioxabicyclooctane and any degradates.

The screening-level risk assessment that will be conducted as part of this registration review will evaluate potential risks to eco logical organisms from exposure to azadioxabicyclooctane.



## 4.3 Ecological Effects Assessment
Azadioxabicyclooctane is a mixture of three si milar compounds used as a materials preservative in latex paints, latex emulsions, pigment dispersions, inks, adhe sives, construction materials, metalworking fluids, textile fiber-finish solutions , pulp and paper, and oi l production/recovery. There is only 1 registered end-use product, Nuosept® 95, which, according to the current CSF contains:

A: 5-hydroxymethoxymethyl-1-aza-3,7-dioxabicy clo(3.3.0)octane; B: 5-hydroxymethyl-1-aza3,7-dioxabicyclo (3.3.0) octane ; and C: 5-hydroxypoly(met hyleneoxy)methyl-1-aza-3,7- dioxabicyclooctane.

Azadioxabicyclooctane is a formaldehyde releas er. This registrati on review case does not address possible risks from formaldehyde de rived from azadioxabicyclooctane for the environmental risk assessment. In the formalde hyde risk assessment phase of the formaldehyde registration review case, the agency will review open literature concerning the toxicity of formaldehyde to non-target organisms and determin e if any formaldehyde studies can be used to evaluate formaldehyde risks derived fr om the uses of azadioxabicyclooctane.

The ecological data summarized in this re gistration review was conducted on the product Nuosept® 95. The percentages of the three octane s in the formulation varied slightly in the submitted studies; ratios are listed in the tables , where information was available. The EPA’s

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

3 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl _pollutant_detail?p_pollutant_group_id=885&p_pollutant_ group_name=PESTICIDES

4 http://www.epa.gov/owow/tmdl/Page 30 of 53 ECOTOX database (EPA, 2002) was also searched for avian, fish, invertebrate, mammalian and plant data on the components of azadi oxabicyclooctane, but no data were found.

Under abiotic conditions, the mixture of these acetals is hydrolytically unstabl e with half-lives of 0.347 days at pH 5, 1.74 days at pH 7 and approxima tely 15 days at pH 9. It is, therefore, not likely to be persistent in water. Components I and II of the mixture are likely to volatilize into the atmosphere as their vapor pressures vary between 0.0004 to 0.003 mm Hg. Component III is likely to have less volatility as the side chai n of CH2O groups are added into the structure. Estimated half lives in the atmosphere for components I and II are 1.2 and 1.4 hours. Hence, these two chemicals are not likely to pe rsist in the atmosphere (RED, 2005).

The estimated log K ow of components I and II are respec tively are -2.23 and -1.55 (very highly miscible in water and show no tendency for dissol ving organic solvents); therefore, the mixture is not likely to bioaccumulate in aquatic organisms (RED, 2005).

MITI linear biodegradability (modified linear biodegradation method) for components I and II indicates a fast biodegradation is highly proba ble in soils and water. These compounds do not likely pose a concern for surface and ground water contamination (RED, 2005).

The uses of azadioxabicyclooctane ar e not likely to pose risk to fish, wildlife or plants due to the low likelihood of exposure. Additional modeling will be conducted to ensure that exposure will be low for of the registered uses (RED, 2005).

Chronic toxicity testing for freshw ater organisms is anticipated to be required for the currently registered uses of azadioxabicyclooctane. A fish early life stage (850.1400) and an aquatic invertebrate life-cycle test (850.1300 ) using the most sensitive organism as determined from the results of the acute toxicity tests are expect ed to be required. Th e ECOTOX database (EPA, 2002) was searched for any appropria te chronic testing with fish or invertebrates, but no such data were located.

Chronic toxicity testing for mari ne/estuarine organisms is not an ticipated to be required for the currently registered uses of azadioxabicyclooctane (see Appendix C).



### 4.3.1 Mode of Action

Azadioxabicyclooctane is highly soluble in water. Aquatic organisms would be exposed to the chemical when azadioxabicyclooctane enters the aquatic environment after industrial discharge and after disposal down th e drain (RED, 2005).



### 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aqua tic and terrestrial organisms. All available ecotoxicity endpoints in the agen cy’s files from chemical studies submitted by registrants or other interested pa rties, federal laboratory data, or from the public literature are tabulated in Appendix C along with the anticipate d data requirements and data gaps. The most sensitive values for each receptor group are used for the risk assessment (Table 12). ThesePage 31 of 53 selected endpoints will be updated during the risk assessment phase based on any additional submitted data or data found in the public literature.

Table 12 – Selected Ecological Effect s Endpoints for Risk Assessment of Azadioxabicyclooctane

Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID)

Birds Mallard duck Acute Oral LD 50 = >2510 mg a.i./kg-bw ACC 250533 Subacute Dietary LC 50 > 10,000 ppm-diet ACC 248878 Chronic Data not anticipated to be required

Mammals Acute Oral LD 50 = 1940 mg/kg-bw 41641601 Subchronic dietary NOEL = 10.6 mg a.i./kg-bw 41641606

Freshwater fish Bluegill sunfish Acute 96-h LC 50 = 34.7 mg a.i./L 48082403
Chronic Data Gap: data anticipated to be required

Freshwater invertebrates Waterflea Acute 48-h EC 50 = 35 mg/L 48082404

Chronic Data Gap: Data anticipated to be required --

Freshwater benthic invertebrates -- Subchronic or Chronic Data not anticipated to be required: Not expected to be associated with sediment because it is water soluable (RED, 2005)

Estuarine/marine fish Sheepshead minnow Acute 96-h LC 50 = 440 mg ai/L ACC 250533

Chronic Data not anticipated to be required due to low acute toxicity --

Estuarine/marine invertebrates Eastern oyster (embryo larval) Acute EC 50 = 42 mg a.i./L ACC 250053

Mysid Acute LC 50 = 88 mg a.i./L ACC 250533 Chronic Data not anticipated to be required --

Estuarine/marine benthic invertebrates -- Subchronic or Chronic Data not anticipated to be required: Not expected to be associated with sediment because it is water soluable (RED, 2005) --

Aquatic plant growth, algae Non-listed Data Gap: data anticipated to be required

-- Listed Aquatic Vascular Plant Non-listed Data Gap: data anticipated to be required -- Listed Seedling Emergence Terrestrial Plants Non-listed Data not anticipated to be required based on a lack of exposure to terrestrial organisms (RED, 2005) -- Listed *The endpoints for formaldehyde will be assessed separa tely in the formaldehyde registration review case.



## 4.4 Exposure Analysis Plan

Available OPP models will be used to determ ine 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. Based on registered uses of azadioxabicyclooctane in Table 5 of this PWP, there are some uses, such as drilling mud, flooding fluids, metalworking fluids, an d textile finishing for which discharges may enter industrial WWTPs rather than domestic WWTPs prior to entering surfacePage 32 of 53 water. The Industrial Releases Module of the E-FA ST will be used to determine the potential for aquatic organisms downstream of the industrial wastewater treatment plants that receive discharges from the end-use of azadioxabicycloo ctane to be exposed th is chemical or their degradates. 

## 4.5 Effects Analysis Plan
Toxicity data presented in this wo rk plan will be used to calculat e risk quotients and/or calculate COCs. Any additional information submitted by the registrant(s), other interested parties or found in the open literature prior to conduct of the risk assessment will also be considered. The open literature studies wi ll be identified using EPA’s ECOTOXicology (ECOTOX) 5 database, which employs a literature search engine for lo cating chemical toxicity data for aquatic life, terrestrial plants, and wildlife. The ECOTOX databa se will be searched when the risk assessment for azadioxabicyclooctane is prepared. The evaluati on of these sources of data can also provide insight into the direct and indirect effects of pesticides on biotic communities from loss of species that are sensitive to the chemicals and from changes in structure and functional characteristics of the affected communities.

Additional open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) database. The ECOTOX database will be sear ched during the risk assessment phase of azadioxabicyclooctane and the data reviewed foll owing the agency’s policy for reviewing public literature for use in assessing risks from pesticides. 6 Those ecotoxicity values found in the public literature to be more sensitive than those currentl y in Table 12 and /or which satisfy an existing data gap(s) will be used during the risk asse ssment phase of azadioxabicyclooctane to update Table 12. ECOTOX was created and is mainta ined by the USEPA, Office of Research and Development, and the National Health and Envi ronmental Effects Research Laboratory's MidContinent Ecology Division.


## 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include e ndpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of the 2005 RED for azadioxabicyclooctane, 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), azadioxabicyclooctane is subject to the endocrine screeni ng part of the Endocrine Disrup tor Screening Program (EDSP).

5 http://cfpub.epa.gov/ecotox

6 http://www.epa.gov/pesticides/science/literature-studies.htmlPage 33 of 53 EPA has developed the EDSP to determine whet her 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 ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e 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 estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the agency must scr een all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/dat a call-ins for the firs t group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredient s. A second list of chemicals identified for EDSP screening was published on June 14, 2013 7 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the ED SP, the policies and procedures, the list of chemicals, future lists, the test guidelines and the Tier 1 screening ba ttery, please visit our website. 8



## 6 Optional Label Changes

The agency invites comment on any label amendments that could be considered to eliminate the anticipated need for EPA to requi re certain data, reduce the possibi lity that EPA’s planned risk assessments overestimate risk due to reliance on conservative assumptions , and/or improve label clarity.


## 7 Next Steps

A DCI will be developed regarding the data needs listed under the “Risk Assessments and Anticipated Data Needs” section of this docum ent. The agency expects to issue the DCI in September of 2015.

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

chemicals.

8 http://www.epa.gov/endo/Page 34 of 53 

## 8 References

41641601 (MRID#) Dilley, J.V. (Unknown). Acute oral toxicity of Nuosept 95 in rats (Interim progress report). SRI International.

41641602 (MRID#) Hersham, R.J. (1984). Summary of results of a primary eye irritation study. Bioresearch Incorporated.

41641603(MRID#) Unwin, S.E. (1983). Primary dermal irritation test of Nuosept® 95 in New Zealand White albino rabbits. Mi dwest Research Institute.

41641605 (MRID#) Elliot, P.H., et al. (1985). Twenty-one Day Dermal Toxicity Study in Rabbits with Nuosept 95/Nuosept C. Huntingdon Research Centre.

41641606 (MRID#) Sasmore, DP. (1980). Reformat of 00109245. Final Report: Effect of Nuosept 95 in Rats 90-Day Toxicity Study - C ontains dose range study for Dominant Lethal Study (OPPTS 870.3100). SRI International.

41671801 (MRID#) Liggett, M.P. and L.A. McRae. ( 1990). Acute dermal toxicity to rabbits of Nuosept 95 (Final report). Hun tingdon Research Centre Ltd.

41684801 (MRID #). Hakin, B., M. Rodgers, A. Anderson and I.S. Dawe. 1990. Nuosept 95: LC50 to Bobwhite Quail. Unpublished data. Conducted by Huntingdon Research Centre, Ltd., for Huls America, Inc.

41699001 (MRID#) Smith, J.A., et al. (1988). A Study of the Effect of Nuosept 95 on Pregnancy of the Rat. Huntingdon Research Centre.

41728601 (MRID#) O’Loughlin, K.G. (1990). Measurement of micronuclei in bone marrow erythrocytes of Swiss-Webster mice follo wing two treatments with Nuosept 95. SRI International.

42650901 (MRID#) Cholakis, J.M. and H. Sprinz. ( 1983). Acute inhalation toxicity of Nuosept 95 in Sprague-Dawley rats. Midwest Research Institute.

42711001 (MRID#) Hamilton, C.M. (1983). Measur ement of unscheduled DNA synthesis in male Fischer-344 rat hepatocytes following in vivo treatment with Nuosep t 95. SRI International.

48082403 (MRID #). Minderhout, T., Kendall, T.Z ., Krueger, H.O. 2008. Nuosept 95: A 96-Hour Static Renewal Acute Toxicity Test with the Bluegill ( Lepomis macrochirus ). An unpublished study performed by Wildlif e International, Ltd., Easton, Ma ryland, USA. Laboratory project number 633A-106. Study sponsored by Internationa l Specialty Products. Sponsor study number 2006-061. Study initiated 01 November 2007. Study completed 10 September 2008.

48082404 (MRID #). Minderhout, T., Kenal, T. Z., Kruger, H.O. 2008. Nuosept 95: A 48Hour Static Renewal Acute Toxicity Test with the Cladoceran (Daphnia magna) . An unpublished study performed by Wildlife Interna tional, Ltd., Easton, Maryland, USA. Laboratory project number 633A-105. Study sponsored by International Specialty Products, Wayne, New Jersey, USA.Page 35 of 53 Sponsor study number 2006-061. Study initiated 26 October 2007. Study completed 10 September 2008.

93050015 (MRID #). Bently, R.E. and B. H. Sl eight. 1974. Acute Toxicity of Nuosept 95 Preservative to Bluegill and Rainbow Trout. Unpublished data. Conducted by EG&G Bionomics, Inc., for Huls America, Inc. (formerly Nuodex, Inc., formerly Tenneco Chemicals, Inc.). Also submitted by Creanova, Inc., 1990.

93050017 (MRID#, Reformat of 00088956) Anonymous (1979). Salmonella /mammalianmicrosome plate incorporation mu tagenesis assay. An Evaluation of Carcinogenic Potential of NUOSEPT® 95 Employing the C3H/10T1⁄2 Cell Transf ormation Assay. EG&G Mason Research Institute.

93050018 (MRID#, Reformat of 00088974) Van Goet hen, D. (1979). Mutagenicity studies on Nuosept 95 Salmonella /microsome test. Midwest Research Institute.

93050019 (MRID#, Reformat of 00088957). Anonym ous (1979). Bacterial DNA damage/repair suspension assay. EG&G Ma son Research Institute.

93050020 (MRID#, Reformat of 00088958) Anonymous (1979). Bacterial DNA repair assay. Midwest Research Institute.

93050021(MRID#, Reformat of 00088959). Anonymous (1980). Evaluation of Nuosept ® 95 in the primary rat hepatocyte unscheduled DNA synthesis assay. Litt on Bionetics, Inc.

93050022 (MRID#, Reformat of 00088960) Thilagar, A., et al. (1979). An Evaluation of Carcinogenic Potential of NUOSEPT® 95 Employing the C3H/10T1⁄2 Cell Transformation Assay. EG&G Mason Re search Institute.

93050023 (MRID#, Reformat of 00088961) Schechtman, M. (1980). Activity of T1597 in an in vitro Mammalian Cell transformation Assay in the Absence of Exogenous Metabolic Activation. Microbiological Associates.

93050024 (MRID#, Reformat of 00088962) Thilagar, A., et al. (1980). An Evaluation of Carcinogenic Potential of R-1162 (NUOS EPT® 95) Employing the C3H/10T1⁄2 Cell Transformation System. EG&G Mason Research Institute.

93050025 (MRID#, Reformat of 00088963) Thilagar, A. (1980). An Evaluation of Carcinogenic Potential of R-1143 (NUOSEPT® 95) Employing the C3H/10T1⁄2 Cell Transformation System. EG&G Mason Research Institute.

93050026 (MRID#, Reformat of 00088953) Anonymous (1979). Dominant lethal study of Nuosept 95. SRI International.

ACC#247878. Truslow Farms, Inc. 1974. Eight-d ay Dietary LC50 - Bobwhite quail Nuosept 95. Unpublished data. Conducted by Truslo w Farms, Inc., for Tenneco Chemicals.Page 36 of 53 ACC#247878. Eight-day Dietary LC50 - Mall ard duck Nuosept 95. Unpublished data. Conducted by Truslow Farms, Inc., for Tenneco Chemicals.

ACC#250533. Ward, G. S. 1983. Ac ute Toxicity of Nuosept 95 to Embryo-larvae of Eastern oysters ( Crassostrea virginica ). Unpublished data. Conduc ted by EG&G Bionomics for Nuodex, Inc.

ACC#250533. Acute Toxicity of Nuosept 95 to Mysid Shrimp ( Mysidopsis bahia ). Unpublished data. Conducted by EG&G Bionomics for Nuodex, Inc.

ACC#250533. Acute Toxicity of Nuosept 95 to Sheepshead Minnows ( Cyprinodon variegatus ). Unpublished data. Conducted by EG &G Bionomics for Nuodex, Inc.

ACC#250533. Suprenant, D.C. 1983. Acute T oxicity of Nuospet 95 to the Water Flea ( Daphnia magna ). Unpublished data. Conducted by EG&G Bionomics for Nuodex, Inc. Also submitted as MRID #930500-16 by Creanova, Inc., 2002.

Kline, 2005. Specialty Biocide North America 2004-2005, Kline and Company, Inc

Petrie, R.C. 2008. Ecological Hazard and Environmental Risk Assessment Chapter Formaldehye, Paraformaldehyde. Reregistrati on Eligibility Document (RED). USEPA.

U.S. Environmental Protection Agency (EPA ). 2002. ECOTOX User Guide: ECOTOXicology Database System. Version 3.0. Av ailable: http://www.epa.gov/ecotox/

US EPA. (2005) Azadioxabicyclooctane - Re port of the Antimicrobial Division Toxicology Endpoint Selection Committee (Memorandum: T. McMahon and M. Centra, April 20, 2005)

US EPA. (2005a) Reregistration Eligibility De cision for Azadioxabicyclooctane. EPA 739-R-05- 0110, September 2005.

US EPA. (2005b) Reregistrati on Eligibility Decision for Azadioxabicyclooctane. 2005.

US EPA. (2012a) Nuosept ® 95: Evaluation of Mammalian Toxicology Data in Support of Registration of Pesticide Products. D399374 (Mem orandum: T. McMahon to W. Powell and L. Wormell, October 1, 2012)

US EPA. (2012b) Acute Toxicity Review for EPA: GDCI.-107001-27848. EPA Reg. No. 1529- 28 and 1529-49. DP Barcode: D405288. Generic Group Name: Azadioxabicyclooctane (Memorandum: I. Blackwell to L. Wormell, November 14, 2012).

US EPA. (2012c) Acute Toxicity Review for EPA: GDCI.-107001-32540. EPA Reg. No. 1529- 28 and 1529-49. DP Barcode: D405272. Generic Group Name: Azadioxabicyclooctane (Memorandum: I. Blackwell to L. Wormell, November 20, 2012).Page 37 of 53 

# Appendix A Toxicology Profile

Acute Toxicity for Product Labeling

Azadioxabicyclooctane has a moderate order of acut e toxicity via the oral and dermal routes of exposure (Toxicity Category III) and a moderate to severe acute toxicity via the inhalation route (Toxicity Category II). Azadioxa bicyclooctane produces severe irritation to the eyes (Toxicity Category I), moderate irritation to the skin (Toxicity Category III) and is a dermal sensitizer. Acute toxicity data for azadioxabicyclooc tane are summarized below in Table 13.

Table A1 – Acute Toxicity Studies for Azad ioxabyciclooctane (Nueosept® 95; 50% a.i.)

Table 13. Acute Toxicity Profile for Azadioxabicyclooctane (Nuosept ® 95; 50% a.i.)

Guideline Number Study Type MRID Number Results Toxicity Category

870.1100 Acute Oral - Rat 41641601 LD 50 = 1940 mg/kg III

870.1200 Acute Dermal - Rabbit 41671801 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation – Rat (whole body exposure) 42650901 LC 50 > 0.441 mg/L < 0.819 mg/L (males + females, combined) II

870.1300 Acute Inhalation – Rat (nose only exposure)* 48082401 LC 50 = 2.861 mg/L (males + females, combined) IV

870.2400 Primary Eye Irritation - Rabbit 41641602 Corrosive I

870.2500 Primary Dermal Irritation - Rabbit 41641603 Moderate irritant III

870.2600 Skin Sensitization (LLNA) - Mouse 47838301 Sensitizer N/A

N/A = Not applicable *This acute inhalation toxicity study was submitted to support registration of EPA Reg. No.’s 1529-28 and 1529-49, the sole products in the azadioxabicyclooctane case. 

## Subchronic Toxicity

Repeat-dose toxicity data for azadioxabicyclooctane include a 90-day oral toxicity study in the rat, a 90-day inhalation t oxicity study in the rat, a 21-day derm al toxicity study in the rabbit, and a dermal prenatal developmenta l toxicity study in the rat.

In a 90-day oral toxicity study (MRID 41641606 reformat of 00109245, supplemental information 410801010), Nuosept® 95 was administ ered to 20 CD1 Sprague-Dawley derivedPage 38 of 53 rats/sex/dose in drinki ng water at dose levels of 0, 125, 625, or 3125 ppm (equivalent to 0, 20, 100, or 500 mg/kg bw/day; actual intake repor ted was 0, 13, 62, and 245 mg/kg/day). Four rats/sex/group were kept for a 4-week recovery pe riod to determine reversib ility of effects. No signs of toxicity due to Nuosept 95 treatment were noted in mortalit y, clinical observations, hematology, clinical chemistry, ophthalmol ogy, gross pathology, or histopathology. Body weight and body weight gain were lower in high-dose males and females compared to their respective controls. Although f ood consumption was reduced in the intermediate and high-dose groups in both males and females, the food effi ciency was unaffected. Water consumption was drastically (approximately 30-50%) reduced in high-dose males and females throughout the entire study period. Due to the reduction in water consumption, the intake of test article did not reach predicted levels. Based on the analytical c oncentration of the test article in the water and the water intake data, the daily doses were estimated to be 10.6, 56.5, and 228.9 mg/kg/day in males and 12.2, 64.3, and 255.9 mg/kg/day for female s. The LOAEL is 56.5 and 64.3 mg/kg/day in males and females, respectively, based on the reduction in water consumption. The NOAEL is 10.6 and 12.2 mg/kg/day for males and females, respectively. The 90-day study is classified Acceptable/Non-guideline . Definitive conclusions regarding the basis of the organ weight changes and enzyme changes could not be made due to the lack of a complete histopathology report. However, although there is missing data , the study contains useful information for establishment of a NOEAEL/LOAEL, with applicat ion of additional uncertainty factors for risk
assessment.
In a 21-day dermal toxicity study (M RID 41641605), Nuosept® 95/Nuosept® C was administered directly to the skin of New Zeal and White rabbits (5/sex/g roup) at doses of 0, 100, 300, and 1000 mg/kg/day, 6 hours/day for 5 days/w eek during a 21-day period. No treatmentrelated effects on clinical obser vations and mean absolute or relative organ weights were observed. Significant findings were presented for food cons umption, body weight, hematology, and clinical chemistry parameters, however these findings were not considered to be treatmentrelated. Extensive damage to the treated skin wa s observed in all of the rabbits in the high-dose group. Numerous microscopic chan ges in the skin as well as increases of neutrophils and platelets were observed and were considered to be secondary to tissue repair. The dermal LOAEL is 100 mg/kg/day (based on severe derm al effects). The dermal NOAEL for Nuosept 95/Nuosept C could not be determined because mild skin effects were observed at the low dose. The systemic NOAEL is greater th an or equal to 1000 mg/kg/day a nd the LOAEL is greater than 1000 mg/kg/day (not established). This 21-day dermal toxicity st udy in the rabbit is classified A cceptable/Non-guideline

. In a subchronic inhalation toxicity study (MRID 48082402), Nuosept 95 was administered to WIST(SPF) rats, 10/sex/dose [mai n study] or 10/sex/dose (control and high dose only) [recovery grou] by nose-only exposure at targeted concentrations of 0, 0.01, 0.05, and 0.5/0.3 mg/L for 6 hours per day, 5 days/week for 13 weeks, Actual m easured concentrations of test material were 0.009, 0.051, and 0.433/0.279 mg/L. The high dose con centration of 0.5 mg/L was reduced to 0.3 mg/L was reduced to 0.3 mg/L after 10 week s of exposure due to excessive toxicity. Toxicity was observed at the 0.5/0.3 mg/L dose leve l. This consisted of increased mortality in males and females, significant reductions in body wei ght gain (55% of control in males, 72% of control in females after 13 week s), decreased partial thromboplas tin time in males and females (14% in males, 19% in females), decreased thym us weight in males and females (11% and 25%, respectively), decreased weight of the liver (20% ), spleen (21%), and epididymides (21%) inPage 39 of 53 males, and histopathological altera tions of the respiratory tract in males and females. At the 0.05 mg/L concentration, transient labored breathing a nd discoloration of the fur was observed in both sexes was not considered toxicologicallhy si gnificant. The LOAEL is 0.3 mg/L (300 mg/m 3 ) based on increased mortality, decreased body wei ght and body weight gain, decreased partial thromboplastin time, decreased organ weights, an d increased incidence of histopathology of the respiratory tract in males and females. The NOAEL is 0.05 mg/L is 0.05 mg/L (5 mg/m 3 ). This 90- day inhalation toxicity st udy in rats is classified Acceptable/Non-guideline . Although this study does not satisfy the guideline requirement for a 90-day inhalation to xicity study in rats [OPPTS 870.3465; OECD 413] due to a protocol deviation (omission of urinalysis and clinical chemistry parameter measurements in high conc entration exposure animals), it does contain useful information that supports identificati on of a Lowest-Observed-Adverse-Effect-Level (LOAEL) based on increased mortality, decreased body weight and body wei ght gain, decreased partial thromboplastin time, decr eased organ weights, and increa sed incidence of histopathology of the respiratory tract in males and females as well as a No-Observed-Adverse-Effect Level (NOAEL). 

## Developmental Toxicity

In a dermal developmental toxicity st udy (MRID 41537501, reformat of 41699001), Nuosept® 95 (Batch No. 006-097-597, 50.38%;) in distilled wate r was applied dermally to mated female Crl:COBS CD (SD) BR VAF + rats (25/dose) at dose levels of 0, 100, 300, or 1000 mg/kg/day from days 6 through 15 of gestation (gd 6-15). An additional 25 mated female rats were administered distilled water from gd 6-15. There were no treatment related effects in mortality, clinical signs, weight gai n, food consumption, gross necropsy parameters and cesarean parameters. There was clear evidence of matern al dermal effects in all treatment groups. The low-dose group had well-defined erythema, scabbing that obscured some of the treatment site, and well-defined edema in most animals by st udy termination. The intermediate-dose group displayed moderate/well-defined erythema. Half of the animals had sc abbing that completely obscured the treatment site, and edema that wa s well-defined by study termination. The highdose group exhibited well-defined erythema, scabbi ng that obscured the treatment site in all animals by gd 10, and moderate to severe edema that extended to the underlying musculature. The LOAEL for maternal dermal toxicity is 100 mg /kg/day (based on severe dermal irritation); a NOAEL could not be established. The systemic maternal toxicity NOAEL is greater than or equal to 1000 mg/kg/day; the systemic maternal toxicity LOAEL is grea ter than 1000 mg/kg/day. There were no other embryotoxic or fetotoxic effect s observed in this study. The developmental NOAEL is greater than or equal to 1000 mg/kg/da y; the developmental LOAEL is greater than 1000 mg/kg/day. This developmental toxic ity study in the ra bbit is classified Acceptable/ Nonguideline. 

## Reproductive Toxicity

There are no data evaluating the potential repr oductive toxicity of azadioxabicyclooctane. For the indirect food use of this chemical mixtur e. Under registration re view, a reproductive and fertility effects study is anticipated to be required due to the currently labeled indirect food use.Page 40 of 53 

## Chronic Toxicity

Although there are no data evaluating the potenti al chronic toxicity of azadioxabicyclooctane, chronic exposures to pesticide products cont aining this active ingred ient mixture are not anticipated. Use patterns that w ould trigger chronic toxicity te sting (e.g., metalworking cutting fluid use) do not apply to azadioxabicyclooctane because this labeled use occurs in closed systems. Consequently, chronic toxicity da ta are not anticipate d to be required. 

## Carcinogenicity

A determination of carcinogenic potential cannot be made for azadioxabicyclooctane; there are no data evaluating the potential carcinogenicity of this chemical mixture. However, the metalworking cutting fluid use, which would trig ger the requirement for carcinogenicity studies based on the potential for long-term exposures, do es not apply to pesticide products containing azadioxabicyclooctane since the labeled metalwor king cutting fluid use is conducted in closed systems. Carcinogenicity testing for azadioxabicy clooctane is not antici pated to be required. 

## Mutagenicity

Azadioxabicyclooctane has been tested for mu tagenic activity in several assays, including reverse gene mutation (Ames) a ssays (MRID 93050017, 93050018), bacterial DNA damage/repair assay (MRID 93050019, 93050020), unsch eduled DNA synthesis assays (MRID 93050021, 42711001), differential killing/grow th inhibition assays (MRID 93050019, 93050020), in vitro cell transformation assays (MRID 93050022, 93050023, 93050024, 93050025), a dominant lethal assay (MRID 00088953) , and a micronucleus assay (41728601). Although several of these studies are classified unacceptable-guideline due to lack of test substance characterization and pur ity, missing data and inadequate reporting of results, there remains sufficient mutagenicity testing to complete the mutagenicity battery for azadioxabicyclooctane. These data suggest negati ve mutagenic responses for this chemical mixture. 

## Additional Data Gaps

A multi-generation reproduction study is identified as a data gap and is antic ipated to be required for an adequate risk characterization.

An immunotoxicity study is a new data requirement for all use patterns of antimicrobial pesticide chemicals (78 FR 26936; May 8, 2013). The regist rant can address this anticipated data requirement by either submitting a study accord ing to the OCSPP 870.7800 guideline, by citing information from the scientific literat ure that addresses immunotoxicity of azadioxabicyclooctane, or by submitting a request fo r waiver of this study using the Agency’s published guidance, available at: http://www.epa.gov/pesticides/r egulating/part158-tox-datarequirement.pdfPage 41 of 53 

## Other Toxicological Effects

The available toxicological database for azad ioxabicyclooctane contains no additional information which would inform the toxicity of this chemical mixture. In addition, published literature for azadioxabicyclooctane have not been identified.Page 42 of 53 

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of Azadioxabicyclooctane

Azadioxabicyclooctane is a formaldehyde releas er. The unique mixture of three components in this mixture is not separable, and the exposure from this active in various environmental media are due to the three components.

The degradates from the three azadioxabicycl ooctane compounds without the formaldehyde (– CH 2 O) moiety are as follows:

 Component I minus the formaldehyde (–CH 2 O) moiety becomes Component II,

 Component II minus the –CH 2 O becomes degradate IIa.

 All of the potential degradates of Co mponent III are unknown and information on the degradates formed is anticipated as needed.

The agency has no environmental fate data on the degradates for azadioxabicyclooctane, see Table 6 for the anticipated data requirements.

Water and Sediment

Hydrolysis

The mixture of the three components in this case do not undergo hydrolysis in the buffered conditions at pH 5, 7, and 9, and in the presen ce of formalin (dissolved formaldehyde) these convert into component I. This is possible by re lease of formaldehyde from the parent molecule, although no o information is provided on the mech anism for how all components convert into Component I. However, in the absence of forma lin, and in buffered media at pH 5, 7, and 9, the degradation of Component I is rapid and in a 24 hour study, co mponent I is 0.65% at pH 5, 19.2% at pH 7, and 28.4 % at pH 9; however, in a 33 day study component I, after 33 day, is 2% left at pH 5, 20.2 % at pH 7, and 27.6% at pH 9. The decrease in pH , result in the degradation of component I rapidly, but the reverse reactions also take place and in a 33 day study. (MRID# 430670-01). The agency anticipates the need to require hydrolysis data for the degradates.

Aqueous Photolysis

There are no measured data available, data ar e anticipated to be required for the parent and degradates.Page 43 of 53 Octanol-Water Partition Coefficient

Estimated Log K ow is less than 1 for the parent, and therefore azadioxabicyclooctane components are not likely to be bioaccumulative. However, si nce no data are available for the degradates, the agency anticipates the need to require data for the degradates.

Aerobic Aquatic Metabolism

No measured or estimated data are available for both parents and degradates , data is anticipated to be required.

Anaerobic Aquatic Metabolism

No measured or estimated data are available is available for both parents and degradates, data is anticipated to be required.

Soil

Adsorption/Desorption Batch Equilibrium

Estimated Log K oc values for the mixture indicate that m obility from soil surfaces is high for the parent. No data are available for the TGAI and degradates, the agency anticipates the need to require data.

Aerobic Soil Metabolism

No measured or estimated data are available for the mixture for either parent or degradates. The agency anticipates the need to require data.

Anaerobic Soil Metabolism

No measured or estimated data are available for the mixture for either the parent or degradates. The agency anticipates the need to require data.

Fate and Transport in WWTP

Activated Sludge Sorption Isotherm

The activated sludge sorption isotherm test is not required if the log K ow is less than 3.0, the log K ow for azadioxabicyclooctane is less than 1.0. EPI Suite was run for degradates with –CH 2 O removed in series. The log K ow for these degradates is le ss than 3.0. The agency does not anticipate the need to re quire the activated sludge sorption isotherm test.

Activated Sludge Biodegradation

Activated sludge respiration inhibition data are not available for azadioxabicyclooctane or its degradates and are anticipated to be required. The results of the ASRI test will also determine thePage 44 of 53 biodegradation tests that are an ticipated to be required. S ee table 6 for th e anticipated biodegradation data requirements.Page 45 of 53 

# Appendix C Ecotoxicology Profile

Azadioxabicyclooctane is a formaldehyde rel easer. The azadioxabicyclooctane registration review case does not addr ess possible risks from formaldehyde derived from azadioxabicyclooctane for the environmental risk assessment. . In the formaldehyde risk assessment phase of the formaldehyde registratio n review case, the agency will review open literature concerning the toxicity of formaldehyde to non-target organisms and determine if any formaldehyde studies can be used to evaluate formaldehyde risks deri ved from the uses of azadioxabicyclooctane. 

## Toxicity to Terrestrial Receptors

Birds

In order to establish the toxicity of the use of this pesticide to bi rds, the agency requires an acute oral toxicity study using the tech nical grade of the active ingredie nt (TGAI). The preferred test species is either mallard duck (a waterfowl) or northern bobwhite quail (a n upland game bird). The results of one toxicity study are provided in the follo wing table (Table C1).

Table C1. Acute Oral Toxicity of Nuosept ® 95 to Birds

Species % Active Ingredient (ai) Endpoint (mg /kg product) Toxicity Category Satisfies Guidelines/ Comments Reference

Mallard duck ( Anas platyrhynch

os ) 107001 24.5%

107002 17.7%

107003

7.8% LD 50 > 2,510

NOEL =

2510 (mortality) Practicall
y nontoxic Yes

- acceptable for formulated product

- 14-day test duration Beavers, 1983 (ACC # 250533)

The results of these studies indicate that Nuos ept® 95 is practically non-toxic to birds on an acute oral basis. Although conducted using a formulated product and not the TGAI, these studies are considered adequate to support the registered uses on azadioxabicyclooctane, as Nuosept® 95 is the only end-use product. Th e study is acceptable and fulfills the Guideline requirements (850.2100/71-1).

A subacute dietary study using the TGAI may be required on a case-by-case basis depending on the results of the lower tier ecological studies and pertinent environmental characteristics to establish the toxicity of a pesticide to avian spec ies. The preferred test species are mallard duckPage 46 of 53 or northern bobwhite quail. This testing is no t anticipated to be re quired for the currently supported uses on azadioxabicyclooctane; however, th ree avian dietary studies were previously submitted to the agency. The results of these ar e provided in the following table (Table C2).

Table C2. Subacute Dietary Toxicity of Nuosept ® 95 to Birds

Species % Active Ingredient (ai) Endpoint (ppm) Toxicity Category Satisfies Guidelines/ Comments Reference

Bobwhite quail ( Colinus virginianus ) 50% LC 50 >5,200 a.i. (>10,400 product)

NOEC 1541 ppm a.i. (3082 ppm product) Practically non-toxic No

- supplemental study

- administered in drinking water rather than food Hakin et al., 1990 (MRID 416848-01)

Bobwhite quail ( Colinus virginianus ) not reported LC50 > 10,000 ppm product

NOEC 10,000 ppm Practically non-toxic Yes

- acceptable for formulated product

- single mortality at 10,000 ppm; no other mortality reported Truslow Farms,

1974. (ACC#248 78)

Mallard duck ( Anas platyrhynch

os ) not reported LC50 > 10,000 ppm product

NOEC 10,000 ppm Practically non-toxic Yes

- acceptable for formulated product

- no mortality reported at any test concentration Truslow Farms,

1974. (ACC#248 78)

The results of the study indicate that Nuosept® 95 is practically non-toxic to birds via dietary exposure. Although conducted using a formulated product and not the TGAI, these studies are considered adequate to support the registered uses on azadioxabicyclooctane, as Nuosept® 95 is the only end-use product. The Guideline requirements (850.2200/71-2) are fulfilled. No additional data are antici pated to be required.Page 47 of 53 Mammals

Wild mammal testing was not required for azadioxabi cyclooctane. In most cases, toxicity values obtained from studies conducted to support data requirements for the human health risk assessment substitute for wild mammal testing. Th ese toxicity values are reported below (Table C3). No additional data are anticipated to be required.

Table C3. Acute Toxicity of Nuosept ® 95 to Mammals

Species Test Type LD 50
(mg/kg) NOEL

(mg/kg/day) Reference

(MRID)

Rat Acute oral 1940, toxicity
category III -- 41641601

Rat Acute dermal >2000, toxicity
category III -- 41671801

Rat Subchronic dietary n/a 10.6 mg/kg/day 41641606

Beneficial Insects

No data are anticipated to be required for toxicity to beneficial insects because the use patterns for azadioxabicyclooctane (i.e. materials preserva tives, industrial processes and water systems) do not cause exposure to be neficial insects.

Terrestrial Plants

No data are anticipated to be required for toxicity to terrestrial plants be cause the use patterns for azadioxabicyclooctane (i.e. materials preservative s, industrial process and water systems) would not cause exposure to non-ta rget terrestrial plants. 

## Toxicity to Aquatic Receptors

Chronic toxicity testing for freshw ater organisms is anticipated to be required for the currently registered uses of azadioxabicyclooctane. A fish early life stage (850.1400) and an aquatic invertebrate life-cycle test (850.1300 ), using the most sensitive organism as determined from the results of the acute toxicity tests, are anticipat ed to be required to be conducted. The ECOTOX database (EPA, 2002) was searched for any appropriate chronic testing with fi sh or invertebrates, but no such data were located.

Chronic toxicity testing for mari ne/estuarine organisms is not an ticipated to be required for the currently registered uses of azadioxabicycl ooctane as Guidelines (850.1025 and 850.1035) are fulfilled.Page 48 of 53 Freshwater Fish

In order to establish the acute t oxicity to pesticides to freshw ater fish, the agency requires freshwater fish toxicity studies using the TGAI. The preferred te st species are rainbow trout (a coldwater fish) or bluegill sunfish (a warm-water fish), although other test species identified in the Guideline [i.e., OPPTS 850.1075 (e )(4)(i)(A)] may also be us ed. Two freshwater fish toxicity studies were submitted to the agency for azadioxabicyclooctane using the formulated product Nuosept95. The results of thes e studies are presented in Table C4.

Table C4: Acute Toxicity of Nuosept95 to Freshwater Fish.

Species % Active Ingredient (ai) Endpoints (ppm product) Toxicity Category Satisfies Guidelines/ Comments Reference

Rainbow trout ( Oncorhyn-chus mykiss ) not reported LC50 = 240

NOEC = 87 practically non- toxic No

- supplemental

- 96h test duration;

- static system Bentley and Sleight, 1974 (ACC #247878; MRID 930500- 15)

Bluegill ( Lepomis macrochirus ) not reported LC 50 = 163

NOEC = 87 practically non-toxic No

- supplemental

- 96h test duration;

- flow-through system Bently and Bevier, 1974 (ACC#247878; MRID 930500- 15)

Bluegill ( Lepomis macrochirus ) Nuosept 95 LC 50 = 34.7 ppm ai

NOAEC = 26.22 ppm ai

(measured) slightly toxic Yes

-96hr test duration

-static renewal (renewed daily) Minderhout, et. al., 2008. MRID 48082403

a.i. is the total of the three components I – III.

Two of these studies were originally submitted and reviewed by OPP in 1982, and were determined to be acceptable for formulated product testing. However, they were resubmitted by Creanova, Inc., and re-reviewed in 2002, and cla ssified as supplemental information due to a lack of details regarding chem ical purity and composition. Thes e studies can potentially be upgraded to acceptable if sufficient informati on on the composition and purity of the test substance used is submitted. At the present time, they do fulfill OCSPP test guidelines. The third study was submitted in 2012 and the results indica te that this pesticide is slightly toxic to fish on an acute basis. The study is accepta ble and fulfills the OCSPP test guideline (850.1075).Page 49 of 53 For freshwater fish, no additional acute toxicity da ta is anticipated to be required; however, the agency anticipates the need to require a fish early life stage (850.1400) us ing the most sensitive organism as determined from the results of the acute toxicity tests. The ECOTOX database (EPA, 2002) was searched for any appropriate chr onic testing with fish, but no such data were located.

Freshwater Invertebrates

The agency requires a freshwater aq uatic invertebrate study using th e TGAI to establish the acute toxicity of a pesticide to fr eshwater invertebrates. Th e preferred test species are Daphnia magna

or

Daphnia pulex . Results of one toxicity study are provided in the fo llowing table (Table C5).

Table C5. Acute Toxicity of Nuosept ® 95 to Freshwater Invertebrates

Species % Active Ingredient (ai) Endpoints (ppm product) Toxicity Category Satisfies Guidelines/ Comments Reference

Water flea

( Daphnia
magna ) 107001 24.5%

107002 17.7%

107003 7.8% EC 50 = 77

NOEC = 7.7 slightly toxic Yes

-acceptable for formulated product

- 48h test duration;

- static system Suprenant, 1983 (ACC# 250533/MROD

#930500-16)

Water flea ( Daphnia
magna ) Nuosept 95 LC 50 = 35

NOAEC = 28.36 slightly toxic Yes

-acceptable for formulated product

-48h test duration

-static system Minderhout, et.al., 2008

MRID 48082404

The results indicate that Nuosept® 95 is slightly toxic to aquatic i nvertebrates on an acute basis. Although conducted on the formulated product and not the TGAI, the studies are considered adequate to support the currently registered uses of azadioxabicyclooctane, since Nuosept® 95 is the only end-use product. The studies are accep table and fulfill the OCSPP test guideline (850.1010). For freshwater i nvertebrates, no additional acute toxi city data is anticipated to be required; however, the agency anticipates the need to require an aquatic invertebrate life-cycle test (850.1300) using the most sensitive organism as determined from the results of the acute toxicity tests. The ECOTOX database (EPA, 2002) was searched for any appropriate chronic testing with invertebrates, but no such data were located.Page 50 of 53 Estuarine/Marine Fish

Acute testing with estuarine/marine fish is requ ired to support the uses of azadioxabicyclooctane. This testing is conducted with one fish species, a bivalve. These data were submitted to the agency, and the results are summarized in Table C6, below.

Table C6. Acute Toxicity of Nuosept ® 95 to Marine/Estuarine Fish

Species % Active Ingredient (ai) Endpoints (ppm product) Toxicity Category Satisfies Guidelines/ Comments Reference

Sheepshead minnow

( Cyprinodon variegatus ) PC code %

107001 24.5%

107002 17.7%

107003 7.8% LC 50 = 440
ppm

NOEC = 250
ppm practically non-toxic Yes

- acceptable for formulated product

- 96h test duration;

- static system Ward,1983. (ACC# 250533)

The results indicate that Nuosept® 95 is practi cally non-toxic to marine /estuarine fish. Although conducted on the formulated product and not th e TGAI, the study is considered adequate to support the currently registered uses of azadioxa bicyclooctane, since Nuosept 95 is the only enduse product. The study is acceptable and fu lfills the OCSPP test guideline (850.1075). No additional data are antici pated to be required.

Estuarine/Marine Invertebrates

Acute testing with estuarine/marine inverteb rates is required to support the uses of azadioxabicyclooctane. This testing is conducted with an invertebrate species. These data were submitted to the agency and the results are summarized in Table C7, below.

Table C7. Acute Toxicity of Nuosept 95 to Marine/Estuarine Invertebrates

Species % Active Ingredient (ai) Endpoints (ppm product) Toxicity Category Satisfies Guidelines/ Comments Reference

Eastern oyster

( Crassostrea virginica ) PCCode %

107001 24.5%

107002 17.7%

107003 7.8% EC 50 = 42

NOEC =25 slightly toxic Yes

- core study on formulated product

- embryo-larvae test Ward, 1983. (ACC#250533)Page 51 of 53 - 48h test duration;

- static system system

- endpoint immobilization Mysid ( Americamysis bahia ) 107001 24.5%

107002 17.7%

107003 7.8% LC50 = 88
ppm

NOEC < 50 ppm\ slightly toxic Yes

- core for formulated product

- 96h test duration

- static system Ward, 1983.

ACC#250533

The results of these studies indicate that Nuos ept® 95 is slightly toxic to marine/estuarine invertebrates. The Guidelines (850.1025 a nd 850.1035) are fulfilled. No additional data are anticipated to be required.

Aquatic Plants

Aquatic plant testing is required to support the registered uses of azadioxabicyclooctane. An aquatic plant growth (aquatic vascular plant) Ti er II-dose response test and aquatic plant growth (algal) Tier II (dose response) tests are anticipa ted to be required, no st udies on plant toxicity have been submitted to the agency. The ECOT OX database (EPA, 2002) was searched for any plant toxicity information on the components of azad ioxabicyclooctane. No data were available. The agency anticipates the need to require aquatic plant growth data.

The Industrial Releases Module of the E-FAST will be used to dete rmine the potential for aquatic organisms downstream of the industrial wastewater treatment plants that receive discharges from the end-use of azadioxabicycloo ctane to be exposed th is chemical or their degradates.Page 52 of 53 

# Appendix D Product Chemistry

The azadioxabicyclooctane product chemistry info rmation is summarized in Table D1 (source: MRIDs 42734301, 42740801, 41671601, 41671602, 41671603, 48691701, ISP MSDS for Nuosept 95 Technical).

Table D1 – Product Chemistry of Nuosept 95 Technical - 50% TGAI; EPA Reg. No. 1529-49

Guideline No. Physical and Chemical Properties Equilibrium Mixture of 3 inseparable AIs in Nuosept 95 Technical::

 5-Hydroxymethoxymethyl-1-aza-3,7-di oxabicyclo(3.3.0)octane....16.0%

 5-Hydroxymethyl-1-aza-3,7-dioxabicycl o(3.3.0)octane........ ..........28.8%

 1H,3H,5H,-Oxazolo(3,4-c)oxazole, pol y(oxymethylene) deriv.........5.2%

830.1550 Product identity and composition Refer to Table 3.
830.1600 Description of materials used to produce the product Confidential Business Information (CBI)

830.1620 Description of production
process CBI

830.1650 Description of Formulation Process CBI

830.1670 Discussion of Formation of Impurities CBI

830.1700 Preliminary analysis CBI 830.1750 Certified limits CBI

830.1800 Enforcement analytical method GC/MS
830.1900 Submittal of samples CBI

830.6302 Color Clear colorless liquid Clear pale yellow liquid 830.6303 Physical State Clear liquid

830.6304 Odor Mild, characteristic odor Formaldehyde odor

830.6313 Stability to normal and elevated temperature, metals/metal ions Stable. This product is stable under normal storage conditions.

830.6314 Oxidation/Reduction Incompatible with oxidizing materials, acids and bases. Condition to avoid: Excessive heat or extremes of pH may cause decomposition. 830.6315 Flammability Flash Point (SCC): 140°F Flash Point (TCC): >200°F 830.6316 Explodability Not explosive 830.6320 Corrosion Characteristic 830.7000 pH 6.0-7.5 830.7050 UV/Visible Absorption Not reported
830.7200 Melting point Not applicable for liquids Freezing point: -2.2 °F 830.7220 Boiling point 100°C 830.7300 Density 1.145 g/ml at 25°CPage 53 of 53 Guideline No. Physical and Chemical Properties Equilibrium Mixture of 3 inseparable AIs in Nuosept 95 Technical::

 5-Hydroxymethoxymethyl-1-aza-3,7-di oxabicyclo(3.3.0)octane....16.0%

 5-Hydroxymethyl-1-aza-3,7-dioxabicycl o(3.3.0)octane........ ..........28.8%

 1H,3H,5H,-Oxazolo(3,4-c)oxazole, pol y(oxymethylene) deriv.........5.2% 830.7100 Viscosity 3.5 to 4 Centistokes at 25°C 830.7370 Dissociation Constant Not Available

830.7550 Partition coefficient ( n

octanol/water) Log K ow: <1
830.7840 Solubility in water Miscible with water in all proportions

830.7860 Solubility in organic solvents Miscible with methanol, ethanol, chlo roform, ethylene glycol and acetone in all proportions.

Hexane 0.2 g/100 g at 25°C Petroleum ether 0.2 g/100 g at 25°C Xylene 1.5 g/100 g at 25°C Benzene 2.8 g/100 g at 25°C Ethyl ether 28.0 g/100 g at 25°C 830.7950 Vapor pressure ~23mm Hg at 25°C (water)