Page 2 of 56 Azadioxabicyclooctane Registration 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 Rose Kypriano u

Office of General Counsel Phillip RossPage 3 of 56 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 a cute p opulation a djusted d ose ASRI a ctivated sludge r espiration i nhibition
atm

- m 3 /mole a tmospheric pressure

- cubic meter per mole BCF b ioconcentration f actor °C d egrees Celsius CAS Chemical Abstracts Service CFR Code of Federal Regulations CHO Chinese h amster o vary

– CH 2 O formaldehyde moiety CMA Chemical Manufacturers Association CO 2 c arbon dioxide COC c oncentration

- of

- c oncern cPAD c hronic p opulation a djusted d ose DCI data call

- in DtD down

- the

- drain EC 50 m edian (or 50 percent) e ffect c oncentration EC 05 5 p ercent e ffect c oncentration ECOTOX ECOTOXicology EDI e stimated daily i ntake EDSP E ndocrine Disruptor Screening Program E

- FAST Exposure and Fate Assessment Screening Tool EPI Suite Estimation Program Interface Suite EPA Environmental Protection Agency °F d egrees Fahrenheit FDA Food and Drug Administration FFDCA Feder al Food, Drug, and Cosmetic Act FGD f lue

- g as d esulfurization FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FWP Final Work Plan g/mol g rams per mole GLN guideline number HPV h igh production v olume IDS Incident Data System ISP International Specialty Products Koc o rganic carbon normalized soil

- water partition coefficient Kd s oil

- water partition coefficient Kow o ctanol

- water partition coefficient LC 50 m edian (or 50 percent) l ethal c oncentration LD 50 m edian (or 50 percent) l ethal d ose LOAEC l owest

- o bserved

- a dverse

- e ffect

- c oncentration LOEC l owest

- o bserved

- e ffect

- c oncentration LOAEL lowest

- observed

- adverse

- e ffect

- l evel Log K ow l ogarithm of the octanol

- water partition coefficient
μg m icrogramPage 4 of 56 ml/g m illiliter p er g ram mg/kg m illigram p er k ilogram mg/kg/day m illigram p er k ilogram p er d ay mg/L m illigram p er l iter mm Hg m illimeter of mercury MOE m argin of e xposure MRID Master Record Identification Number MRL m aximum r esidue l imit MSDS material safety data sheet NA not available N/A n ot a pplicable

nm n anometers NOAEC no

- observed

- adverse

- effect

- c oncentration NOAEL n o

- o bserved

- a dverse

- e ffect

- l evel OCSPP Office of Chemical Safety and Pollution Prevention OECD Organization for Economic Co

- operation and Development OPP Office of Pesticide Programs PAD p opulation a djusted d ose PAI p ure active i ngredient PDM Probabilistic Dilution Model % p ercent PC Code Pesticide Chemical Code PCF p ounds p er c ubic foot pH power of h ydrogen or power of the con centration of the hydrogen ion PHED Pesticide Handler’s Exposure Dat a PIS primary i rritation s core pKa p ower of the acid dissociation constant or negative base

- 10 logarithm of the acid dissociation constant of a solution ppb p arts p er b illion
ppm p arts p er m illion PWP Preliminary Work Plan QSAR q uantitative s tructure

- a ctivity r elationship RED Rere gistration Eligibility Decision SAR s tructure a ctivity r elationship SDF stream dilution factor SF s afety f actor SSTS Section Seven Tracking System TEP t ypical e nd

- u se p roduct TGAI t echnical grade active i ngredient TMDL total maximum daily l oads UF uncertainty factor UV/VIS ultraviolet/v isible light a bsorption % w / w p ercent weight per weight. WP w ettable powder WWTPs w astewater treatment plantsPage 5 of 56 

### Table of Contents
1 Introduction

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

................................ ................................ ................. 7 1.2 Case Overview

................................ ................................ ................................ ............... 10 1.3 Chemical Identification an d Properties

................................ ................................ .......... 10 1.4 Use/Usage Description

................................ ................................ ................................ ... 14 1.4.1 Registrations

................................ ................................ ................................ ........... 14 1.4.2 Summar y of Registered Uses

................................ ................................ .................. 14 1.4.3 Usage Information

................................ ................................ ................................ .. 14 1.5 Regulatory History

................................ ................................ ................................ ......... 15 1.5.1 Recent/Pending Regulatory Actions

................................ ................................ ....... 15 1.5.2 Tolerance Information

................................ ................................ ............................ 15 1.6 Incidents

................................ ................................ ................................ ......................... 16 1.6.1 Human Health

................................ ................................ ................................ ......... 16 1.6.2 Ecological

................................ ................................ ................................ ............... 16 2 Anticipated Data Needs

................................ ................................ ................................ ........ 16 3 Human Health Risk Assessment

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

................................ ................................ .................. 21 3.2 Dietary Exposure

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

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

- Application Exposures

................................ ................................ . 27 3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 27 3.4.1 Aggregate Exposures

................................ ................................ .............................. 27 3.4.2 Cumulative Exposures

................................ ................................ ............................ 27 4 Environmental Risk Assessment

................................ ................................ ........................... 28 4.1 Environmental Fate Assessment

................................ ................................ .................... 28 4.1.1 Leaching from Paint, Adhesives, Caulks, Textiles

................................ ................. 28 4.1.2 Water and Sediment

................................ ................................ ................................ 29 4.1.3 Soil

................................ ................................ ................................ .......................... 29 4.1.4 Air

................................ ................................ ................................ ........................... 29 4.1.5 Wastewater Treatment Plant (WWTP)

................................ ................................ ... 29 4.1.6 Water Quality

................................ ................................ ................................ .......... 29 4.2 Conceptual Models for Environmental Exposure Pathways

................................ .......... 29 4.3 Ecological Effects Assessment

................................ ................................ ....................... 30 4.3.1 Mode of Action

................................ ................................ ................................ ....... 31 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 31 4.4 Exposure Analysis Plan

................................ ................................ ................................ .. 32 4.5 Ef fects Analysis Plan

................................ ................................ ................................ .......... 32 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 33 6 Optional Label Changes

................................ ................................ ................................ ........ 34 7 Guidance for Commenters

................................ ................................ ................................ .... 34Page 6 of 56 7.1 Preliminary Work Plan

................................ ................................ ................................ ... 34 7.1.1 Trade Irritants

................................ ................................ ................................ .......... 34 7.1.2 Water Quality

................................ ................................ ................................ .......... 34 7.1.3 Environmental Justice

................................ ................................ ............................. 34 7.1.4 Structure Activity Relationships

................................ ................................ ............. 35 7.1.5 Additional Information

................................ ................................ ........................... 36 8 Next Steps

................................ ................................ ................................ ............................. 36 9 References

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

Appendix A T oxicology Profile

................................ ................................ ............................... 41 Appendix B Environmental Fate

................................ ................................ ............................. 46 Ap pendix C Ecotoxicology Profile

................................ ................................ .......................... 48 Appendix D Product Chemistry

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

List of Tables Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registration Review: 9 Table 2

– Anticipated Registration Review Schedule

................................ ................................ .. 10 Table 3

– Chemical Identification of Azadioxabicyclooctane

................................ ...................... 11 Table 4

– Physical

- Chemical and Environmental Fate Properties for Azadioxabicyclooctane

... 12 Table 5

– Summary of Azadioxabicyclooctane Registered Uses

................................ ................. 14 Table 6

– Studies Anticipated as Needed for the Registration Review of Azadioxabicyclooctane

................................ ................................ ................................ ................................ ....................... 17 Table 7

– Data Needs Required by the Data Call

- In for the Azadioxabicyclooctane RED

......... 19 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

- Application Exposure Scenarios for Formaldehyde Released from Azadioxabicyclooctane Treated Paint

................................ ................................ ........................... 27 Table 12

– Selected Ecological Effects Endpoints for Risk Assessment of A zadioxabicyclooctane

................................ ................................ ................................ ................. 31 Table 13

– Acute Toxicity Studies for A zadioxabicyclooctane (Nuosept ® 95; 50% a.i.)

............ 41

List of Figures No table of figures entries found.Page 7 of 56 

## 1 Introduction

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

a gency”) Preliminary Work Plan (PWP) for a zadioxabicyc l ooctane

. Azadioxabicyclooctane was evaluated in the 2005 Registration Eligibility Decision (RED) for a zadioxabicyclooctane as an active ingredient (a.i.) consist ing of an equilibrium mixture of three ch emicals : (component I ) 5

- hydroxymethoxymethyl

- 1

- aza

- 3,7

- dioxabicyclo(3,3,0)octane (PC Code 107001) ; (component II ) 5

- hydroxymethyl

- 1

- aza

- 3,7

- dioxabicyclo(3,3,0)octane (PC Code 107002) ; and (component III ) : 1H,3H,5H,

- Oxazolo(3,4

- c)oxazole, poly(oxymethylene) deriv ative (PC Code 107003)

. The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about azadi o xabicyc l ooctane , highlighting anticipated data and assessment needs, identifying the types of information that would be especially useful to the a gency in conducting the review, and providing an anticipated timeline for completing azadioxabicy c looctane’s review.

A zadioxabicyclooctane is a formaldehyde releaser. This registration review case only addresses potential ex posure to formaldehyde in the occupational and residential post

- application risk assessments, resulting from the volatilization of formaldehyde from indoor exposure to surfaces painted with products containing azadioxabicyclooctane

. T his registration review case does not address possible risks from formaldehyde 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 assessmen t is conducted, any other risks identified in Table 1 from formaldehyde derived from the use s of azadioxabicyclooctane will be considered at that time

. The a gency issued a Reregistration Eligibility Decision (RED) document for formaldehyde in 2008 to addre ss potential risks associated with formaldehyde. The formaldehyde RED did not include potential exposure to formaldehyde resulting from the use of products containing azadioxabicyclooctane as an active ingredient

. The registration review process was desig ned to include a public participation component to solicit input from interested stakeholders. The a gency intends, by sharing this information in the docket, to inform the public of what it knows about azadioxabicyclooctane and what types of new data or ot her information would be helpful for the a gency to receive as it moves toward a decision on azadi o xabicyclooctane

. T he a gency encourages all interested stakeholders to review the PWP and to provide comments and additional information that will help the a ge ncy’s decision

- making process for this chemical.



## 1.1 Statutory and Regulatory Authority
The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distributed or sold in the United States generally must be registered by the USEPA based on scientific data showing that they will not cause unreasonable risks to human health or the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continu e to meet the statutory standard of no unreasonable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the agencyPage 8 of 56 periodically re evaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at http://www.epa.gov/oppsrrd1/registration_revi ew/

.
The agency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet t he FIFRA standard for registration. The regulations governing registration review begin at 40 CF R 155.40. The a gency 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

a gency’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. After reviewing and responding to comments and data received in the docket during this initial comment period, the a gency will develop and commit to a F inal W ork P lan (FWP) and anticipated schedule for the a zadioxabicy c looctane c ase.
Documents associated with this registration review can be viewed at http://www.regulations.gov in docket EPA

- HQ

- OPP

- 20 13

- 06 04

. Tables 1

- 2 b elow summar ize the issues relevant to this registration review case and the anticipated registration review schedule

.Page 9 of 56 Table 1

– Summary of Anticipated Risk Assessments 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 detail s )

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 Product Use Reproduction and fertility effects Immunotoxicity Occupational Post

- Application

Inhalation Yes July, 2005 New Inhalation Exposure (vol a ti li zation of formaldehyde) Product Use

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

Resident i al Post Application

- Inhalation Yes July, 2005 New Inhalation Exposure (vol a ti li zation 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 1.5.2 ) N/A None None

Ecological Yes May, 2005 Updated Adsorption

– desorption (Batch equilibrium) Leaching

– absorption

- desorption 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 Aquatic plant growth Tier II Aquatic plant growth (algal) Activated sludge, respiration inhibition
test Special Leaching Study Table 1 is a summary of the anticipated risk assessments and data needs for r egistration r eview. For data called in through the post

- RED DCI, see Table 7

.Page 10 of 56 Table 2

– Anticipated Registration Review Schedule
Anticipated Activity Target Date * Completion Date Phase 1: Opening the Docket Open Docket and 60

- Day Comment Period for Preli minary Work Plan 2014

- 03 2014

- 03

- 2 8 Close Public Comment Period 2014

- 05 Phase 2: Case Development Issue Final Work Plan 201 4

- 09 Issue Data Call

- In (DCI) 201 5

- 0 9 Receive Data to be Considered in Risk Assessment 201 9

- 0 9 Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 20 21

- 03 Close Public Comment Period 20 21

- 0 4 Phase 3: Registration Review Decision and Implementation Open 60

- Day Public Comment Period for Pro posed Decision 20 21

- 0 9 Close Public Comment Period 20 21

- 11 Issue Final Decision 202 2

- 03 Begin Post

- Decision Follow

- up 202 2 Total (years) 8

* The anticipated schedule will be revised as necessary ( e.g ., need ed schedule adjustments arising from data requirements in the formaldehyde registration review or under the Endocrine Disruptor Screening Program with respect to the active ingredients in this case).



## 1.2 Case Overview

The docket for a zadioxabicyclooctane ( c ase 3023 ) has been established at http://www.regulations.gov in docket number EPA

- HQ

- OPP

- 2 0 13

- 06 04

. 

## 1.3 Chemical Identification and Properties

As described in the Section 1 Introduction , a zadioxabicyclooctane is a formaldehyde releaser consist ing of a mixture of three chemic als in equilibrium in the product . E ach chemical component has an individual OPP Pesticide Chemical Code (PC Code) and is listed on the label

as a separate active ingredient , even though they occur as part of a mixture

. Table 3 presents the three components in the azadioxabicyclooctane chemical 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

- dioxabicyclo(3.3.0)octane (PC Code 107002 ) ; and 1H,3H,5H,

- Oxazolo(3,4

- c)oxazole, poly(oxymethylene) deriv ative (PC Code 107003 )

. For more information
on t he azadioxabicyclooctane product che mistry, see Appendix D.

The deg radates from the three azadioxabicyclooctane compounds without the formaldehyde (

- CH 2 O) moiety are as follows :

• C omponent I minus the formaldehyde (

– CH 2 O ) moiety becomes Component II

,

• Component II minus the

– CH 2 O becomes degradate II a

.

• 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 present has not been found in the records. The agencyPage 11 of 56 anticipates needing information about the polymer n distribution as well as about the rate of release for use in determin ing appropriate equivalent formaldehyde release levels and expo sure 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

- Hydroxymethoxymethyl

- 1

- aza

3,7

- 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) deriv ative 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 mole s 1 mole n = Data gap (n = 5 for the representative CAS Number)

n = number of repeating formaldehyde units in the polymer

.

I nternational Specialty Products (ISP) is the sole producer of a zadioxa bi cyclooctane under the name Nuo s ept 95 (Kline, 2004)

. The azadioxabicyclooctane product chemistry information ( MRIDs 42734301, 42740801, 41671601, 41671602, 41671603, 48691701, and mate rial safety data sheet ( MSDS ) for Nuosept 95 Technical ) relevant to risk assessment and environmental fate properties are summarized in Table 4. Data about individual component s are anticipated as being needed for exposure modeling and risk assessment.Page 12 of 56 T able 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 point:

- 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 Octanol

water 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 56 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 (atm

m 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

. NA = Not AvailablePage 14 of 56 

## 1.4 Use/Usage Description

1.4.1 Registrations

There are currently two products registered with azadioxabicyclooctane as the active ingredient; one is a manufacturing use product, EPA R eg . No. 1529

- 49, and one is an end

- use

- product , EPA Reg. No. 1529

- 28 . Both products contain 5

- Hydroxymethoxymethyl

- 1

- aza

- 3,7

- dio xabicyclo(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) deriv ative as the active ingredient. The percent a.i. , as shown on the label, for both is as follows: 28.8 percent for 5

- Hydroxymethoxymethyl

- 1

- aza

- 3,7

- dioxabicyclo(3

, 3

, 0)octane , 16 percent for 5

- Hydroxymethyl

1

- aza

- 3,7

- dioxabicyclo(3

, 3

, 0)octane , and 5.2 percent for 1H,3H,5H,

- Oxazolo(3,4

- c)oxazole, poly(oxymethylene) deriv ative

. 

### 1.4.2 Summary of Registered Uses

Table 5 presents a summary of the registered uses of a zadioxabicyclooctane that will be assessed in this registration review

. A zadioxabicyclooctane can be applied by the following application methods: open pour, brush/roller, and airless sprayer.

Table 5

– Summary of A zadioxabicyclooctane 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.



### 1.4.3 Usage Information

Azadioxa bi cyclooctane is registered for use to control slime forming bacteria and fungi at the following use sites: oil recovery drilling muds and packer fluids; industrial adh esives 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 200 5 Kline Report for az adioxa bi cyclooctane.Page 15 of 56 

## 1.5 Regulatory Histor y Azadioxabicyclooctane

The first pesticide product containing azadioxabicyclooctane was registered in October 1975. The registration and all data to support reregistration were transferred from Tenneco Chemicals on December 22, 1982 to Nuodex Inc. The Nuosept 95 product was purchased by International Specialty Products on March 26, 2002. The a gency completed a RED for a zadioxabicyclooctane in 2005. Three post

- RED Generic Data Call

- Ins ( G DCIs) 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 GDCI s , two hav e 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 status of data requirements, see Table 7

. Formaldehyde

EPA prepared a separate formal dehyde RED to address potential risks associated with non

azadioxabicyclooctane 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, b ackground regulatory history information is provided here for the reader’s conveni en ce. The first product containing formalde hyde was registered in the United States in1967, 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 processing plants as well as in citrus packing and

mus hroom houses. It is also registered for use as a hard surface disinfectant in commercial premises, industrial premises and veterinary clinics. Formaldehyde is also registered as a materials preservative for consumer products such as laundry detergents, gen eral purpose cleaners and wall paper adhesives.

The a gency identified the following confirmatory data requirements in the 2008 formaldehyde RED and anticipates issuing a post

- RED DCI: 90 Day Dermal Toxicity (GLN 870.3250), Developmental Toxicity in Non

- Rod ents (GLN 870.37000), and Acute Daphnia magna using formaldehyde (GLN 850.1010).



### 1.5.1 Recent/Pending Regulatory Actions There are no recent regulatory actions for azadioxabicyclooctane . EPA anticipates issuing a Registration Review DCI.



### 1.5.2 Tolerance Information

Fo r the active ingredient, t he EPA has no established tolerances or exemptions from tolerances in raw agricultural commodities or processed food and feed products under the Federal Food, Drug and Cosmetic Act (FFDCA) Section 408 for azadioxabicy c looctane

. 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 56 

## 1.6 Incidents

1.6.1 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.



### 1.6.2 Ecological

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


## 2 A nticipated Data Needs

Table 6 presents a summary of the data anticipated as being needed to support this registration review. Table 7 outlines the data requirements required by the post

- RED G DCI s issued on August 11, 2008

. 1 The a gency anticipates reviewing any data received in response to the post

RED DCI s as well as data that are requ ired for this registration review prior to conducting the registration review risk assessments for azadioxabicyclooctane

.

1 See Section 1.5 for a list of the GDCIs.Docket Number EPA

- HQ

- OPP

- 20 13

- 06 04 www.regulations.gov

Page 17 of 56 Table 6

– Studies Anticipated as Needed for the Registration Review of Azadioxabicyclooctane

GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Risk Assessment(s) Data Will Support Use Si te(s) Triggering Anticipated Data

Requirement Applicable Exposure Scenario

Studies Anticipated to be Required through the Registration Review DCI

835.1230 1 Adsorption

- desorption (Batch equilibrium) TGAI 24 Fate and persistence
assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Release into water

835.1240 1 Leaching

- adsorption

desorption TGAI 12 Fate and persistence
assessment Drilling Muds and Flooding Fluids, Textiles Oral exposure to drinking water and to aquatic organisms

835.2120 1 Hydrolysis TGAI 12 Fate and persistence
assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Release into water

835.2240 1 Aqueous p hotolysis TGAI 12 Fate and persistence
assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Release into water

835.3110 3 , 4
835.3220 835.3240 835.3280 Ready biodegradability or one of three biodegradation in activated sludge simulation tests TGAI 24 Fate and persistence in WWTPs Down the drain
assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Toxicity to WWTP organisms

835.4100 1 Aerobic Soil metabolism TGAI 24 Fate and persistence
assessment Paints, Material Preservatives, Textiles Release into water

835.4200 1 , 5 Anaerobic soil metabolism TGAI 12 Fate and persistence
assessment Paints, Material Preservatives, Textiles Release into waterPage 18 of 56 835.4300 1 Aqueous Aerobic metabolism TGAI 12 Fate and persistence
assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Release into water

850.1300 Aquatic invertebrate life

cycle TGAI, Degr 24 Ecological
assessment Paints, Material Preservatives, Drilling Muds, and Flooding Fluids Release into water

850.1400 Fish early life stage TGAI, Degr 24 Ecological
assessment Paints, Material Preservatives, Drilling Muds, and Flooding Fluids Release into water

850.4400 Aquatic plant growth (aquatic vascular plant) Tier II

- dose response TGAI, Degr 12 Ecological
assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Release into water

850.5400 8 Aquatic plant growth (algal) Tier II (dose response) TGAI, Degr 12 Ecological
assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Release into water

850.3300 3

, 6 or OECD 209 Activated sludge, respiration inhibition test TGAI, Degr 24 Fate and persistence in WWTPs Down the drain
assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Toxicity to WWTP organisms

870.3800 Reproduction and fertility effects TGAI 48 Human Health Assessment All use sites All exposure scenarios

870.7800 Immunotoxicity TGAI 12 Human Health Assessment All use sites 9 All exposure scenarios

875.1700 Product Use TEP 12 Occupational Handler Paints, Material Preservatives, Drilling Muds and Flooding Fluids Pour liquids Brush/Roller Airless Sprayer

875.2500 2 Inhalation Exposure TEP 24 Occupational and Residential Post

Application Paints PaintsPage 19 of 56 *Degradates for Table 6 are defined here as well as in Section 1.3: Component I minus formaldehyde (

– CH 2 O ) becomes or Component II

, Component II minus (

– CH 2 O ) becomes degradate II a , Component III degradates are unknown and are considered data gaps. Degr = Degradates TEP = Typical end

- use product TGAI = Technical grade of the active ingredient
1 T he half

- life of all major degradates also needs to be determined , e.g., Component II, degradate IIa, unknown degradates for Component III

. 2 A small chamber study is anticipated to be needed

. P ost

- application inhalation data are anticipated as needed to assess the exposures of formaldehyde in paint.
3 The anticipated data requirement for degradates could be wa i ved in cases where the degradates are less toxic than the parent compound.
4 The results of the ASRI test will determine which of these four biodegradation tests is/are anticipated to be required. If th e ASRI test EC 50 is less than or equal to 20 mg/L, th en either the (i)Biodegradation in Activated Sludge Study or (ii) Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units or (iii) the Porous Pot Test is expected to be required. If the ASRI test EC 50 is greater than 20 mg/L, then the registr ant would likely be required to conduct either: (i) Ready Biodegradability or (ii) a) Biodegradation in Activated Sludge or b) Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units or c) the Porous Pot Test. If the Ready Biodegradability st udy is conducted and passes, then no further testing would be expected to be required. If, however, the antimicrobial 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.
5 Data are expected to be conditionally required based on a weight

- of

- evidence evaluation of the results of the hydrolysis, photodegradation in water, biodegradability, and acti vated sludge, respiration inhibition tests. 6 For degradates, the agency anticipates requiring data only for degradate II a

. EPA published draft guidance under guideline 850.6800 and has since published final guidance for this study under guideline 850.3300 : http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0154

- 0021 . OECD Test Guideline 209 can also be used as guidance for this study, available online at http://www.oecd

- ilibrary.org/content/book/9789264070080

- en

. 7 The anticipated DCI will pro vide that the s tudy must include measure of formaldehyde released.
8 For industrial processes and water systems, Tier II (dose response) studies are anticipated to be required on four species ( Anabaena flos

- aquae, Navicula pelliculosa, Skeletonema costatum, and Selenastrum capricornutum ).
9 All use sites listed in Table 5.

Table 7

– Data Need s Required by the Data Call

- In for the Azadioxabicyclooctane RED

GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Risk Assessment(s) Data Will Support Use Site(s) Triggering Anticipated Data

Requirement Applicable Exposure Scenario

870.2600 Skin sensitization Data requirement is satisfied

. 870.3465 90 Day Inhalation Toxicity Data requirement is satisfied

. 875.2700 Product Use TEP 12 Occupational Post

Application Paints Paints

Special Study 3 ,7 Leaching from Paint, Adhesives, Caulks, Textiles Degr 24 Down the Drain Paints, Adhesives, Caulks, Textiles Release into waterPage 20 of 56 GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Risk Assessment(s) Data Will Support Use Site(s) Triggering Anticipated Data

Requirement Applicable Exposure Scenario

870.4200 Carcinogenicty Waiver request pending.

875.1200 1

, 2 Indoor Dermal Exposure TGAI 24 Occupational and Residential Handler All uses Pour liquids Brush/Roller Airless Sprayer

875.1400 1

, 2 Indoor Inhalation Exposure TGAI 24 Occupational and Residential Handler All uses Pour liquids Brush/Roller Airless Sprayer

875.1600 2 Application exposure monitoring data reporting TGAI 24 Occupational Handler Paints Pour liquids Brush/Roller Airless Sprayer

875.2800 2 Description of Human Activity TGAI 24 Post

- application Paints Metal working Fluids

TGAI= technical grade of the active ingredient.

1 It may be possible to use proprietary surrogate exposure data if data compensation issues are appropriately and adequately ad dressed.
2 According to the existing data call

- in, the registrant is a member of the Antimicrobial Exposure Assessment Task Force II (AEATF). AEATF will be conducting exposure studies for liquid pour, brush/roller, and airless sprayer applications, as well as numerous other applicati on methods, and these data will be submitted as required under the DCI

.Docket Number EPA

- HQ

- OPP

- 20 13

- 06 04 www.regulations.gov

Page 21 of 56 

## 3 Human Health Risk Assessment

A zadioxabicyclooctane is a formaldehyde releaser. This registration review case only addresses potential exposure to formaldehyde in the occupational and residential post

- application risk assessments, resulting from the volatilization of formaldehyde from indoor exposure to surfaces painted with products containing azadioxabicyclooctane

. T his registration review case does not address possible risks from formaldehyde derived from azadioxabicyclooctane for the other areas identified for risk assessment listed in Table 1 . When the formaldehyde registration re view case is at the stage in which a risk assessment is conducted, any other risks identified in Table 1 from formaldehyde derived from the use s of azadioxabicyclooctane will be considered at that time

.
The a gency anticipates the need to conduct a human he alth risk assessment for

a zadioxabicy c looctane. The a gency anticipates new exposure data from the RED data call

- in and expects to require additional exposure data to conduct new assessments for registration review to assess the volatilization of formaldeh yde from indoor exposure to painted surfaces. Additionally, t he agency anticipates the need to require additional toxicology data (reproduction and fertility effects, and immunotoxicity studies) to support the human health risk assessment for all use patte rns of antimicrobial pesticide chemicals , 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 information including new and existing toxicology studies, valid scient ific literature, and the studies that are expected to be required for registration review will be considered in establishing the endpoints to be used in the registration review risk assessment. A detailed description of the toxicity studies is provided in Appendix A

. 

## 3.1 Existing Toxicological Endpoints

The Antimicrobials Division’s Toxicity Endpoint Selection Committee (ADTC) reviewed the available toxicology data for azadioxabicyclooctane and selected endpoints to conduct occupational and residential risk assessments for the registration eligibility decision ( RED, 200 5 ). In addition, increased sensitivity of infants and children potentially exposed to azadioxabicyclo octane was assessed by the Committee in order to meet the statutory requirements of the Food Quality Protection Act (FQPA) of 1996.

Although there was no evidence of special sensitivity to infants and children, the ADTC recommended that the special 10x haz ard

- based safety factor under the FQPA be re tain ed (1 0 x) for a zadioxabicyclooctane. There is a limited developmental and reproductive toxicology data base for azadioxabicyclooctane: one prenatal dermal developmenta l toxicity study in rats and no reproduct ion and fertility effects study or information. 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 rout e. Consequently, the 10x FQPA hazard

- based safety factor was utilized in the human health risk assessment conducted for the 2005 azadioxabicyclooctane RED to account for this uncertainty as well as the absence of a reproductive toxicity study (US EPA, 200 5 b)

. A reproductive and fertility effects study is anticipated to be required in registration review due to the currently labeled indirect food use s

.Page 22 of 56 Following issuance of the post

- RED DCI, several toxicity studies identified as data gaps for azadioxabic yclooctane were submitted to the a gency; a skin sensitization assay (870.2600) and a subchronic inhalation toxicity study (870.3465). These data have been reviewed and classified 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 currently selected for inhalation risk assessments. Under registration review, a re

- evalu ation of selected toxicological dose, endpoint and uncertainty factors for inhalation risk assessment is required (Table 8 ).

Table 8

– Existing Tox i cological Endpoints

Table 8 . Summary of Toxicological Dose/ Endpoint 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 inter

species 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

- D ay O ral T oxicity in R ats (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 inter

species 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 56 Table 8 . Summary of Toxicological Dose/ Endpoint 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 inter

species 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 R ats (MRID 41641606)

LOAEL = 56.5 mg/kg/day based

on decreased water consumption at in males.

Incidental Oral Short

- Term, Intermediate

Term (1

- 30 days, 30 days

- 6 months) No endpoint is required based on the use patterns for pesticide products containing azadioxabicyclooctane.

Dermal (all durations) Short

- Term, Intermediate

Term, Long

Term (1

- 30 days, 30 days

- 6 months, > 6 months) LOAEL(dermal) = 100 mg/kg/day Target MOE (ST/IT occupational) = 300 (10x inter

- species extrapolation, 10x intra

species variation, 3x lack of a NOAEL)

Target MOE (LT occupational) = 3000 (10x inter

- species extrapolation, 10x intra

species variation, 10x extrapolation from an oral endpoint, 3x lack of a NOAEL) C o

- 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 56 Table 8 . Summary of Toxicological Dose/ Endpoint 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, Intermediate

Term, Long

Term (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

- species extrapolation, 10x intra

species 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, LOC = level of concern, NA = n ot a pplicable

a The availability of a n acceptable route

- specific inhalation toxicity study for azadioxabicyclooctane requires a re

evaluation of toxicological dose, endpoint and uncertainty factors for inhalation ri sk assessments.



## 3.2 Dietary Exposure

3.2.1 Food The only approved uses of azadioxabicyc l ooctane 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 azadi o xabicyclooctane

were summariz ed in the 2005 RED. The treatment rate was 2500 ppm active ingredient in the adhesive and the coati ng 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

a PAD 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 children. Dietary risks may need to be reassessed if there is a change in the acute or chronic dietary endpoint and/or if aggregate risks exceed the

a gency’s levels of concern. No residue chemistry data are expected to be needed at this time to characterize residues of az a dioxabicyclooctane in food

.


### 3.2.2 Drinking Water A drinking water assessment has not been conducted for azadi oxabicyc l ooctane i n the past. There are no direct aquatic uses of azadioxabicyc l ooctane . However, several approved uses as a material preservative are likely to result in azadioxabicyc l ooctane being discharg ed in waste water or leached from preserved materials and subsequently running off into surface water. These are uses as a preservative of drilling muds, flooding fluids, latex paints, sealants, and metalworking fluids. Since the residues of concern in drinking water have y et to be determined (i.e., azadioxabicyc l ooctane and/or its biotic or abiotic product s), the magnitude of the potential residues in drinking water, their mammalian toxicities, how persistent they will be, and if they are likely to pass through a wastewater treatment plant (WWTP) is unknown . Therefore, the

a gency anticipates needing certain environmental fate data listed in Section 4 of this PWP . ThesePage 25 of 56 data will be useful to determine whether, and to what extent, residues of azadioxabicyc l ooctane pass throug h a WWTP. T hese data will be used during the risk assessment stage to determine the potential for discharged or leached residues of azadioxabicyc l ooctane to result in human dietary exposure via drinking water which may trigger a drinking water assessment. No residue chemistry data are expected to be needed at this time to characterize residues of azadioxabicyc l ooctane in drinking water.



## 3.3 Occupational and Residential Exposures

The a gency anticipates the need to revise the occupational and residential assessments conducted in support of the 2005 RED based on receipt of new exposure and toxicity data . Uses of

a zadiox a bicy c looctane that may result in occupational and residential scenario s are identified in Table s 9 and 10 below.



### 3.3.1 Occupational Handler Expo sure EPA anticipates the need to revise the occupational handler assessment conducted in support of the 2005 RED. Occupational handler dermal and inhalation exposures to a zadioxabicyclooctane were assessed in the 2005 RED for applications using brush/rolle r, and airless sprayer applications and mixing /loading via the liquid pump and pour liquid scenario for the registered uses specified in Table 5 . These exposures were assessed using unit exposure data from the Pesticide Handler Exposure Database (PHED) an d Chemical Manufacturer’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. EPA anticipates the need to revise the occupational handler assessment conducted in sup port of the 2005 RED with the AEATF data.

All of the handler scenarios listed in Table 9 will need to be revised during registration review upon receipt of the new unit exposure data. The a gency will also need to address occupational post

- application exposures to the 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 Dermal and Inhalation Short and Intermediate

- Term Liquid Pour for Drilling Muds and Flooding Fluids Dermal and Inhalation Short and Intermediate

- Term Liquid Pour for a Material Preservative Slurries 2 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 scenarios in registration review . The paper coating scenario which was speci fi ed in the RED as a metered pump system will not be assessed

. In addition metalworking systems are specified in the l abels as an enclosed system , an occupational handler risk assessment is also not required for this scenario

.Page 26 of 56 2 Includes adhesives (natural

- based or synthetic), caulks, latex emulsions, wax emulsions, inks, pigment dispersions, pigment slurries, sealants,

a nd textile fiber finishes. 

### 3.3.2 Occupational Post

- Application Exposures

The 2005 RED assessed the dermal and inhalation 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. In the 2005 RED, the dermal exposure estimates were derived using the 2

- hand immersion model from ChemSTEER. The model is available at www.epa.gov/opptintr/exposure/docs/chemsteer.htm

. The screening

- level inhalation exposure estimate for treated metalworking fluids w as developed using the OSHA PEL for oil mist. The agenc y does not anticipate the need to conduct another assessment since the metalworking fluid uses are fully enclosed.

According to the 2005 RED, the inhalation MOEs for the metal working fluids were above the target MOE of 3,000. Dermal risks were also assess ed assuming that the worker fully immerses both hands into the already treated fluid, and the MOEs were compared to the target LT MOE of 1,000. Using the 2

- hand immersion model, at an application rate of 0.3% (0.15% a.i.), the der mal MOE was 540 and exceed the a gency’s level of concern. As a result of the 2005 RED, the registrant agreed to reduce the application rate to 0.2% and agreed to fully enclosed metalworking fluids . The reduced rates and updated mitigation language for the metalworking fluids are cu rrently reflected on the existing labels

.

The a gency anticipates the need to conduct a post

- application inhalation assessment to examine the potential formaldehyde vapor exposures for professional painters inhaling formaldehyde
vapors

. As such, formaldeh yde monitoring data are anticipated as needed to assess th i s post

application exposure scenario (e.g., small air chamber tests)

. 

### 3.3.3 Residential Handler Exposures

EPA conducted a residential painter assessment for the RED in 2005. The calculated risks for the brush/roller application were not at a level of concern. However the calculate d risks (e.g., dermal MOE=236) for the airless sprayer were a t a potential risk of concern because they were below the target MOE of 300 . As a result, the RED specified that the maximum diluted concentrations of active ingredient in paint should be reduced to 0.4% a.i. These reduced rates are currently reflected on the existing labels. An additional assessment is needed due to the expected submission of new dermal and inhalation exposure surrogate data for paint

, required by the post

RED 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 TermPage 27 of 56 

### 3.3.4 Residential Post

- Application Exposures

EPA anticipates the need to revise the residential post

- application assessment conducted in support of the 2005 RED. Residential post

- application exposures could result when bystanders (adults and children) inhale volatilized formaldehyde release d from treated paint (e.g., treated hard surfaces/ walls )

. Table 1 1 lists the residential post

- application scenarios. The agency anticipates the need to require additional inhalation exposure data.

Table 11

– Residential Post

- Application Exposure Scenarios for Formaldehyde Released from Azadioxabicyc l ooctane Treated Paint

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



## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures In examining aggregate exposure for azadioxabicyclooctane, 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 a gency will determine the need for a new aggregate assessment once the a gency has identified the toxicological endpoints for each route of exposure. If the toxicological endpoints change, the a gency will develop a new aggregate exposure assessment. In addition, the a gency may need to conduct a new aggregate risk assessment if the a gency determines the need for a new drinking water exposure assessment. If drinking water exposure is added then the a gency would need to consider aggregating drinking water with the existin g food exposure from indirect dietary exposures from residue found in paper coatings and adhesives. The a gency does not anticipate the need to aggregate residential exposures (handler or post

- application exposures to paint) with dietary and/or drinking wat er exposures since the toxicological endpoints and effects for the dermal and inhalation routes of exposure are anticipated to be different from the oral exposure route.

Residential bystander inhalation exposures for formaldehyde will be assessed in regist ration review. However, the agency anticipates that the aggregate assessment for formaldehyde will be complicated by the fact that formaldehyde is released from a variety of other sources (such as pressed wood and oxygenated fuels).



### 3.4.2 Cumulative Exposures

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to azadioxabicyclooctane and any other su bstances. For the purposes of this registration review , therefore, EPA has not assumed thatPage 28 of 56 azadioxabicyclooctane has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common m echanism of toxicity and to evaluate the cumulative effects of such chemicals, see http://www.epa.gov/pesticides/cumulative/

. 

## 4 Environmental Risk Assessment

T his registration review case does not addre ss possible risks from formaldehyde for the environmental risk assessment . When the formaldehyde registration review case is at the stage in which a risk assessment is conducted, the agency anticipates focusing on formaldehyde and degradates of formaldehyd e derived from the use s of azadioxabicyclooctane

.

The a gency 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 ass essment of the industrial uses and processes will be conducted during the future risk assessment of azadi o xabicyclooctane . This would include modeling of exposure scenarios that were not considered when the original assessment was conducted. The ecologic al risk assessment planned during registration review will allow the

a gency to determine potential acute and chronic risks to aquatic organisms exposed to azadioxabicyclooctane that are transported from treatment sites into the aquatic environment

. Aquati c organisms could be exposed to azadioxabicyclooctane

. E xposure 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 resul t in parent chemical and/or degradate releases. The risk assessment also will allow the a gency to determine whether each use of the azadioxabicyclooctane has 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or their designated critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a listed species or its designated critical habitat, the

a gency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Serv ices (the Services), as appropriate.



## 4.1 Environmental Fate Assessment
The unique mixture of three components in this mixture is not separable, and the exposure f r om this active in various environmental media are due to the three components. The a gency has no environmental fate data on the degradates ; please 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 down the drain screen was conducted for azadioxabicyclooctane. The results indicate that if everything leached out of consumer products (e.g., paint, texti les, etc) and went down

- the

- drain, there would be no risk. S till

, the a gencyPage 29 of 56 anticipates the need to require leaching data for the azadioxabicyclooctane degradates as there

are no data for the degradates.



### 4.1.2 Water and Sediment

The three co mponents are highly water solub l e (miscible in all proportions with water ). Since t he 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 parti ti ons in to aqueous med i um. The components are not expected to partition fr o m water into sediments

.


### 4.1.3 Soil The three components are highly water soluble (miscible 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 f r om water into soils

.


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



### 4.1.5 W astewater T rea t ment P lant (WWTP) There are not enough data for asse ss ment of azadioxabicyclooctane and its degrad at es . For a list of anticipated and al r eady imposed data requirements, see T able s 6 and 7

.


### 4.1.6 Water Quality

A zadioxabicyclooctane 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 az a dioxabicyclooctane compounds

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

. 4



## 4.2 Conceptual Model s for Environmental 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 industrial wastewater treatment plants. A quatic organisms in surface water downstream of both direct and indirect sources of azadioxabicyclo octane c ould be expected to be exposed to azadioxabicyclooctane and any degradates

.

2 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885
3 http://iaspub.e pa.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 56 The screening

- level risk assessment that will be conducted as part of t his registration review w ill evaluate potent ial risks to ecological organisms from exposure to azadio xabicyclooctane

. 

## 4.3 Ecological Effects Assessment

Aza dioxabicyclooctane is a mixture of three similar compounds used as a materials preservative in latex paints, latex emulsions, pigment dispersions, inks, adhesives, construction materials, metalworking fluids, textile fiber

- finish solutions, pulp and paper, and oil 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

- dioxabicyclo(3.3.0)octane; B: 5

- hydroxymethyl

- 1

- aza

3,7

- dioxabicyclo (3.3.0) octane; and C: 5

- hydroxypoly(methyleneoxy)methyl

- 1

- aza

- 3,7

- dioxabicyclooctane.

Azadioxabicyclooctane is a formaldehyde releaser. T his registration review case does not address possible risks from formaldehyde derived from azadioxabicyclooctane for the environmental risk assessment

. In the formaldehyde risk assessment phase of the formaldehyde registration review case

, the agency will review o pen literature concerning the toxicity of formaldehy d e to non

- target organism s and determine if any formaldehyde studies can be used to evaluate formaldehyde risks derived from the use s of azadioxabicyclooctane

. The ecological data summarized in this registration review was conducted on the product Nuosept® 95. The percentages of the three octanes in the formulation varied slightly in the submitted studies; ratios a re listed in the tables, where information was available. The EPA’s ECOTOX database (EPA, 2002) was also searched for avian, fish, invertebrate, mammalian and plant data on the components of azadioxabicyclooctane , but no data were found.

Under abiotic con ditions, the mixture of these acetals is hydrolytically unstable with half

- lives of 0.347 days at pH 5, 1.74 days at pH 7 and approximately 15 days at pH 9. It is, therefore, not likely to be persistent in water. Components I and II of the mixture are lik ely 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 chain of CH2O groups are added into the structure. Estimated half lives in the atmosphere for com ponents I and II are 1.2 and 1.4 hours. Hence, these two chemicals are not likely to persist in the atmosphere (RED, 2005)

.
The e stimated log K ow of components I and II are respectively are

- 2.23 and

- 1.55 (very highly miscible in water and show no tendency for dissolving organic solvents); therefore, the mixture is not likely to bioaccumulate in aquatic organisms (RED, 2005)

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

.
The uses of a za dioxabicyclooctane a re 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)

.Page 31 of 56 Chronic toxicity testing for freshwater organis ms is anticipated to be required for the currently registered uses of a za dioxabicyclooctane . 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 expected to be required . The ECOTOX database (EPA, 2002) was searched for any appropriate chronic testing with fish or invertebrates, but no such data were located.

Chronic toxicity testing for marine/estuarine organisms is not an ticipated to be required for th e currently registered uses of a za dioxabicyclooctane (see Appendix C)

.


### 4.3.1 Mode of Action

Aza dioxabicyclooctane is highly solu ble in water. Aquatic organisms would be exposed to the chemical when a za dioxabicyclooctane enters the aquatic environment after industrial discharge and after disposal down the drain (RED, 2005)

.


### 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aquatic and terrestrial organisms. All a vailable ecotoxicity endpoints in the a gency’s files from chemical studies submitted by registrants or other interested parties, federal laboratory data, or from the public literature are tabulated in Appendix C along with the anticipated data requirements and data gaps. The most sensitive values for each receptor group are used for the risk assessment ( Table 12 ). These 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 Effects Endpoints for Risk Assessment of A zadioxabicyclooctane

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 > 10,00 0 ppm

- diet ACC 248878 Chronic Data not anticipated to be required

Mammals Acute Oral LD 50 = 1940 mg/kg

- bw 41641601 Subc hronic dietary NOEL = 10.6 mg a.i./kg

- bw 41641606

Freshwater fish Bluegill sunfish Acute 96

- h LC 50 = 3 4.7 m g a.i./L 48082403

Chronic Data Gap: data anticipated to be required

Freshwater invertebrates Waterflea Acute 48

- h EC 50 = 35 m g/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 m g ai/L ACC 250533

Chronic Data not anticipated to be required due to low acute toxicity --Page 32 of 56 Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID)

Estuarine/marine invertebrates Eastern o yster ( embryo larval ) Acute E C 50 = 42 m g 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 separately in the formaldehyde registration review case.


## 4.4 Exposure Analysis Plan

Available OPP models will be used to determine the estimated environmental concentration (EECs) in the aquatic environment. Resulting exposure estimates will be compared to the toxicity endpoints to determine if levels of concern are exceeded for each receptor group. Based on registered uses of azadioxabicyclooctane in Table 5 of this PWP, there are some use s , such as drilling mud, flooding fluids, metalworking fluids

, and textile finishing for which discharges may enter industrial WWTPs rather than domestic WWTPs prio r to entering surface
water. The Industrial Releases Module of the E

- FAST 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 azadioxabicycloocta ne to be exposed this chemical or their degradates. 

## 4.5 Effects Analysis Plan
Toxicity data presented in this work plan will be used to calculate risk quotients and/or calculate COCs

. Any additional information submitted by the registrant(s), other interes ted parties or found in the open literature prior to conduct of the risk assessment will also be considered. The open literature studies will be identified using EPA’s ECOTOXicology (ECOTOX) 5 database

, which employs a literature search engine for locating chemical toxicity data for aquatic life,
te rrestrial plants, and wildlife. The ECOTOX database will be searched when the risk assessment for azadioxabicyclooctane is prepared. The evaluation 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 searched during the risk assessment phase of

5 http://cfpub.epa.go v/ecotoxPage 33 of 56 azadioxabicyclooctane and the data reviewed following the a gency’s policy for reviewing public literature for use in assessing risks from pesticide s

. 6 Those ecotoxicity values found in the public literature to be more sensitive than those currently in Table 12 and / or which satisfy an existing data gap(s) will be used during the risk assessment phase of azadioxabicyclooctane to update Table 12 . ECOTOX was created and is maintained by the USEPA, Office of Research and Development, and the National Health and Environmental Effects Research Laboratory's Mid

- Continent Ecology Division.


## 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of 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 endocri ne screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect prod uced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to i dentify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems wil l proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establi sh a dose

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

Under FFDCA section 408(p), the a gency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 7 and includes some pesticides scheduled for registration review and chemicals found i n water

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

6 http://www.epa.gov/pesticides/science/literature

- studies.html
7 See http://w ww.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.Page 34 of 56 For further information on the status of the EDSP, the policies and procedures, the list of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website

. 8



## 6 Optional Label Changes

The a gency invites comment on any label amendments that could be considered to eliminate the anticipated need for EPA to require certain data, reduce the possibility that EPA’s planned r isk assessments overestimate risk due to reliance on conservative assumptions, and/or improve label clarity.


## 7 Guidance for Commenters

7.1 Preliminary Work Plan
The public is invited to comment on EPA’s Preliminary Work Plan and rationale. The a gency will carefu lly consider all comments as well as any additional information or data provided in a timely manner prior to issuing a final work plan for the azadioxabicyclooctane registration review case.



### 7.1.1 Trade Irritants Through the re gistration review process, the a gency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The a gency will work to harmonize tolerances and international maximum residue limits (MRLs) and may modify tolerance l evels to do so, when possible. Stakeholders are asked to comment on any trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the nature of the concern.



### 7.1.2 Water Quality

The a gency invites submission of water quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Bo dy and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 9 in order to ensure they can be used quantitatively or qualitatively in pesticide risk assessments.



### 7.1.3 Environmental Justice

EPA seeks to achieve environmenta l justice, the fair treatment and meaningful involvement of all people, regardless of race, color, national origin, or income, in the development, implementation, and enforcement of environmental laws, regulations, and policies. To help address potential

e nv ironmental justice issues, the a gency seeks information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have

8 http://www.epa.gov/endo/
9 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htmPage 35 of 56 atypical, unusually high exposure to aza dioxabicyclooctane compared to the general population. Please comment if you are aware of any sub

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



### 7.1.4 Structure Activity Relationships EPA must rely upon information of appropriate quality and r eliability for each decision made by the a gency. In the OPP, the evaluation process for a pesticide chemical traditionally begins with the applicant’s submission of a set of studies conducted with the specific pesticide chemical of interest. The use of the results of such testing (measured data) is a logical, scientifically rigorous process that identifies the physical, chemical, and environmental fate properties of the pesticide, as well as the dose and endpoints at which an adverse effect can occur in var ious animal species.

Today, there is significant interest in alternative techniques, i.e., techniques other than data generation that could significantly inform the a gency’s decision

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

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

Since SAR assessments and QSAR modeling are another set of t ools that are available to a gency scientists, OPP has begun a process shift that envisions shifting from the current study

- by

- study approach to an approach in which the use of predicted data, generated using validated models, is considered along with infor mation from open literature and studies specifically generated under Part 161 requirements. All relevant information would be considered as part of a weight

- of

- the

evidence evaluation.

At this time, EPA believes that for certain endpoints, especially phys ical/chemical and fate properties, that SAR and QSAR might be effectively utilized to fulfill these data requirements for many antimicrobial pesticide chemicals. When considering biological properties, at this time, EPA believes that SAR and QSAR can be mo st effectively utilized in the evaluation of chemicals that exhibit lower toxicity for human health and/or ecotoxicity parameters. This is appropriate because the risk assessment for lower toxicity chemicals can be stream

- lined, i.e., a screening

- level ass essment procedure rather than multiple tiers of assessments with progressively more data requirements.

If stakeholders believe that submission of predicted data can fulfill one of the data needs for the A zadioxabicyclooctane Case, then the a gency invites submission of this information. The submitter would be expected to supply a rationale describing the utility of the information and provide documentation on the scientific validity of the information. The determination that the predicted data fulfills the data requirement would be at the sole discretion of the a gency. Pre

su bmission consultation with the a gency is encouraged.Page 36 of 56 

### 7.1.5 Additional Information

Stakeholders are also specifically asked to provide available information and data that will assist the a gency in refining its risk assessments, including any species

- specific ecologic al effects determinations. The a gency is interested in receiving the following information:

1. Confirmation on the following label information: A. Sites of application B. Formulations C. Application methods and equipment D. Maximum application rates E. Frequency of application, application intervals and maximum number of applications F. Geographic limitations on use 2. Use or potential use distribution 3. Use history 4. Usage/use information for non

- agricultural uses (e.g., materials preservation) 5. Typical application interval 6. State or local use restrictions 7. Ecological incidents (non

- target plant damage and avian, fish, reptilian, amphibian and mammalian mortalitie s) not already reported to the a ge ncy 8. Monitoring data



## 8 Next Steps

After the 60

- day comment period closes in May, 2014 , the a gency will review and respond to any comments received in a timely manner, and then issue a Final Work Plan for the

a zadioxabicyclooctane c ase.Page 37 of 56 

## 9 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. Midwest 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). R eformat of 00109245

. Final Report: Effect of Nuosept 95 in Rats 90

- Day Toxicity Study

- Contains 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). Huntingdon Research Centre Ltd.

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 following 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). Measurement of unscheduled DNA synthesis in male Fischer

- 344 rat hepatocytes following in vivo treatment with Nuose pt 95. SRI International.

93050017 (MRID#, R eformat of 00088956 ) Anonymous (1979)

. Salmonella /mammalian

microsome plate incorporation mutagenesis assay. An Evaluation of Carcinogenic Potential of NUOSEPT® 95 Employing the C3H/10T1⁄2 Cell Transformation Assa y. EG&G Mason Research Institute.

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

93050019 (MRID# , R eformat of 00088957 )

. Anonymous (1979). Bacterial DNA damage/repair suspension assay. EG&G Mason Research Institute.

93050020 (MRID# , R eformat of 00088958 ) Anonymous (1979). Bacterial DNA repair assay. Midwest Research Institute.Page 38 of 56 93050021 (MRID# , R eformat of 00088959 )

. Anonymous (1980). Evaluation of Nuos ept ® 95 in the primary rat hepatocyte unscheduled DNA synthesis assay. Litton Bionetics, Inc.

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

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

9305 0024 (MRID# , R eformat of 00088962 ) Thilagar, A., et al. (1980). An Evaluation of Carcinogenic Potential of R

- 1162 (NUOSEPT® 95) Employing the C3H/10T1⁄2 Cell Transformation System. EG&G Mason Research Institute.

93050025 (MRID# , R eformat of 00088963 ) Thilaga r, 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# , R eformat of 00088953 ) Anonymous (1 979). Dominant lethal study of Nuosept 95. SR I International.

US EPA. (2005) Azadioxabicyclooctan e

- Report of the Antimicrobial Division Toxicology Endpoint Selection Com mittee (Memorandum: T. McMahon and M. Centra, April 20, 2005)

US EPA. (2005 a ) Reregistration Eligibility Decision for Azadioxabicyclooctane. EPA 739

- R

- 05

- 0110, September 2005.

US EPA. (2005b) Reregistration Eligibility Decision for Azadioxabicyclooctan e. 2005.

US EPA. (2012a) Nuosept ® 95: Evaluation of Mammalian Toxicology Data in Support of Registration of Pesticide Products. D399374 (Memorandum: 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 (Me morandum: 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. Wo rmell, November 20, 2012).

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

41641606 reformat of 00109245 (MRID #): Sasmore, DP. (19 80). Final Report: Effect of Nuosept 95 in Rats 90

- Day Toxicity Study

- Contains dose range study for Dominant Lethal Study (OPPTS 870.3100). SRI International.Page 39 of 56 41671801 (MRID #): Liggett, M.P. and L.A. McRae. (1990). Acute dermal toxicity to rabbits of Nu osept 95 (Final report). Huntingdon Research Centre Ltd.

MRID 41684801. 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.

MRID#48082403. 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 Wildlife International, Ltd., Easton, Maryland, USA. Lab oratory project number 633A

- 106. Study sponsored by International Specialty Products. Sponsor study number 2006

- 061. Study initiated 01 November 2007. Study completed 10 September 2008.

MRID#48082404. M inderhout, T., Kenal, T.Z., Krug er, H.O. 2008. Nuos ept 95: A 48 Hour Static Renewal Acute Toxicity Test with the Cladoceran (Daphnia magna) . An unpublished study performed by Wildlife International, Ltd., Easton, Maryland, USA. Laboratory project number 633A

- 105. Study sponsored by International Specialty P roducts, Wayne, New Jersey, USA. Sponsor study number 2006

- 061. Study initiated 26 October 2007. Study completed 10 September 2008.

ACC#250533. Ward, G. S. 1983. Acute Toxicity of Nuosept 95 to Embryo

- larvae of Eastern oysters ( Crassostrea virginica ). Unpublished data. Conducted by EG&G Bionomics for Nuodex, Inc.

ACC#247878. Truslow Farms, Inc. 1974. Eight

- day Dietary LC50

- Bobwhite quail Nuosept 95. Unpublished data. Conducted by Truslow Farms, Inc., for Tenneco Chemicals.

ACC#247878. Eight

- day Dietary LC50

- Mallard duck Nuosept 95. Unpublished data. Conducted by Truslow Farms, Inc., for Tenneco Chemicals.

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

ACC#250533. Acute Toxicity of Nuosept 95 to Mysid Shrimp ( Mysidopsis bahia ). Unpublis hed 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 Toxicity 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.

U.S. Environmental Protection Agency (EPA). 2002. ECOTOX User Guide: ECOT OXicology Database System. Version 3.0. Available: http://www.epa.gov/ecotox/Page 40 of 56 Kline, 200 5 . Specialty Biocide North America 2004

- 2005 , Kline and Company, Inc

Petrie, R.C. 2008. Ecological Hazard and Environmental Risk Assessment Chapter Formaldehye, Para formaldehyde. Reregistration Eligibility Document (RED). USEPA.Page 41 of 56 

# Appendix A T oxicology Profile

Acute Toxicity for Product Labeling

Azadioxabicyclooctane has a moderate order of acute 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). Azadioxabicyclooctane produces severe irritation to the eyes (Toxicity Category I ), moderate irritation to the skin (Toxicity Category III) and is a dermal sens itizer

. A cute toxicity data for a zadioxabicyclooctane are summarized below in Table 1 3

.

Table 13

– Acute Toxicity Studies for A zadioxabicyclooctane (Nuosept ® 95; 50% a.i.)

Table 1 3 . 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 5 0 = 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 a zadioxabicyclooctane include a 90

- day oral toxicity study in the rat, a 90

- day inhalation toxicity study in the rat, a 21

- day dermal toxicity study in the rabbit, and a dermal prenatal developmental toxicity study in the rat.

In a 90

- day oral toxicity study (MRID 41641606 reformat of 00109245 , supplemental information 410801 010 ), Nuosept ® 95 was administered to 20 CD1 Sprague

- Dawley derivedPage 42 of 56 rats/sex/dose in drinking water at dose levels of 0, 1 25, 625, or 3125 pp m (equivalent to 0, 20, 100, or 500 mg/kg bw/day; actual intake reported was 0, 13, 62, and 245 mg/kg/day). Four

r ats/sex/group were kept for a 4

- week recovery period to determine reversibility of effects. No signs of toxicity due to Nuosept 95 treatment were noted in mortality, clinical observations, hematology, clinical chemistry, ophthalmology, gross pathology, or histopathology. Body weight and body weight gain were lower in high

- dose males and females compared to their respective controls. Although food consumption was reduced in the intermediate and high

- dose groups in both males and females, the food efficien cy 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 concentration 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 females. 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 A cceptable / Non

- g uideline

. 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 establishme nt of a NOEAEL/LOAEL, with application of additional uncertainty factors for risk
assessment.

In a 21

- day dermal toxicity study (MRID 41641605), Nuosept ® 95/Nuosept ® C was administered directly to the skin of New Zealand White rabbits (5/sex/group) at do ses of 0, 100, 300, and 1000 mg/kg/day, 6 hours/day for 5 days/week during a 21

- day period. No treatment

related effects on clinical observations 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 treatment

related. Extensive damage to the treated skin was observed in all of the rabbits in the high

- dose group. Numerous microscopic changes 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 dermal 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 than or equal to 1000 mg/kg/day and the LOAEL is greater than 1000 mg/kg/day (not established)

. This 21

- day dermal toxicity study in the rabbit is cl assified A cceptable /Non

- guideline

. In a subchronic inhalation toxicity study (MRID 48082402), Nuosept 95 was administered to WIST(SPF) rats, 10/sex/dose [main study] or 10/sex/dose (control and high dose only) [recovery grou] by nose

- only exposure at targ eted 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 measured concentrations of test material were 0.009, 0.051, and 0.433/0.279 mg/L. The high dose concentration of 0.5 mg/L was reduced to 0.3 mg/L was reduced to 0.3 mg/L after 10 weeks of exposure due to excessive toxicity. Toxicity was observed at the 0.5/0.3 mg/L dose level. This consisted of increased mortality in males and females, significant reductions in body weight gain (55% of control in males, 72% of control in females after 13 weeks), decreased partial thromboplastin time in males and females (14% in males, 19% in females), decreased thymus weight in males and females (11% and 25%, respectively), decreased weight of the liver (20%), spl een (21%), and epididymides (21%) inPage 43 of 56 males, and histopathological alterations of the respiratory tract in males and females. At the 0.05 mg/L concentration, transient labored breathing and discoloration of the fur was observed in both sexes was not consid ered toxicologicallhy significant. The LOAEL is 0.3 mg/L (300 mg/m 3 ) based on increased mortality, decreased body weight and body weight gain, decreased partial thromboplastin time, decreased organ weights, and 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 study in rats is classified Acceptable/Non

- g uideline . Although this study does not satisfy the guideline requirement for a 90

- day in halation toxicity study in rats [OPPTS 870.3465; OECD 413] due to a protocol deviation (omission of urinalysis and clinical chemistry parameter measurements in high concentration exposure animals), it does contain useful information that supports identific ation of a Lowest

- Observed

- Adverse

- Effect

- Level (LOAEL) based on increased mortality, decreased body weight and body weight gain, decreased partial thromboplastin time, decreased organ weights, and increased incidence of histopathology of the respiratory t ract in males and females as well as a No

- Observe d

- Adverse

- Effect Level (NOAEL ). 

## Developmental Toxicity

In a dermal developmental toxicity study (MRID 41537501, reformat of 416990 01), Nuosept ® 95 (Batch No. 006

- 097

- 597 , 50.38%;) in distilled water 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. Th ere were no treatment related effects in mortality, clinical signs, weight gain, food consumption, gross n ecropsy parameters and cesarean parameters. There was clear evidence of maternal 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 study termination. The intermediate

- dose group displayed moderate/well

- defined erythema. Half of the animals had scabbing that completely obsc ured the treatment site, and edema that was well

- defined by study termination. The high

dose group exhibited well

- defined erythema, scabbing that obscured the treatment site in all animals by gd 10, and moderate to severe edema that extended to the underl ying 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 toxici ty LOAEL is greater than 1000 mg/kg/day. There were no other embryotoxic or fetotoxic effects observed in this study. T he developmental NOAEL is greater than or equal to 1000 mg/kg/day; the developmental LOAEL is greater than 1000 mg/kg/day. This devel opme ntal toxicity study in the rabbi t is classified A cceptable/ Non

g uideline

. 

## Reproductive Toxicity

There are no data evaluating the potential reproductive toxicity of a zadioxabicyclooctane. For the indirect food use of this chemical mixture

. Under regis tration review, a reproductive and fertility effects study is anticipated to be required due to the currently labeled indirect food use

.Page 44 of 56 

## Chronic Toxicity

Although t here are n o data evaluating the potential chronic toxicity of a zadioxabicyclooctane

, chronic exposures to pesticide products containing this active ingredient mixture are not anticipated. Use patterns that would trigger chronic toxicity testing (e.g., metalworking cutting fluid use) do not apply to azadioxabicyclooctane because this labele d use occurs in closed systems. Consequently, chronic toxicity data are not anticipated to be required. 

## Carcinogenicity

A determination of carcinogenic potential cannot be made for azadioxabicyclooctane; there are no data evaluating the potential carcinog enicity of this chemical mixture

. However, the

m etalworking cutting fluid use

, which would trigger the requirement for carcinogenicity studies based on the potential for long

- term exposures, does not apply to pesticide products containing azadioxabicycloo ctane since the labeled metalworking cutting fluid use is conducted in closed systems. Carcinogenicity testing for azadioxabicyclooctane is not anticipated to be required. 

## Mutagenicity

Azadioxabicyclooctane has been tested for mutagenic activity in severa l assays, including reverse gene mutation (Ames) assays (MRID 93050017, 93050018), bacterial DNA damage/repair assay (MRID 93050019

, 93050020), unscheduled DNA synthesis assays (MRID 93050021, 42711001), differential killing/growth 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 du e to lack of test substance characterization and purity, missing data and inadequate reporting of results, there remains sufficient mutagenicity testing to complete the mutagenicity battery for azadioxabicyclooctane. These data suggest negative mutagenic r esponses for this chemical mixture. 

## Additional Data Gaps

A multi

- generation reproduction study is identified as a data gap and is anticipated 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 registrant can address this anticipated data requirement by either submitting a study according to the OCSPP 870.7800 guideline, by citing information from the scientific li terature that addresses immunotoxicity of

a zadioxabicyclooctane , or by submitting a request for waiver of this study using the Agency’s published guidance, available at: http://www.epa.gov/pesticides/regulating/part158

- tox

- data

requirement.pdfPage 45 of 56 

## Other Toxicological Effects

The available toxicological database for azadioxabicyclooctane contains no additional information which would inform the toxicity of this chemical mixture . In addition, published literature for azadioxabicyclooctane have not been identified.Page 46 of 56 

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of Azadioxabicyclooctane

Azadioxabicyclooctane is a formaldehyde releaser. The unique mixture of three components in this mixture is not separable, and the exposure f r om this active in various environmental media are due to the three components.

The degradates from the three azadioxabicyclooctane compounds without the formaldehy de (

– 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 the degradates f ormed is anticipated as needed.

The a gency 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 presence of formalin (dissolved formaldehyde) these convert into component I. This is possible by release of formaldehyde from the parent molecule, although no o information is provided on the mechanism for how all components convert into Component I. However, in the absence of formalin, and in buffered media at pH 5, 7, and 9, the degradation of Component I is rapid and in a 24 hour study, component 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 a gency anticipates the need to require hydrolysis data for the degradates.

Aqu eous Photoly s is

There are no measured data available , data are anticipated to be required for the parent and degradates

.Page 47 of 56 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, since no data are ava ilable 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.

A n a erobic Aquatic Metabolism

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

Soil

Soil Leaching/Adsorption/Desorption Batch Equilibrium

Estimated Log K oc values for the mixture indicate that mobility from soil surfaces is high for the parent

. No dat a are ava ilable for the degradates, the a gency anticipates the need to require data.

Aerobic Soil Metabolism

No measured or estimated data are available for the mixture for ei ther parent or degradates. The

a gency anticipates the need to require data

.

A n a erobic Soil Metabolism

No measured or estimated data are available for the mixture for either the parent or degradates. The a gency 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 less than 3.0. The a gency doe s not anticipate the need to require 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 the biodegradation tests that are anticipated to be required. See table 6 for the anticipated biodegradation data requirements.Page 48 of 56 

# Appendix C Ecotoxicology Profile

Azadioxabicyclooctane is a formaldehyde releaser. T h e azadioxabicyclooctane registration review case does not address possible risks from formaldehyde derived from azadioxabicyclooctane for the env ironmental risk assessment

. . In the formaldehyde risk assessment phase of the formaldehyde registration review case

, the agency will review open literature concerning the toxicity of formaldehyde to non

- target organism s and determine if any formaldehyde s tudies can be used to evaluate formaldehyde risks derived from the uses of azadioxabicyclooctane

. 

## Toxicity to Terrestrial Receptors

Birds

In order to establish the toxicity of the use o f this pesticide to birds, the a gency requires an acute oral toxicity study usin g the technical grade of the active ingredient (TGAI). The preferred test species is either mallard duck (a waterfowl) or northern bobwhite quail (an upland game bird). The results of one toxicity study are provided in the following table (Tabl e C 1).

Table C 1. 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 non

toxic Yes

- acceptable for formulated product

- 14

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

The results of these studies indicate that Nuosept® 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 a za dio xabicyclooctane , as Nuosept® 95 is the only end

- use product. The 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 l ower tier ecological studies and pertinent environmental characteristics to establish the toxicity of a pesticide to avian species. The preferred test species are mallard duckPage 49 of 56 or northern bobwhite quail. This testing is not anticipated to be required for the currently supported uses on a za dioxabicyclooctane ; however, three avian dietary studies were previously submitted to the a gency. The results of these are provided in the following table (Table C 2).

Table C 2. Subacute Dietary Toxicity of Nuose pt ® 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 a za dioxabicy clooctane , as Nuosept® 95 is the only end

- use product. The Guideline requirements (850.2200/71

- 2) are fulfilled. No additional data are anticipated to be required.Page 50 of 56 Mammals

Wild mammal testing was not required for a za dioxabicyclooctane . In most cases, toxicity values obtained from studies conducted to support data requirements for the human health risk assessment substitute for wild mammal testing. These toxicity values are reported below (Table C 3). No additional data are anticipated to be required.

Table C 3. 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 preservatives, industrial processes and water systems) do not cause exposure to beneficial insects

.
Terrestrial Plants

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

- target terrestrial plants

. 

## Toxicity to Aquatic Receptors

Chronic toxicity testing for freshwater 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 anticipated to be required to be conducted. The ECOTOX database (EPA, 2002) was searched for any appropriate chronic testing with fish or invertebrates, but no such data were located.

Chronic toxicity testing for marine/e stuarine organisms is not anticipated to be required for the currently registered uses of azadioxabicyclooctane as Guidelines (850.1025 and 850.1035) are fulfilled

.Page 51 of 56 Freshwater Fish

In order to establish the acute toxicity to pest icides to freshwater fish, the a gency requires freshwater fish toxicity studies using the TGAI. The preferred test 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 used. Two freshwater fish toxicity stud ies were submitted to the a gency for a za dioxabicyclooctane using the formulated product Nuosept95. The results of these studies are presented in Table C 4.

Table C 4: 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 t hese 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 classified as supplemental information d ue to a lack of details regarding chemical purity and composition. These studies can potentially be upgraded to acceptable if sufficient information on the composition and purity of the test substance used is submitted. At the present time, they do fulfil l OCSPP test g uideline s

. The third study was submitted in 2012 and the results indicate that this pesticide is slightly toxic to fish on an acute basis. The study is acceptable and fulfills the OCSPP test guideline ( 850.1075 )

.Page 52 of 56 For freshwater fish, no add itional acute toxicity data is anticipated to be required; however, the agency anticipates the need to require a fish early life stage (850.1400) using the most sensitive organism as determined from the results of the acute toxicity tests. The ECOTOX datab ase (EPA, 2002) was searched for any appropriate chronic testing with fish, but no such data were located.

Freshwater Invertebrates

The a gency requires a freshwater aquatic invertebrate study using the TGAI to establish the acute toxicity of a pesticide to freshwater invertebrates. The preferred test species are Daphnia magna

or Daphnia pulex . Results of one toxicity study are provided in the following table (Table C 5).

Table C 5. 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

Th e results indicate that Nuosept ® 95 is slightly toxic to aquatic invertebrates 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 a za dioxabicyclooctane , since Nuosept ® 95 is th e only end

- use product. The studies are acceptable and fulfill the OCSPP test g uideline (850.1010). For freshwater invertebrates, n o additional acute toxicity 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 d ata were located.Page 53 of 56 Estuarine/Marine Fish

Acute testing with estuarine/marine fish is required to support the uses of a za dioxabicyclooctane

. This testing is conducted with one fish species, a bivalve. Th ese data were submitted to the

a gency, and the resul ts are summarized in Table C 6, below.

Table C 6. 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 practically non

- toxic to marine/estuarine fish. Although conducted on the formulated product and not the TGAI, the study is considered adequate to support the currently registered uses of a za dioxabicyclooctane , sinc e Nuosept 95 is the only end

use product. The study is acceptable and fulfills the OCSPP test g uideline (850.1075). No additional data are anticipated to be required.

Estuarine/Marine Invertebrates

Acute testing with estuarine/marine invertebrates is required to support the uses of

a za dioxabicyclooctane . This testing is conducted with an invertebrate species. Th ese data were submitted to the a gency and the results are summarized in Table C 7, below.

Table C 7. 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 54 of 56 - 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 Nuosept® 95 is slightly toxic to marine/estuarine invertebrates. The Guidelines (850.1025 and 850.1035) are fulfilled. No additional data are anticipated to be required.

Aquatic Plants

A quatic plant testing is required to support the registered uses of a za dioxabicyclooctane . An aquatic plant growth (aquatic vascular plant) Tier II

- dose response test and an aquatic plant growth (algal) Tier II (dose response) test is required, n o studies on plant toxic ity have been submitted to the a gency. The ECOTOX database (EPA, 2002) was searched for any plant toxicity information on the components of a za dioxabicyclooctane . 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 determine the potential for aquatic organisms downstream of the industrial wastewater treatment plants that receive discharges from the end

- use of azadioxabicyclooctane to be exposed this chemical or their degradates.Page 55 of 56 

# Appendix D Product Chemistry

The azadioxabicyclooctane p roduct chemistry information is summarized in Table D 1 (source: MRIDs 42734301, 42740801, 41671601, 41671602, 41671603, 48691701, ISP MSDS for Nuosept 95 Technical )

.

Table D 1

– 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

- dioxabicyclo(3.3.0)octane...

. 16.0%

• 5

- Hydroxymethyl

- 1

- aza

- 3,7

- dioxabicyclo(3.3.0)octane..................28.8%

• 1H,3H,5H,

- Oxazolo(3,4

- c)oxazole, poly(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 Clea r 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 Incompa tible with oxidizing materials, acids and bases. C ondition 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 56 of 56 Guideline No. Physical and Chemical Properties Equilibrium Mixture of 3 inseparable AIs in Nuosept 95 Technical: :

• 5

- Hydroxymethoxymethyl

- 1

- aza

- 3,7

- dioxabicyclo(3.3.0)octane...

. 16.0%

• 5

- Hydroxymethyl

- 1

- aza

- 3,7

- dioxabicyclo(3.3.0)octane..................28.8%

• 1H,3H,5H,

- Oxazolo(3,4

- c)oxazole, poly(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, chloroform, 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)