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 Kyprianou

Office of General Counsel

Phillip Ross
Page 3 of 56

TERMS, ABBREVIATIONS AND SYMBOLS

–CH2O Formaldehyde moiety group

–CH2–OH Hydroxy methyl group

AD Antimicrobials Division

A.I. or a.i. active ingredient

aPAD acute population adjusted dose 

ASRI activated sludge respiration inhibition

atm-m3

/mole atmospheric pressure-cubic meter per mole

BCF bioconcentration factor 

°C degrees Celsius

CAS Chemical Abstracts Service 

CFR Code of Federal Regulations 

CHO Chinese hamster ovary

–CH2O formaldehyde moiety

CMA Chemical Manufacturers Association

CO2 carbon dioxide

COC concentration-of-concern

cPAD chronic population adjusted dose 

DCI data call-in

DtD down-the-drain

EC50 median (or 50 percent) effect concentration

EC05 5 percent effect concentration

ECOTOX ECOTOXicology

EDI estimated daily intake

EDSP Endocrine Disruptor Screening Program 

E-FAST Exposure and Fate Assessment Screening Tool

EPI Suite Estimation Program Interface Suite

EPA Environmental Protection Agency 

°F degrees Fahrenheit

FDA Food and Drug Administration 

FFDCA Federal Food, Drug, and Cosmetic Act

FGD flue-gas desulfurization

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act 

FWP Final Work Plan

g/mol grams per mole

GLN guideline number

HPV high production volume

IDS Incident Data System 

ISP International Specialty Products

Koc organic carbon normalized soil-water partition coefficient

Kd soil-water partition coefficient

Kow octanol-water partition coefficient

LC50 median (or 50 percent) lethal concentration

LD50 median (or 50 percent) lethal dose

LOAEC lowest-observed-adverse-effect-concentration 

LOEC lowest-observed-effect-concentration

LOAEL lowest-observed-adverse-effect-level

Log Kow logarithm of the octanol-water partition coefficient

μg microgram
Page 4 of 56

ml/g milliliter per gram

mg/kg milligram per kilogram

mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury

MOE margin of exposure 

MRID Master Record Identification Number

MRL maximum residue limit 

MSDS material safety data sheet

NA not available

N/A not applicable 

nm nanometers

NOAEC no-observed-adverse-effect-concentration

NOAEL no-observed-adverse-effect-level

OCSPP Office of Chemical Safety and Pollution Prevention

OECD Organization for Economic Co-operation and Development

OPP Office of Pesticide Programs

PAD population adjusted dose

PAI pure active ingredient

PDM Probabilistic Dilution Model

% percent

PC Code Pesticide Chemical Code

PCF pounds per cubic foot

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

PHED Pesticide Handler’s Exposure Data

PIS primary irritation score

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

dissociation constant of a solution

ppb parts per billion 

ppm parts per million

PWP Preliminary Work Plan

QSAR quantitative structure-activity relationship

RED Reregistration Eligibility Decision

SAR structure activity relationship

SDF stream dilution factor

SF safety factor

SSTS Section Seven Tracking System

TEP typical end-use product

TGAI technical grade active ingredient

TMDL total maximum daily loads

UF uncertainty factor

UV/VIS ultraviolet/visible light absorption

% w/w percent weight per weight.

WP wettable powder

WWTPs wastewater treatment plants
Page 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 and Properties.......................................................................... 10

1.4 Use/Usage Description................................................................................................... 14

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

1.4.2 Summary 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 Effects Analysis Plan.......................................................................................................... 32

5 Endocrine Disruptor Screening Program (EDSP)................................................................. 33

6 Optional Label Changes........................................................................................................ 34

7 Guidance for Commenters.................................................................................................... 34
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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 Toxicology Profile............................................................................................... 41

Appendix B Environmental Fate ............................................................................................. 46

Appendix 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 

Azadioxabicyclooctane ................................................................................................................. 31

Table 13 – Acute Toxicity Studies for Azadioxabicyclooctane (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 

agency”) Preliminary Work Plan (PWP) for azadioxabicyclooctane. Azadioxabicyclooctane was

evaluated in the 2005 Registration Eligibility Decision (RED) for azadioxabicyclooctane as an 

active ingredient (a.i.) consisting of an equilibrium mixture of three chemicals: (component I) 5-

hydroxymethoxymethyl-1-aza-3,7-dioxabicyclo(3,3,0)octane (PC Code 107001); (component II)

5-hydroxymethyl-1-aza-3,7-dioxabicyclo(3,3,0)octane (PC Code 107002); and (component III): 

1H,3H,5H,-Oxazolo(3,4-c)oxazole, poly(oxymethylene) derivative (PC Code 107003).

The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about 

azadioxabicyclooctane, highlighting anticipated data and assessment needs, identifying the types 

of information that would be especially useful to the agency in conducting the review, and 

providing an anticipated timeline for completing azadioxabicyclooctane’s review.

Azadioxabicyclooctane 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. This 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 assessment is conducted, any other risks identified in Table 1 

from formaldehyde derived from the uses of azadioxabicyclooctane will be considered at that 

time. The agency issued a Reregistration Eligibility Decision (RED) document for formaldehyde 

in 2008 to address 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 designed to include a public participation component to 

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

docket, to inform the public of what it knows about azadioxabicyclooctane and what types of 

new data or other information would be helpful for the agency to receive as it moves toward a 

decision on azadioxabicyclooctane. The agency encourages all interested stakeholders to review 

the PWP and to provide comments and additional information that will help the agency’s 

decision-making process for 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 continue to meet the statutory standard of no unreasonable 

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

pesticide use practices will occur over time. Through the registration review program, the agency
Page 8 of 56

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

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

http://www.epa.gov/oppsrrd1/registration_review/.

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

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

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

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

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

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

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

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

reviewing and responding to comments and data received in the docket during this initial 

comment period, the agency will develop and commit to a Final Work Plan (FWP) and 

anticipated schedule for the azadioxabicyclooctane case. 

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

in docket EPA-HQ-OPP-2013-0604. Tables 1-2 below summarize the issues relevant to this 

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 details)

Dietary (food) Yes July, 2005 Updated Reproduction and fertility effects 

Immunotoxicity

Dietary (drinking water) No (see 3.2.2) July, 2005 None None 

Occupational Handler Yes July, 2005 Updated

Product Use

Reproduction and fertility effects

Immunotoxicity

Occupational

Post-ApplicationInhalationYes July, 2005 New

Inhalation Exposure (volatilization of 

formaldehyde)

Product Use

Residential Handler Yes July, 2005 Updated Reproduction and fertility effects

Immunotoxicity

Residential Post 

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

Aggregate Yes July, 2005 Updated Reproduction and fertility effects

Immunotoxicity

Cumulative No (see 3.4.2) July, 2005 None None 

Tolerance Review No (see 1.5.2) 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 registration review. 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 Preliminary Work Plan 2014-03 2014-03-28

Close Public Comment Period 2014-05

Phase 2: Case Development 

Issue Final Work Plan 2014-09

Issue Data Call-In (DCI) 2015-09

Receive Data to be Considered in Risk Assessment 2019-09

Open 30-Day Public Comment Period for Preliminary Risk Assessment(s) 2021-03

Close Public Comment Period 2021-04

Phase 3: Registration Review Decision and Implementation 

Open 60-Day Public Comment Period for Proposed Decision 2021-09

Close Public Comment Period 2021-11

Issue Final Decision 2022-03

Begin Post-Decision Follow-up 2022

Total (years) 8

*The anticipated schedule will be revised as necessary (e.g., needed schedule adjustments 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 azadioxabicyclooctane (case 3023) has been established at 

http://www.regulations.gov in docket number EPA-HQ-OPP-2013-0604.

1.3 Chemical Identification and Properties

As described in the Section 1 Introduction, azadioxabicyclooctane is a formaldehyde releaser 

consisting of a mixture of three chemicals in equilibrium in the product. Each chemical 

component has an individual OPP Pesticide Chemical Code (PC Code) and is listed on the label 

as a separate active ingredient, 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) derivative (PC Code 107003). For more information 

on the azadioxabicyclooctane product chemistry, see Appendix D.

The degradates from the three azadioxabicyclooctane compounds without the formaldehyde (-

CH2O) moiety are as follows:

• Component I minus the formaldehyde (–CH2O) moiety becomes Component II, 

• Component II minus the –CH2O becomes degradate IIa.

• All of the potential degradates of Component III are unknown and information on 

degradates formed is anticipated as needed (see below). 

Component III is a polymer with repeating–CH2O 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 agency 
Page 11 of 56

anticipates needing information about the polymer n distribution as well as about the rate of 

release for use in determining appropriate equivalent formaldehyde release levels and exposure 

concentrations.

Table 3 – Chemical Identification of Azadioxabicyclooctane

Constituent of 

mixture Component I

Component II

(also a degradate of 

Component I)

Component III

Chemical 

Name

5-Hydroxymethoxymethyl-1-aza3,7-dioxabicyclo(3,3,0)octane5-Hydroxymethyl-1-aza-3,7-

dioxabicyclo (3,3,0)octane

1H,3H,5H,-Oxazolo(3,4-

c)oxazole, poly(oxymethylene) 

derivative

Chemical

Classification Bicyclic Oxazolidine Bicyclic Oxazolidine Bicyclic Oxazolidine

PC Code 107001 107002 107003

CAS Number 59720-42-2 6542-37-6 56709-13-8

Molecular 

Formula C7H13NO4 C6H11NO3

(CH2O)n C6H11NO3

n = Data gap

Molecular 

Weight 

(grams/mole)

175.08 145.07 (30.03)n + 145.07

n = Data gap

Proportion in a 

50% technical 

product

16% 28.8% 5.2%

Molecular 

Structure

Moles of 

formaldehyde 

per mole of 

component

2 moles 1 mole

n = Data gap

(n = 5 for the representative CAS 

Number)

n = number of repeating formaldehyde units in the polymer.

International Specialty Products (ISP) is the sole producer of azadioxabicyclooctane under the 

name Nuosept 95 (Kline, 2004). The azadioxabicyclooctane product chemistry information 

(MRIDs 42734301, 42740801, 41671601, 41671602, 41671603, 48691701, and material safety 

data sheet (MSDS) for Nuosept 95 Technical) relevant to risk assessment and environmental fate 

properties are summarized in Table 4. Data about individual components are anticipated as being 

needed for exposure modeling and risk assessment.
Page 12 of 56

Table 4 – Physical-Chemical and Environmental Fate Properties for 

Azadioxabicyclooctane 

Guideline 

No. Parameter

Equilibrium Mixture of 3 

inseparable components in 

Nuosept 95 Technical:50% 

TGAI; EPA Reg. No. 1529-491

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

Octanolwater 

partition 

coefficient 

at 25 oC 

(Log Kow)

Log Kow: <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 NA
Page 13 of 56

Guideline 

No. Parameter

Equilibrium Mixture of 3 

inseparable components in 

Nuosept 95 Technical:50% 

TGAI; EPA Reg. No. 1529-491

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 oC (atmm3

/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 oC 

(Log KOA)

Log Kow: <1 for the parent NA NA NA

Mobility

Organic 

Carbon 

Partitioning 

Coefficient 

(Koc)

The values of log Koc 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 oC: 

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-m3/mol = atmosphere cubic meter per mole; oC = degrees Celsius; oF = degrees Fahrenheit; mg/L = milligrams 

per liter; mmHg = millimeters of mercury.

NA = Not Available
Page 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 Reg. No. 1529-49, and one is an end-use-product, EPA 

Reg. No. 1529-28. Both products contain 5-Hydroxymethoxymethyl-1-aza-3,7-

dioxabicyclo(3,3,0)octane; 5-Hydroxymethyl-1-aza-3,7-dioxabicyclo(3,3,0)octane; and 

1H,3H,5H,-Oxazolo(3,4-c)oxazole, poly(oxymethylene) derivative as the active ingredient. The 

percent a.i., as shown on the label, for both is as follows: 28.8 percent for 5-

Hydroxymethoxymethyl-1-aza-3,7-dioxabicyclo(3,3,0)octane, 16 percent for 5-Hydroxymethyl1-aza-3,7-dioxabicyclo(3,3,0)octane, and 5.2 percent for 1H,3H,5H,-Oxazolo(3,4-c)oxazole, 

poly(oxymethylene) derivative.

1.4.2 Summary of Registered Uses

Table 5 presents a summary of the registered uses of azadioxabicyclooctane that will be assessed 

in this registration review. Azadioxabicyclooctane can be applied by the following application 

methods: open pour, brush/roller, and airless sprayer.

Table 5 – Summary of Azadioxabicyclooctane Registered Uses

Use Application Method Application Rate

Material Preservatives

Industrial Adhesives, Caulks, Inks, Sealants, 

Paper Coatings1 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

Azadioxabicyclooctane is registered for use to control slime forming bacteria and fungi at the 

following use sites: oil recovery drilling muds and packer fluids; industrial adhesives and 

coatings; resin/latex/polymer emulsions; metalworking cutting fluids; latex paints; paper/paper 

products; and for industrial processing chemicals. EPA did not find any specific distribution of 

usage or market data in the 2005 Kline Report for azadioxabicyclooctane. 
Page 15 of 56

1.5 Regulatory History

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 agency completed a RED for azadioxabicyclooctane

in 2005. Three post-RED Generic Data Call-Ins (GDCIs) were issued for azadioxabicyclooctane 

in 2008, they are the following: GDCI-107001-27848, GDCI-107002-27890, and GDCI-107003-

27849. Of seven studies identified in the GDCIs, two have been satisfied: 1.) EPA guideline 

870.2600, a skin sensitization study; and 2.) EPA guideline 870.3465, a 90 day inhalation 

toxicity study. For more information on the status of data requirements, see Table 7.

Formaldehyde

EPA prepared a separate formaldehyde RED to address potential risks associated with nonazadioxabicyclooctane uses of formaldehyde. This document is available in the formaldehyde 

public docket at http://www.regulations.gov in docket number EPA-HQ-OPP-2008-0121. 

Though the formaldehyde registration review data requirements will be handled separately, 

background regulatory history information is provided here for the reader’s convenience. The 

first product containing formaldehyde 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 

mushroom 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, general purpose 

cleaners and wall paper adhesives.

The agency 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-Rodents (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

For the active ingredient, the 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 azadioxabicyclooctane. Azadioxabicyclooctane 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 agency’s Ecological 

Incident Information System (EISS) for the time period spanning 2005 to 2013.

2 Anticipated Data Needs

Table 6 presents a summary of the data anticipated as being needed to support this registration 

review. Table 7 outlines the data requirements required by the post-RED GDCIs issued on 

August 11, 2008.

1

 The agency anticipates reviewing any data received in response to the postRED DCIs as well as data that are required for this registration review prior to conducting the 

registration review risk assessments for azadioxabicyclooctane.

 1 See Section 1.5 for a list of the GDCIs.
Docket Number EPA-HQ-OPP-2013-0604

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 Site(s) 

Triggering 

Anticipated Data 

Requirement

Applicable Exposure 

Scenario

Studies Anticipated to be Required through the Registration Review DCI

835.12301 Adsorption-desorption 

(Batch equilibrium) TGAI 24 Fate and persistence 

assessment

Paints, Material

Preservatives, 

Drilling Muds and 

Flooding Fluids, 

Textiles

Release into water

835.12401 Leaching-adsorptiondesorption TGAI 12 Fate and persistence 

assessment

Drilling Muds and 

Flooding Fluids, 

Textiles

Oral exposure to 

drinking water and to 

aquatic organisms

835.21201 Hydrolysis TGAI 12 Fate and persistence 

assessment

Paints, Material 

Preservatives, 

Drilling Muds and 

Flooding Fluids, 

Textiles

Release into water

835.22401 Aqueous photolysis TGAI 12 Fate and persistence 

assessment

Paints, Material 

Preservatives, 

Drilling Muds and 

Flooding Fluids, 

Textiles

Release into water

835.31103, 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

835.41001 Aerobic Soil metabolism TGAI 24 Fate and persistence 

assessment

Paints, Material 

Preservatives, 

Textiles

Release into water

835.42001, 5 Anaerobic soil metabolism TGAI 12 Fate and persistence 

assessment

Paints, Material 

Preservatives, 

Textiles

Release into water
Page 18 of 56

835.43001 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 lifecycle 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

850.54008

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

850.33003,

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 sites9

 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

875.25002 Inhalation Exposure TEP 24

Occupational and 

Residential PostApplicationPaints Paints
Page 19 of 56

*Degradates for Table 6 are defined here as well as in Section 1.3: Component I minus formaldehyde (–CH2O) becomes or Component II, Component II minus (–

CH2O) becomes degradate IIa, Component III degradates are unknown and are considered data gaps.

Degr = Degradates

TEP = Typical end-use product

TGAI = Technical grade of the active ingredient

1 The 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. Post-application inhalation data are anticipated as needed to assess the exposures of formaldehyde in paint. 3

The anticipated data requirement for degradates could be waived 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 the ASRI test EC50 is less than or equal to 

20 mg/L, then 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 EC50 is greater than 20 mg/L, then the registrant 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 study 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 activated sludge, respiration inhibition tests.

6 For degradates, the agency anticipates requiring data only for degradate IIa. 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 provide that the study 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 Needs 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 PostApplication Paints Paints

Special Study3,7 Leaching from Paint, 

Adhesives, Caulks, Textiles Degr 24 Down the Drain Paints, Adhesives, Caulks, Textiles Release into water
Page 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.

875.12001,2 Indoor Dermal Exposure TGAI 24 Occupational and 

Residential Handler All uses

Pour liquids

Brush/Roller

Airless Sprayer 

875.14001, 2 Indoor Inhalation Exposure TGAI 24 Occupational and 

Residential Handler All uses

Pour liquids

Brush/Roller

Airless Sprayer 

875.16002 Application exposure 

monitoring data reporting TGAI 24 Occupational 

Handler Paints 

Pour liquids

Brush/Roller

Airless Sprayer

875.28002 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 addressed. 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 application methods, and these data will be submitted as 

required under the DCI.
Docket Number EPA-HQ-OPP-2013-0604

www.regulations.gov

Page 21 of 56

3 Human Health Risk Assessment

Azadioxabicyclooctane 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. This 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 assessment is conducted, any other risks identified in Table 1 from 

formaldehyde derived from the uses of azadioxabicyclooctane will be considered at that time.

The agency anticipates the need to conduct a human health risk assessment for 

azadioxabicyclooctane. The agency anticipates new exposure data from the RED data call-in 

and expects to require additional exposure data to conduct new assessments for registration 

review to assess the volatilization of formaldehyde from indoor exposure to painted surfaces.

Additionally, the 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 patterns 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 scientific 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, 

2005). In addition, increased sensitivity of infants and children potentially exposed to 

azadioxabicyclooctane 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 hazard-based safety factor under the FQPA be retained (10x) 

for azadioxabicyclooctane. There is a limited developmental and reproductive toxicology data 

base for azadioxabicyclooctane: one prenatal dermal developmental toxicity study in rats and no 

reproduction 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 route. 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, 2005 b). A reproductive and fertility effects study is 

anticipated to be required in registration review due to the currently labeled indirect food uses.
Page 22 of 56

Following issuance of the post-RED DCI, several toxicity studies identified as data gaps for 

azadioxabicyclooctane were submitted to the agency; 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-evaluation of selected toxicological dose, endpoint 

and uncertainty factors for inhalation risk assessment is required (Table 8).

Table 8 – Existing Toxicological Endpoints

Table 8. Summary of Toxicological Dose/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 interspecies extrapolation, 10x 

intra-species variation)

FQPA SF = 10x

Acute RfD = NOAEL ÷ 

UF = 10.6 ÷ 100 = 0.106 

mg/kg/day

aPAD = acute RfD ÷ 

FQPA SF = 0.106 ÷ 10 = 

0.01 mg/kg/day

90-Day Oral Toxicity in Rats

(MRID 41641606)

LOAEL = 56.5 mg/kg/day based 

on decreased water consumption in 

males. 

Acute Dietary

(females 13+)

NOAEL = 10.6 

mg/kg/day

UF = 100 (10x interspecies extrapolation, 10x 

intra-species variation)

FQPA SF = 10x

Acute RfD = NOAEL ÷ 

UF = 10.6 ÷ 100 = 0.106 

mg/kg/day

aPAD = acute RfD ÷ 

FQPA SF = 0.106 ÷ 10 = 

0.01 mg/kg/day

90-Day Oral Toxicity in Rats

(MRID 41641606)

LOAEL = 56.5 mg/kg/day based 

on decreased water consumption at 

in males.
Page 23 of 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 interspecies extrapolation, 10x 

intra-species variation, 3x 

lack of a chronic endpoint)

FQPA SF = 10x

Chronic RfD = NOAEL ÷ 

UF = 10.6 ÷ 300 = 0.03 

mg/kg/day

cPAD = chronic RfD ÷ 

FQPA SF = 0.03 ÷ 10 = 

0.003 mg/kg/day

90-Day Oral Toxicity in Rats

(MRID 41641606)

LOAEL = 56.5 mg/kg/day based 

on decreased water consumption at 

in males.

Incidental Oral 

Short-Term, 

IntermediateTerm 

(1-30 days, 30 

days-6 months)

No endpoint is required based on the use patterns for pesticide products containing 

azadioxabicyclooctane.

Dermal 

(all durations)

Short-Term, 

IntermediateTerm, LongTerm (1-30 

days, 30 days-6 

months, > 6 

months)

LOAEL(dermal)

= 100 mg/kg/day

Target MOE 

(ST/IT occupational) = 

300 (10x inter-species 

extrapolation, 10x intraspecies variation, 3x lack 

of a NOAEL) 

Target MOE 

(LT occupational) = 

3000 (10x inter-species 

extrapolation, 10x intraspecies variation, 10x 

extrapolation from an oral 

endpoint, 3x lack of a 

NOAEL) 

Co-critical studies: 

21-Day Dermal Toxicity in Rats

(MRID 41641605)

LOAEL = 100 mg/kg/day (severe 

dermal effects)

Developmental Toxicity in Rats

(MRID 41699001)

LOAEL = 100 mg/kg/day (severe 

dermal effects)
Page 24 of 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

Inhalationa

(all durations)

Short-Term, 

IntermediateTerm, LongTerm (1-30 

days, 30 days-6 

months, > 6 

months)

NOAEL= 10.6 

mg/kg/day

(inhalation 

absorption rate = 

100%)

Target MOE

(ST/IT/LT occupational)

= 3000 (10x inter-species 

extrapolation, 10x intraspecies variation, 10x 

extrapolation from an oral 

endpoint, 3x lack of a 

histopathology data)

90-Day Oral Toxicity in Rats

(MRID 41641606)

LOAEL = 56.5 mg/kg/day based 

on decreased water consumption at 

in males.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, 

LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic), RfD = 

reference dose, MOE = margin of exposure, LOC = level of concern, NA = not applicable a The availability of an acceptable route-specific inhalation toxicity study for azadioxabicyclooctane requires a reevaluation of toxicological dose, endpoint and uncertainty factors for inhalation risk assessments. 

3.2 Dietary Exposure

3.2.1 Food

The only approved uses of azadioxabicyclooctane that may result in residues in food are as 

antibacterial preservatives of food-contact adhesives and paper coatings in contact with dry 

foods. Acute and chronic dietary risks associated with these FDA uses of azadioxabicyclooctane

were summarized in the 2005 RED. The treatment rate was 2500 ppm active ingredient in the 

adhesive and the coating which remains the maximum label rate in each preserved material. The 

aPAD and cPAD were 0.01 mg/kg/day and 0.003 mg/kg/day, respectively, both from a 90-day 

rat oral toxicity study. Combined (adhesives plus coatings) acute dietary risks were 5.1% of the

aPAD in adults and 12% of the aPAD in children. Combined chronic dietary risks were 17% of 

the cPAD in adults and 40% of the cPAD in 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 

agency’s levels of concern. No residue chemistry data are expected to be needed at this time to 

characterize residues of azadioxabicyclooctane in food.

3.2.2 Drinking Water

A drinking water assessment has not been conducted for azadioxabicyclooctane in the past. 

There are no direct aquatic uses of azadioxabicyclooctane. However, several approved uses as a

material preservative are likely to result in azadioxabicyclooctane being discharged 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 yet to be determined

(i.e., azadioxabicyclooctane and/or its biotic or abiotic products), the magnitude of the potential 

residues in drinking water, their mammalian toxicities, how persistent they will be, and if they 

are likely to pass through a wastewater treatment plant (WWTP) is unknown. Therefore, the 

agency anticipates needing certain environmental fate data listed in Section 4 of this PWP. These 
Page 25 of 56

data will be useful to determine whether, and to what extent, residues of azadioxabicyclooctane

pass through a WWTP. These data will be used during the risk assessment stage to determine the 

potential for discharged or leached residues of azadioxabicyclooctane 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 

azadioxabicyclooctane in drinking water.

3.3 Occupational and Residential Exposures

The agency 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 

azadioxabicyclooctane that may result in occupational and residential scenarios are identified in 

Tables 9 and 10 below.

3.3.1 Occupational Handler Exposure

EPA anticipates the need to revise the occupational handler assessment conducted in support of 

the 2005 RED. Occupational handler dermal and inhalation exposures to azadioxabicyclooctane

were assessed in the 2005 RED for applications using brush/roller, 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) and 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 support 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 agency 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 Slurries2 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 specified 

in the RED as a metered pump system will not be assessed. In addition metalworking systems are specified in the labels 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, 

and 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 was developed 

using the OSHA PEL for oil mist. The agency 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 assessed 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 dermal 

MOE was 540 and exceed the agency’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 currently reflected on the existing labels.

The agency 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, formaldehyde monitoring data are anticipated as needed to assess this postapplication exposure scenario (e.g., small air chamber tests).

3.3.3 Residential Handler Exposures

EPA conducted a residential painter assessment for the RED in 2005. The calculated risks for the 

brush/roller application were not at a level of concern. However the calculated risks (e.g., dermal 

MOE=236) for the airless sprayer were at a potential risk of 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 postRED DCI (see Table 7). The residential handler exposure scenarios are listed in Table 10.

Table 10 – Residential Handler Exposure Scenarios for Azadioxabicyclooctane

Scenario Exposure Route(s) Duration

Residential Exposures

Applying paints with brush/roller Dermal/Inhalation Short and Intermediate Term 

Applying paints with airless spray Dermal/Inhalation Short and Intermediate Term 
Page 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 released from treated paint (e.g., treated 

hard surfaces/walls). Table 11 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 Azadioxabicyclooctane 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 agency will determine the 

need for a new aggregate assessment once the agency has identified the toxicological endpoints 

for each route of exposure. If the toxicological endpoints change, the agency will develop a new 

aggregate exposure assessment. In addition, the agency may need to conduct a new aggregate 

risk assessment if the agency determines the need for a new drinking water exposure assessment.

If drinking water exposure is added then the agency would need to consider aggregating drinking 

water with the existing food exposure from indirect dietary exposures from residue found in 

paper coatings and adhesives. The agency does not anticipate the need to aggregate residential 

exposures (handler or post-application exposures to paint) with dietary and/or drinking water 

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 registration 

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 substances. 

For the purposes of this registration review, therefore, EPA has not assumed that 
Page 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 mechanism 

of toxicity and to evaluate the cumulative effects of such chemicals, see 

http://www.epa.gov/pesticides/cumulative/.

4 Environmental Risk Assessment

This registration review case does not address 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 formaldehyde derived from the uses of azadioxabicyclooctane.

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

species determination for azadioxabicyclooctane. An ecological hazard and environmental risk 

assessment chapter for the RED was completed in May, 2005. At the time, most uses of 

azadioxabicyclooctane were considered indoor and were considered to have little chance of 

exposure to the environment. An assessment of the industrial uses and processes will be 

conducted during the future risk assessment of azadioxabicyclooctane. This would include 

modeling of exposure scenarios that were not considered when the original assessment was 

conducted. The ecological risk assessment planned during registration review will allow the 

agency to determine potential acute and chronic risks to aquatic organisms exposed to 

azadioxabicyclooctane that are transported from treatment sites into the aquatic environment. 

Aquatic organisms could be exposed to azadioxabicyclooctane. Exposure from industrial uses, 

such as drilling muds, textile manufacturing and metal working fluids, will need to be assessed 

during the risk assessment. The agency will determine if these uses result in parent chemical 

and/or degradate releases. The risk assessment also will allow the agency to determine whether 

each use of the azadioxabicyclooctane has 'no effect' or 'may affect' federally listed threatened or 

endangered species (listed species) or their designated critical habitats. When an assessment 

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

agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries 

Services (the Services), as appropriate.

4.1 Environmental Fate Assessment

The unique mixture of three components in this mixture is not separable, and the exposure from 

this active in various environmental media are due to the three components. The agency 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, textiles, etc) and went down-the-drain, there would be no risk. Still, the agency 
Page 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 components are highly water soluble (miscible in all proportions with water). Since the 

log Koc is 1.00 and the agency considers values of log Koc from 1 to 10 as showing high mobility 

in soils, azadioxabicyclooctane is mobile in soil medium and easily partitions into aqueous 

medium. The components are not expected to partition from water into sediments.

4.1.3 Soil

The three components are highly water soluble (miscible in all proportions with water). The log 

Koc for the components is a maximum of 1.00, and thus these are highly mobile in aqueous 

medium. The three components are not expected to partition from water into soils.

4.1.4 Air

The half lives in air for the three components vary from 1 to 1.5 hours (EPI Suite, version 4.1), 

and these are not persistent in the atmosphere.

4.1.5 Wastewater Treatment Plant (WWTP)

There are not enough data for assessment of azadioxabicyclooctane and its degradates. For a list 

of anticipated and already imposed data requirements, see Tables 6 and 7.

4.1.6 Water Quality

Azadioxabicyclooctane is not identified as a cause of impairment for any water bodies listed as 

impaired under section 303(d) of the Clean Water Act.

2 In addition, no Total Maximum Daily 

Loads (TMDL) have been developed for the mixture of these azadioxabicyclooctane 

compounds.

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

website.

4

4.2 Conceptual Models for 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. Aquatic 

organisms in surface water downstream of both direct and indirect sources of 

azadioxabicyclooctane could be expected to be exposed to azadioxabicyclooctane and any 

degradates.

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

3

http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_

group_name=PESTICIDES

4 http://www.epa.gov/owow/tmdl/
Page 30 of 56

The screening-level risk assessment that will be conducted as part of this registration review will 

evaluate potential risks to ecological organisms from exposure to azadioxabicyclooctane.

4.3 Ecological Effects Assessment

Azadioxabicyclooctane 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-aza3,7-dioxabicyclo (3.3.0) octane; and C: 5-hydroxypoly(methyleneoxy)methyl-1-aza-3,7-

dioxabicyclooctane. 

Azadioxabicyclooctane is a formaldehyde releaser. This 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 open literature concerning the toxicity of 

formaldehyde to non-target organisms and determine if any formaldehyde studies can be used to 

evaluate formaldehyde risks derived from the uses 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 are 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 conditions, 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 likely to volatilize into 

the atmosphere as their vapor pressures vary between 0.0004 to 0.003 mm Hg. Component III is 

likely to have less volatility as the side chain of CH2O groups are added into the structure. 

Estimated half lives in the atmosphere for components I and II are 1.2 and 1.4 hours. Hence, 

these two chemicals are not likely to persist in the atmosphere (RED, 2005).

The estimated log Kow 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 linear 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 azadioxabicyclooctane are 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 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 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 anticipated to be required for the 

currently registered uses of azadioxabicyclooctane (see Appendix C).

4.3.1 Mode of Action

Azadioxabicyclooctane is highly soluble in water. Aquatic organisms would be exposed to the 

chemical when azadioxabicyclooctane enters the aquatic environment after industrial discharge 

and after disposal down 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 available ecotoxicity endpoints in the agency’s files from chemical studies submitted by 

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

tabulated in Appendix C along with the 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 

Azadioxabicyclooctane

Receptor 

Group

Surrogate

Species

Risk

Scenario

Toxicity

Endpoint

Reference

(MRID)

Birds Mallard duck

Acute Oral LD50 = >2510 mg a.i./kg-bw ACC 250533

Subacute Dietary LC50 > 10,000 ppm-diet ACC 248878

Chronic Data not anticipated to be required

Mammals

Acute Oral LD50 = 1940 mg/kg-bw 41641601

Subchronic

dietary NOEL = 10.6 mg a.i./kg-bw 41641606

Freshwater fish Bluegill sunfish

Acute 96-h LC50 = 34.7 mg a.i./L 48082403

Chronic Data Gap: data anticipated to be required

Freshwater 

invertebrates Waterflea

Acute 48-h EC50 = 35 mg/L 48082404

Chronic Data Gap: Data anticipated to be 

required --

Freshwater benthic 

invertebrates -- Subchronic or 

Chronic

Data not anticipated to be required: Not expected to be 

associated with sediment because it is water soluable 

(RED, 2005)

Estuarine/marine 

fish

Sheepshead

minnow

Acute 96-h LC50 = 440 mg 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 oyster

(embryo larval) Acute EC50 = 42 mg a.i./L ACC 250053

Mysid Acute LC50 = 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 uses, 

such as drilling mud, flooding fluids, metalworking fluids, and textile finishing for which 

discharges may enter industrial WWTPs rather than domestic WWTPs prior 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 azadioxabicyclooctane 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 interested 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, 

terrestrial 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.gov/ecotox
Page 33 of 56

azadioxabicyclooctane and the data reviewed following the agency’s policy for reviewing public 

literature for use in assessing risks from pesticides.

6

 Those ecotoxicity values found in the 

public literature to be more sensitive than those 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 endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

identified for EDSP screening was published on June 14, 20137 and includes some pesticides 

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

construed as a list of known or likely endocrine disruptors.

 6 http://www.epa.gov/pesticides/science/literature-studies.html 7 See http://www.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 agency 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 risk 

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 agency 

will carefully consider all comments as well as any additional information or data provided in a 

timely manner prior to issuing a final work plan for the azadioxabicyclooctane registration 

review case. 

7.1.1 Trade Irritants

Through the registration review process, the agency intends to solicit information on trade 

irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The agency 

will work to harmonize tolerances and international maximum residue limits (MRLs) and may 

modify tolerance levels to do so, when possible. Stakeholders are asked to comment on any 

trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and 

MRLs in key export markets, providing as much specificity as possible regarding the nature of 

the concern.

7.1.2 Water Quality

The agency 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 Body and Other Water Quality Data in OPP’s 

Registration Review Risk Assessment and Management Process9 in order to ensure they can be 

used quantitatively or qualitatively in pesticide risk assessments.

7.1.3 Environmental Justice 

EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all 

people, regardless of race, color, national origin, or income, in the development, implementation, 

and enforcement of environmental laws, regulations, and policies. To help address potential 

environmental justice issues, the agency seeks information on any groups or segments of the 

population who, as a result of their location, cultural practices, or other factors, may have 

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

9 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm
Page 35 of 56

atypical, unusually high exposure to azadioxabicyclooctane 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 reliability for each decision made by 

the agency. 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 various animal species. 

Today, there is significant interest in alternative techniques, i.e., techniques other than data 

generation that could significantly inform the agency’s decision-making process. Recently, OPP 

has made increasing use of structure activity relationship (SAR) as part of its regulatory 

decision-making 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 predictive 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 tools that are available to agency 

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 information from open literature and studies specifically generated under 

Part 161 requirements. All relevant information would be considered as part of a weight-of-theevidence evaluation. 

At this time, EPA believes that for certain endpoints, especially physical/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 most 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 assessment 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 

Azadioxabicyclooctane Case, then the agency 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 agency. Presubmission consultation with the agency 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 agency in refining its risk assessments, including any species-specific ecological effects 

determinations. The agency is interested in receiving the following information: 

1. Confirmation on the following label information: 

A. Sites of application 

B. Formulations

C. Application methods and equipment 

D. Maximum application rates 

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

applications 

F. Geographic limitations on use 

2. Use or potential use distribution 

3. Use history 

4. Usage/use information for non-agricultural uses (e.g., materials preservation) 

5. Typical application interval 

6. State or local use restrictions 

7. Ecological incidents (non-target plant damage and avian, fish, reptilian, amphibian and 

mammalian mortalities) not already reported to the agency 

8. Monitoring data 

8 Next Steps

After the 60-day comment period closes in May, 2014, the agency will review and respond to 

any comments received in a timely manner, and then issue a Final Work Plan for the 

azadioxabicyclooctane case.
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). Reformat 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 Nuosept 95. SRI International.

93050017 (MRID#, Reformat of 00088956) Anonymous (1979). Salmonella/mammalianmicrosome plate incorporation mutagenesis assay. An Evaluation of Carcinogenic Potential of 

NUOSEPT® 95 Employing the C3H/10T1⁄2 Cell Transformation Assay. EG&G Mason Research 

Institute.

93050018 (MRID#, Reformat of 00088974) Van Goethen, D. (1979). Mutagenicity studies on 

Nuosept 95 Salmonella/microsome test. Midwest Research Institute.

93050019 (MRID#, Reformat of 00088957). Anonymous (1979). Bacterial DNA damage/repair 

suspension assay. EG&G Mason Research Institute.

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

Midwest Research Institute.
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93050021(MRID#, Reformat of 00088959). Anonymous (1980). Evaluation of Nuosept ® 95 in 

the primary rat hepatocyte unscheduled DNA synthesis assay. Litton Bionetics, Inc.

93050022 (MRID#, Reformat of 00088960) Thilagar, A., et al. (1979). An Evaluation of 

Carcinogenic Potential of NUOSEPT® 95 Employing the C3H/10T1⁄2 Cell Transformation 

Assay. EG&G Mason Research Institute.

93050023 (MRID#, Reformat of 00088961) Schechtman, M. (1980). Activity of T1597 in an in 

vitro Mammalian Cell transformation Assay in the Absence of Exogenous Metabolic Activation. 

Microbiological Associates.

93050024 (MRID#, Reformat of 00088962) Thilagar, A., et al. (1980). An Evaluation of 

Carcinogenic Potential of R-1162 (NUOSEPT® 95) Employing the C3H/10T1⁄2 Cell 

Transformation System. EG&G Mason Research Institute.

93050025 (MRID#, Reformat of 00088963) Thilagar, A. (1980). An Evaluation of Carcinogenic 

Potential of R-1143 (NUOSEPT® 95) Employing the C3H/10T1⁄2 Cell Transformation System. 

EG&G Mason Research Institute.

93050026 (MRID#, Reformat of 00088953) Anonymous (1979). Dominant lethal study of 

Nuosept 95. SRI International.

US EPA. (2005) Azadioxabicyclooctane - Report of the Antimicrobial Division Toxicology 

Endpoint Selection Committee (Memorandum: T. McMahon and M. Centra, April 20, 2005)

US EPA. (2005a) Reregistration Eligibility Decision for Azadioxabicyclooctane. EPA 739-R-05-

0110, September 2005.

US EPA. (2005b) Reregistration Eligibility Decision for Azadioxabicyclooctane. 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 

(Memorandum: I. Blackwell to L. Wormell, November 14, 2012).

US EPA. (2012c) Acute Toxicity Review for EPA: GDCI.-107001-32540. EPA Reg. No. 1529-

28 and 1529-49. DP Barcode: D405272. Generic Group Name: Azadioxabicyclooctane 

(Memorandum: I. Blackwell to L. Wormell, November 20, 2012).

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. (1980). 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 

Nuosept 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. Laboratory 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. Minderhout, T., Kenal, T.Z., Kruger, H.O. 2008. Nuosept 95: A 48Hour 

Static Renewal Acute Toxicity Test with the Cladoceran (Daphnia magna). An unpublished 

study performed by Wildlife International, Ltd., Easton, Maryland, USA. Laboratory project 

number 633A-105. Study sponsored by International Specialty Products, 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. Unpublished data. Conducted by EG&G 

Bionomics, Inc., for Huls America, Inc. (formerly Nuodex, Inc., formerly Tenneco Chemicals, 

Inc.). Also submitted by Creanova, Inc., 1990.

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

data. Conducted by EG&G Bionomics for Nuodex, Inc.

ACC#250533. Acute Toxicity of Nuosept 95 to Sheepshead Minnows (Cyprinodon variegatus). 

Unpublished data. Conducted by EG&G Bionomics for Nuodex, Inc.

ACC#250533. Suprenant, D.C. 1983. Acute 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: ECOTOXicology 

Database System. Version 3.0. Available: http://www.epa.gov/ecotox/
Page 40 of 56

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

Petrie, R.C. 2008. Ecological Hazard and Environmental Risk Assessment Chapter 

Formaldehye, Paraformaldehyde. Reregistration Eligibility Document (RED). USEPA. 
Page 41 of 56

Appendix A Toxicology 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 sensitizer. 

Acute toxicity data for azadioxabicyclooctane are summarized below in Table 13.

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

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

Guideline 

Number

Study Type MRID 

Number Results Toxicity 

Category

870.1100 Acute Oral - Rat 41641601 LD50 = 1940 mg/kg III

870.1200 Acute Dermal - Rabbit 41671801 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation – Rat

(whole body exposure)

42650901 LC50 > 0.441 mg/L < 0.819 mg/L

(males + females, combined)

II

870.1300 Acute Inhalation – Rat

(nose only exposure)*

48082401 LC50 = 2.861 mg/L 

(males + females, combined)

IV

870.2400 Primary Eye Irritation - Rabbit 41641602 Corrosive I

870.2500 Primary Dermal Irritation - Rabbit 41641603 Moderate irritant III

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

N/A = Not applicable

*This acute inhalation toxicity study was submitted to support registration of EPA Reg. No.’s 1529-28 and 1529-49, 

the sole products in the azadioxabicyclooctane case.

Subchronic Toxicity 

Repeat-dose toxicity data for azadioxabicyclooctane include a 90-day oral toxicity study in the 

rat, a 90-day inhalation 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 410801010), Nuosept® 95 was administered to 20 CD1 Sprague-Dawley derived 
Page 42 of 56

rats/sex/dose in drinking water at dose levels of 0, 125, 625, or 3125 ppm (equivalent to 0, 20, 

100, or 500 mg/kg bw/day; actual intake reported was 0, 13, 62, and 245 mg/kg/day). Four 

rats/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 efficiency 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 

Acceptable/Non-guideline. Definitive conclusions regarding the basis of the organ weight 

changes and enzyme changes could not be made due to the lack of a complete histopathology 

report. However, although there is missing data, the study contains useful information for 

establishment of a NOEAEL/LOAEL, with 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 doses of 0, 100, 

300, and 1000 mg/kg/day, 6 hours/day for 5 days/week during a 21-day period. No treatmentrelated effects on clinical observations and mean absolute or relative organ weights were 

observed. Significant findings were presented for food consumption, body weight, hematology, 

and clinical chemistry parameters, however these findings were not considered to be treatmentrelated. 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 classified 

Acceptable/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 targeted concentrations of 0, 0.01, 0.05, and 0.5/0.3 mg/L for 6 

hours per day, 5 days/week for 13 weeks, Actual 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%), spleen (21%), and epididymides (21%) in 
Page 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 considered toxicologicallhy significant. The LOAEL is 0.3 mg/L (300 mg/m3) 

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/m3

). This 

90- day inhalation toxicity study in rats is classified Acceptable/Non-guideline. Although this 

study does not satisfy the guideline requirement for a 90-day inhalation 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 identification 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 tract in males and females as well as a No-Observed-Adverse-Effect Level 

(NOAEL).

Developmental Toxicity 

In a dermal developmental toxicity study (MRID 41537501, reformat of 41699001), 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. There were no treatment related effects in mortality, 

clinical signs, weight gain, food consumption, gross necropsy 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 

obscured the treatment site, and edema that was well-defined by study termination. The highdose 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 underlying musculature. 

The LOAEL for maternal dermal toxicity is 100 mg/kg/day (based on severe dermal irritation); a 

NOAEL could not be established. The systemic maternal toxicity NOAEL is greater than or 

equal to 1000 mg/kg/day; the systemic maternal toxicity LOAEL is greater than 1000 mg/kg/day. 

There were no other embryotoxic or fetotoxic effects observed in this study. The developmental 

NOAEL is greater than or equal to 1000 mg/kg/day; the developmental LOAEL is greater than 

1000 mg/kg/day. This developmental toxicity study in the rabbit is classified Acceptable/ Nonguideline.

Reproductive Toxicity

There are no data evaluating the potential reproductive toxicity of azadioxabicyclooctane. For 

the indirect food use of this chemical mixture. Under registration 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 there are no data evaluating the potential chronic toxicity of azadioxabicyclooctane, 

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 labeled 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 carcinogenicity of this chemical mixture. However, the 

metalworking 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 

azadioxabicyclooctane 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 several 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 due 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 responses 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 literature that addresses immunotoxicity of 

azadioxabicyclooctane, 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-datarequirement.pdf
Page 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 from this active in various environmental media 

are due to the three components.

The degradates from the three azadioxabicyclooctane compounds without the formaldehyde (–

CH2O) moiety are as follows: 

• Component I minus the formaldehyde (–CH2O) moiety becomes Component II, 

• Component II minus the –CH2O becomes degradate IIa.

• All of the potential degradates of Component III are unknown and information on the 

degradates formed is anticipated as needed. 

The agency has no environmental fate data on the degradates for azadioxabicyclooctane, see 

Table 6 for the anticipated data requirements.

Water and Sediment

Hydrolysis

The mixture of the three components in this case do not undergo hydrolysis in the buffered 

conditions at pH 5, 7, and 9, and in the 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 agency anticipates the need to require hydrolysis data for the degradates.

Aqueous Photolysis

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 Kow is less than 1 for the parent, and therefore azadioxabicyclooctane 

components are not likely to be bioaccumulative. However, since no data are available for the 

degradates, the agency anticipates the need to require data for the degradates.

Aerobic Aquatic Metabolism

No measured or estimated data are available for both parents and degradates, data is anticipated 

to be required.

Anaerobic Aquatic Metabolism

No measured or estimated data are available is available for both parents and degradates, data is 

anticipated to be required.

Soil

Soil Leaching/Adsorption/Desorption Batch Equilibrium

Estimated Log Koc values for the mixture indicate that mobility from soil surfaces is high for the 

parent. No data are available for the degradates, the agency anticipates the need to require data.

Aerobic Soil Metabolism

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

agency anticipates the need to require data.

Anaerobic Soil Metabolism

No measured or estimated data are available for the mixture for either the parent or degradates. 

The agency anticipates the need to require data.

Fate and Transport in WWTP

Activated Sludge Sorption Isotherm

The activated sludge sorption isotherm test is not required if the log Kow is less than 3.0, the log 

Kow for azadioxabicyclooctane is less than 1.0. EPI Suite was run for degradates with –CH2O 

removed in series. The log Kow for these degradates is less than 3.0. The agency does 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. The azadioxabicyclooctane 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 open 

literature concerning the toxicity of formaldehyde to non-target organisms and determine if any 

formaldehyde studies 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 of this pesticide to birds, the agency requires an acute 

oral toxicity study using 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 (Table C1).

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

Species % Active 

Ingredient 

(ai)

Endpoint 

(mg /kg 

product) 

Toxicity 

Category

Satisfies Guidelines/ 

Comments

Reference

Mallard 

duck (Anas 

platyrhynch

os)

107001 

24.5%

107002 

17.7%

107003 

7.8%

LD50 > 

2,510

NOEL = 

2510 

(mortality)

Practicall

y nontoxic

Yes

- acceptable for 

formulated product

- 14-day test duration 

Beavers, 

1983 (ACC 

# 250533)

The results of these studies indicate that 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 azadioxabicyclooctane, 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 lower tier ecological studies and pertinent environmental characteristics to 

establish the toxicity of a pesticide to avian species. The preferred test species are mallard duck 
Page 49 of 56

or northern bobwhite quail. This testing is not anticipated to be required for the currently 

supported uses on azadioxabicyclooctane; however, three avian dietary studies were previously 

submitted to the agency. The results of these are provided in the following table (Table C2).

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

Species % Active 

Ingredient 

(ai)

Endpoint 

(ppm) 

Toxicity 

Category

Satisfies Guidelines/ 

Comments

Reference

Bobwhite 

quail 

(Colinus 

virginianus)

50% LC50 >5,200 

a.i. (>10,400 

product)

NOEC 1541 

ppm a.i. 

(3082 ppm 

product)

Practically 

non-toxic

No

- supplemental study 

- administered in 

drinking water rather 

than food

Hakin et 

al., 1990 

(MRID 

416848-01)

Bobwhite 

quail 

(Colinus 

virginianus)

not 

reported

LC50 > 

10,000 ppm 

product 

NOEC 

10,000 ppm

Practically 

non-toxic

Yes

- acceptable for 

formulated product

- single mortality at 

10,000 ppm; no other 

mortality reported

Truslow 

Farms, 

1974. 

(ACC#248

78)

Mallard 

duck (Anas 

platyrhynch

os)

not 

reported

LC50 > 

10,000 ppm 

product 

NOEC 

10,000 ppm

Practically 

non-toxic

Yes

- acceptable for 

formulated product

- no mortality reported 

at any test concentration

Truslow 

Farms, 

1974. 

(ACC#248

78)

The results of the study indicate that Nuosept® 95 is practically non-toxic to birds via dietary 

exposure. Although conducted using a formulated product and not the TGAI, these studies are 

considered adequate to support the registered uses on azadioxabicyclooctane, as Nuosept® 95 is 

the only end-use product. The Guideline requirements (850.2200/71-2) are fulfilled. No 

additional data are anticipated to be required.
Page 50 of 56

Mammals

Wild mammal testing was not required for azadioxabicyclooctane. 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 

C3). No additional data are anticipated to be required.

Table C3. Acute Toxicity of Nuosept® 95 to Mammals

Species Test Type LD50

(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/estuarine 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 pesticides to freshwater fish, the agency 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 studies were submitted to the agency for azadioxabicyclooctane using the formulated 

product Nuosept95. The results of these studies are presented in Table C4.

Table C4: Acute Toxicity of Nuosept95 to Freshwater Fish.

Species % Active 

Ingredient (ai)

Endpoints (ppm 

product) 

Toxicity 

Category

Satisfies Guidelines/ Comments Reference

Rainbow trout

(Oncorhyn-chus 

mykiss)

not reported LC50 = 240

NOEC = 87

practically 

non- toxic

No

- supplemental 

- 96h test duration; 

- static system

Bentley and 

Sleight, 1974 

(ACC #247878; 

MRID 930500-

15)

Bluegill 

(Lepomis 

macrochirus)

not reported LC50 = 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 LC50 = 34.7

ppm ai

NOAEC = 

26.22 ppm ai

(measured)

slightly toxic Yes

-96hr test duration

-static renewal (renewed 

daily)

Minderhout, et.

al., 2008. MRID 

48082403 

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

Two of these studies were originally submitted and reviewed by OPP in 1982, and were 

determined to be acceptable for formulated product testing. However, they were resubmitted by 

Creanova, Inc., and re-reviewed in 2002, and classified as supplemental information due 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 fulfill OCSPP test guidelines. 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 additional 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 database 

(EPA, 2002) was searched for any appropriate chronic testing with fish, but no such data were 

located.

Freshwater Invertebrates

The agency 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 C5). 

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

Species % Active 

Ingredient 

(ai)

Endpoints 

(ppm 

product)

Toxicity 

Category

Satisfies Guidelines/ 

Comments

Reference

Water flea

(Daphnia 

magna)

107001 

24.5%

107002 

17.7%

107003 

7.8%

EC50 = 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 LC50 = 35

NOAEC = 

28.36

slightly toxic Yes

-acceptable for formulated 

product

-48h test duration

-static system

Minderhout, 

et.al., 2008

MRID 

48082404

The results indicate that Nuosept® 95 is slightly toxic to aquatic 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 azadioxabicyclooctane, since Nuosept® 95 is 

the only end-use product. The studies are acceptable and fulfill the OCSPP test guideline 

(850.1010). For freshwater invertebrates, no 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 data were located.
Page 53 of 56

Estuarine/Marine Fish

Acute testing with estuarine/marine fish is required to support the uses of azadioxabicyclooctane. 

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

agency, and the results are summarized in Table C6, below.

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

Species % Active 

Ingredient 

(ai)

Endpoints 

(ppm 

product)

Toxicity 

Category

Satisfies Guidelines/ 

Comments

Reference

Sheepshead 

minnow

(Cyprinodon 

variegatus)

PC code %

107001 24.5%

107002 17.7%

107003 7.8%

LC50 = 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 azadioxabicyclooctane, since Nuosept 95 is the only enduse product. The study is acceptable and fulfills the OCSPP test guideline (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 

azadioxabicyclooctane. This testing is conducted with an invertebrate species. These data were 

submitted to the agency and the results are summarized in Table C7, below.

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

Species % Active 

Ingredient 

(ai)

Endpoints 

(ppm 

product)

Toxicity 

Category

Satisfies Guidelines/ 

Comments

Reference

Eastern oyster

(Crassostrea 

virginica)

PCCode %

107001 24.5%

107002 17.7%

107003 7.8%

EC50 = 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

Aquatic plant testing is required to support the registered uses of azadioxabicyclooctane. 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, no studies on plant toxicity have been 

submitted to the agency. The ECOTOX database (EPA, 2002) was searched for any plant 

toxicity information on the components of azadioxabicyclooctane. 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 product chemistry information is summarized in Table D1 (source: 

MRIDs 42734301, 42740801, 41671601, 41671602, 41671603, 48691701, ISP MSDS for 

Nuosept 95 Technical).

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

Guideline 

No.

Physical and Chemical 

Properties

Equilibrium Mixture of 3 inseparable AIs in Nuosept 95 Technical::

• 5-Hydroxymethoxymethyl-1-aza-3,7-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 Clear colorless liquid

Clear pale yellow liquid

830.6303 Physical State Clear liquid

830.6304 Odor Mild, characteristic odor

Formaldehyde odor

830.6313 

Stability to normal and 

elevated temperature, 

metals/metal ions 

Stable.

This product is stable under normal storage conditions.

830.6314 Oxidation/Reduction Incompatible with oxidizing materials, acids and bases.

Condition to avoid: Excessive heat or extremes of pH may cause 

decomposition.

830.6315 Flammability Flash Point (SCC): 140°F

Flash Point (TCC): >200°F

830.6316 Explodability Not explosive

830.6320 Corrosion Characteristic

830.7000 pH 6.0-7.5

830.7050 UV/Visible Absorption Not reported

830.7200 Melting point Not applicable for liquids

Freezing point: -2.2 °F

830.7220 Boiling point 100°C

830.7300 Density 1.145 g/ml at 25°C
Page 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 (noctanol/water) Log Kow: <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)