Page 2 of 59Bioban P

- 1487 Registration Review Team

Human Health & Environmental Effects Nate Mottl Jenny Tao Najm Shamim Pat Jennings Bill Erickson Katelynn King Sumitra Biswas

Risk Management Karen Leavy Seiichi Murasaki SanYvette Williams Rose Kyprianou

Office of General Counsel Philip Ross

Page 3 of 59TERMS, ABBREVIATIONS AND SYMBOLS

AD Antimicrobials Division A.I. or a.i. active ingredient aPAD a cute p opulation a djusted d ose ASRI a ctivated sludge r espiration i nhibition atm

- m 3 /mole a tmospheric pressure

- cubi c meter per mole BCF b ioconcentration f actor °C d egrees Celsius CAS Chemical Abstracts Service CFR Code of Federal Regulations CHO Chinese h amster o vary CMA Chemical Manufacturers Association CO 2 c arbon dioxide COC c oncentration

- of

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

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

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

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

- water partition coefficient Kd s o il

- water partition coefficient Kow o ctanol

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

- o bserved

- a dverse

- e ffect

- c oncentration LOEC l owest

- o bserved

- e ffect

- c oncentration LOAEL lowest

- observed

- adverse

- e ffect

- l evel Log K ow l ogarithm of the octanol

- water partition coefficient μg m icrogram ml/g m illiliter p er g ram mg/kg m illigram p er k ilogram mg/kg/day m illigram p er k ilogram p er d ay mg/L m illigram p er l iter mm Hg m illim eter of mercury MOE m argin of e xposure Page 4 of 59MRID Master Record Identification Number MRL m aximum r esidue l imit N/A n ot a pplicable
nm n anometers NOAEC no

- observed

- adverse

- effect

- c oncentration NOAEL n o

- o bserved

- a dverse

- e ffect

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

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

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

- a ctivity r elationship RED Rere gistration Eligibility Decision SAR s tructure a ctivity r elationship SF s afe ty f actor SSTS Section Seven Tracking System TEP t ypical e nd

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

Page 5 of 59

### Table of Contents 1 Introduction

................................ ................................ ................................ ............................. 8 1.1 Statutory and Regulatory Authority

................................ ................................ ................. 8 1.2 Case Overview

................................ ................................ ................................ ................. 8 1.3 Chemical Identification and Properties

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

................................ ................................ ................................ ... 12 1.4.1 Registrations

................................ ................................ ................................ ........... 12 1.4.2 Summary of Registered Uses

................................ ................................ .................. 12 1.4.3 Usage Information

................................ ................................ ................................ .. 12 1.5 Regulatory History

................................ ................................ ................................ ......... 12 1.5.1 Tolerance Information

................................ ................................ ............................ 13 1.6 Incidents

................................ ................................ ................................ ......................... 13 1.6.1 Human Health

................................ ................................ ................................ ......... 13 1.6.2 Ecological

................................ ................................ ................................ ............... 13 2 Anticipated Data Needs

................................ ................................ ................................ ........ 13 3 Human Health Risk Assessment

................................ ................................ ........................... 16 3.1 Existing Toxicologica l Endpoints

................................ ................................ .................. 16 3.2 Dietary Exposure

................................ ................................ ................................ ............ 18 3.2.1 Food

................................ ................................ ................................ ........................ 18 3.2.2 Dr inking Water

................................ ................................ ................................ ....... 18 3.3 Occupational and Residential Exposures

................................ ................................ ....... 18 3.3.1 Occupational Handler Exposure

................................ ................................ ............. 18 3.3.2 Occupational Post

- application Exposures

................................ ............................... 19 3.3.3 Residential Handler Exposures

................................ ................................ ............... 19 3.3.4 Residential Post

- Application Exposures

................................ ................................ . 19 3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 19 3.4.1 Aggregate Exposures

................................ ................................ .............................. 19 3.4.2 Cumulative Exposures

................................ ................................ ............................ 19 4 Environmental Risk Assessment

................................ ................................ ........................... 19 4. 1 Environmental Fate Assessment

................................ ................................ .................... 20 4.1.1 Fate and Effects during Wastewater Treatment

................................ ...................... 21 4.2 Conceptual Models for Environment al Exposure Pathways

................................ .......... 21 4.3 Ecological Effects Assessment

................................ ................................ ....................... 22 4.3.1 Mechanism of Action

................................ ................................ .............................. 22 4.3.2 Measure of Effects (Ecotoxicology Endpoints)

................................ ...................... 22 4.3.3 Open Literature

................................ ................................ ................................ ....... 23 4.4 Exposure Analy sis Plan

................................ ................................ ................................ .. 23 4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............ 23 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 23 6 Optional Label Changes

................................ ................................ ................................ ........ 24 7 Guidance for Commenters

................................ ................................ ................................ .... 24 7.1 Pre liminary Work Plan

................................ ................................ ................................ ... 24 7.1.1 Trade Irritants

................................ ................................ ................................ .......... 24 7.1.2 Water Quality

................................ ................................ ................................ .......... 25 7.1.3 Environmental Justice

................................ ................................ ............................. 25 7.1.4 Structure Activity Relationships

................................ ................................ ............. 25
Page 6 of 597.1.5 Additional Information

................................ ................................ ........................... 26 8 Next Steps

................................ ................................ ................................ ............................. 27 9 References

................................ ................................ ................................ ............................. 28 Appendix A T oxicology Profile

................................ ................................ ............................... 29 Appendix B Environmental Fate

................................ ................................ ............................. 48 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 52 Appendix D Screening Level Down

- the

- Drain Analysis

................................ ........................ 56 Appendix E Product Chemistry

................................ ................................ ............................... 57

List of Tables Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registration Review: Bioban P

- 1487

................................ ................................ ................................ ................................ 9 Table 2

– Anticipated Registration Review Schedule

................................ ................................ .... 9 Table 3

– Chemical Identification of Bioban P

- 1487 Mixture

................................ ..................... 10 Table 4

– Physical

- Chemical and Environmental Fate Properties for Bioban P

- 1487

................. 11 Table 5

– Physical/Chemical Properties of Bioban P

- 1487 Degradates Based on Estimated Values from EPI

- Suite 4.11

................................ ................................ ................................ .......... 11 Table 6

– Summary of Bioban P

- 1487 Registered Uses

................................ ............................... 12 Table 7

– Studies Anticipated as Needed for the Registration Review of Bioban P

- 1487

........... 14 Table 8

– Data Required by the February 23 and April 7, 2010 Data Call

- In for the Bioban P

1487 RED

................................ ................................ ................................ ................................ ...... 15 Table 9

– Existing Toxicological Endpoints for Bioban P

- 1487

................................ .................. 16 Table 10

– Available Ecological Effects Endpoints

................................ ................................ ..... 22

Page 7 of 59

## 1 Introduction

This document is the United States Environmental Protection Agency ’s ( USEPA, EPA or “ the agency ”) Preliminary Work Plan (PWP) for Bioban P

- 1487 . The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about B ioban P

- 1487 , highlighting anticipated data and assessment needs, identifying the types of information that wou ld be especially useful to the agency in conducting the review, and providing an anticipated timeline for completing B ioban P

- 1487 ’s review. The registration review process was designed to include a public participation component to solicit input from inte rested stakeholders. The agency intends, by sharing this information in the docket, to inform the public of what it knows about B ioban P

- 1487 and what types of new data or other information would be helpful for the agency to receive as it moves toward a de cision

. 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 Prote ction 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 statutor y standard of no unreasonable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the agency periodically reevaluates pesticides t o make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at http://www2.epa.gov/pesticide

- reevaluation

. The agency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registrati on. The regulations governing registration review begin at 40 CF R 155.40. The agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docke t 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 i n the docket during this initial comment period, the agency will develop and commit to a F inal W ork P lan (FWP) and anticipated schedule for the B ioban P

- 1487 case

. 

## 1.2 Case Overview
The docket for Bioban P

- 1487 ( c ase 3028 ) has been established at http://www.regulations.gov in docket number EPA

- HQ

- OPP

- 2014

- 0802. Documents associated with this registration review

Page 8 of 59can be viewed in this docket. Tables 1 and 2 b elow summar ize the issues relevant to this registration review case and the anticipated registration review schedule

. Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registration Review : Bioban P

- 1487

Risk Assessment Assessment Necessary to

Support Registration Review D ate of Most Recent Assessment Type of Assessment

Required (New/Updated) Data Anticipated as Needed (See Table 7 for detail s)

Dietary (food) No N/A None None Dietary (drinking water) Yes N/A New None Occupational Handler Yes September 2007 Updated See Table 7 Occupational Post

application Yes September 2007 Updated See Table 7

Residential Handler No N/A None None Resident i al Post Application

- Incidental Oral and Dermal No N/A None None

Resident i al Post Application

- Inhalation No N/A None None Aggregate No N/A None None Cumulative No N/A None None Tolerance Review No N/A None None Ecological Yes N/A New See Table 7 N/A = Not applicable * Table 1 is a summary of the anticipated risk assessments a nd data needs for Registration Review. For d ata called in through the post

Reregistration Eligibility Decision (RED) Data Call

- In (DCI), see Table 8

.

Table 2

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

- Day Comment Period for Preli minary Work Plan 2015

- 03 2015

- 03

Close Public Comment Period 2015

- 05
Phase 2: Case Development
Issue Final Work Plan 2015

- 09

Issue Data Call

- In (DCI) 2016

- 09

Receive Data to be Cons idered in Risk Assessment 2018

- 09
Open 30

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

- 03
Close Public Comment Period 2020

- 04
Page 9 of 59Phase 3: Registration Review Decision and Implementation Open 60

- Day Public Comment Period for Pro po sed Decision 2020

- 09

Close Public Comment Period 2020

- 11

Issue Final Decision 2021

- 03
Begin Post

- Decision Followup 2021 Total (years) 6

* The anticipated schedule will be revised as necessary ( e.g ., need arising under the Endocrine Disruptor Scr eening Program with respect to the active ingredients in this case). 

## 1.3 Chemical Identification and Properties

Table 3 presents chemical identification data for the actives:

Bioban P

- 1487 (case No. 3028) consists of two activ e ingredients: ( 1) 4

- (2

- Nitrobutyl) morpholine ( 81% , PC code: 100801 , Bioban P

- 1447 ) and ( 2) 4,4’

- (2

- ethyl

- 2

- nitromethylene)dimorpholine (5 %, PC Code 100802, Bioban P

- 1490 ) . Ingredient I is called P

- 1447 and ingredient II is called P

- 1490. Together they co mprise Bioban P

- 1487.

Table 3

– Chemical Identification of Bioban P

- 1487 Mixture

Chemical Name 4

- (2

- nitrobutyl)morpholine ( P

- 1447, 81%) 4,4’

- (2

- ethyl

- 2

- nitrotrimthyelene) dimorpholine (P

- 1490, 5%) Chemical Classification 1

- aza

- 4

- o xacyclohexane 1

- aza

- 4

- oxacyclohexane
PC Code 100801 10080 2 CAS N umber 2224

- 44

- 4 1854

- 23

- 5 Molecular Formula C 8 H 16 N 2 O 3 C 13 H 25 N 3 O 4 Molecular Weight (grams/mole) 208 287

Molecular Structure

4

- (2

- nitrobutyl) Morpholine; CAS# 2224

- 44

- 4 4,4’

- (2

- e thyl

- 2

- nitromethylene)dimorpholine: CAS# 1854

- 23

- 5

The Bioban P

- 1487 product chemistry information relevant to risk assessment is summarized in Table 4 . The details of the product chemistry informat ion are discussed in Appendix E

. Page 10 of 59Table 4

– Physical

- Chemical and Environmental Fate Properties for Bioban P

- 1487
Guideline No. P arameter 4

- (2

- nitrobutyl) Morpholine P

- 1447 4,4’

- (2

- ethyl

- 2

- nitromethylene)dimor pholine P

- 1490 Sourc e (MRID unless specified)

830.7050 UV Visible absorption Sorption below 210 nm (acid and neutral) and below 275 nm (basic) Sorption below 210 nm (acid and neutral) and below 275 nm (basic) 48511302

830.7550 Octanol

- water partition coefficient at 25 o C (L og K ow ) 0.18

- 0.54 EPI Suite 4.11

830.7840 Solubility in water (mg/L) 11 ,000 m g/L 11 ,000 m g/L 41995101

830.7950 Vapor pressure (mmHg) 20

- 43 mm Hg (90 o C )

__________________ 7.58 x 10

- 3 (25 o C) 20

- 43 mm Hg (90 o C)

_____________________ 5.07 x10

- 6 (25 o C) 41995101

___________ EPI Suite (version 4.1)

None Henry’s Law (atm m 3 mol

- 1 ) 1.1 x10

- 10 1.51 x 10

- 15 EPI Suite (version 4.1)

o C = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury; Henry’s Law in atm m 3 mol

- 1 According t o a hydrolysis study of Bioban P

- 1487 (MRID 43494001), the primary residues in the env ironment are expected to be P

- 1447 and degradates 2

- nitropropane, 2

- nitro

- 1

- butanol and 2

- nitro

- 1

- butene. Table 5 pre s ents the estimated chemical and physical properties of these degradates.

Table 5

– Physical/Chemical Properties of Bioban P

- 1487 Degradates Based on Estimated Values from EPI

- Suite 4.11
P/Chem and Environmental Fate Property Degradate 2

- Nitropropane

CAS# 79

- 46

- 9 2

- Nitro

- 1

- Butano l CAS# 609

- 31

- 4 2

- Nitro

- 1

- Butene CAS# 2783

- 12

- 2 Structure

Molecular weight (g/mol) 89.9 119.2 101.12
Log Kow 0.87

- .101

- 0.101 Solubility in water (mg/L) 8 , 18 0 50 , 3 00 50 ,300
Log Koc 1.65 0.73 0.73 Vapor pressure (mm Hg) 15.5 0.056 0.43
Henry ’s Law (atm
m 3 mol

- 1 ) 2.2 x 10

- 4 1.7 x 10

- 7 1.1 x 10

- 6

Page 11 of 59

## 1.4 Use/Usage Description 1.4.1 Registrations The first product containing Bioban P

- 1487 was registered on June 7, 1972. There are three antimicrobial products registered that contain the Bioban P

- 1487 m ixture.


### 1.4.2 Summary of Registered Uses For inhibition of microorganism growth, Bioban P

- 1487 is applied to various sites, including industrial processes and water systems such as metalworking fluids; oil storage tank bottom water, fuel storage tank bottom wate r; and to diesel oil, fuel oil, gasoline, and kerosene, as a hydrocarbon preservative. As a materials preservative, Bioban P

- 1487 is formulated into products such as metal die cast lubricants, corrosion inhibiting metal coatings, mold

- release agents (for t he manufacture of plastics), and fuel conditioners (for diesel engines). It is not registered for any direct or indirect food uses

. Table 6 presents a summary of the registered uses
o f Bioban P

- 1487 that will be assessed in this registration review

. Table 6

– Summary of Bioban P

- 1487 Registered Uses

Use Application Method Application Rate Material Preservatives

Metal Working Machinist Exposure Liquid Pour Liquid P ump 2580 ppm 860 ppm 854 ppm Corrosion Inhibiting Metal Coatings and Mold

- Release agents* Unknown 100

- 3000 ppm

Fuel Liquid Pour Liquid Pump 860 ppm 854 ppm 155 ppm

* Directions for use for the corrosion inhibiting metal co atings and mold

- releasing agents do not specify an application method. In the absence of updated labels clarifying application method, EPA will assume products are applied by liquid pour or pump

. 

### 1.4.3 Usage Information According to the Kline Biocides Report for 2004/2005 (Kline, 2005 ), ~ 177 ,000 kg of Bioban P

1487 was estimated to be produced in 2005

. 

## 1.5 Regulatory H istor y The first product containing Bioban P

- 1487 was registered on June 7, 1972. Currently, Bioban P

1487 consists of a mixture of two active ingre dients: compound I (P

- 1447 ) , 4

- (2

- nitrob utyl) morpholine , and compound II (P

- 1490 ) , 4,4’

- (2

- ethyl

- 2

- nitromethylene) dimorpholine. Products containing Bioban P

- 1487 are registered for indoor use as a materials preservative and as a microbial growth inhibitor of slime

- forming fungi and bacteria.

Page 12 of 59In 2007 , EPA completed the Reregistration Eligibility Decision ( RED ) for Bioban P

- 1487

. DCI’s were issued in February and Ap ril of 2010 for confirmatory data needed to support the RED

. 

### 1.5.1 Tolerance Information For Bioban P

- 1487, th ere are no registered direct or indirect food contact uses . Therefore, EPA has not established tolerances or exemptions from tolerances in/on any raw agricultural commodities or processed food and feed products under the Federal Food, Drug and Cosmetic Act (FFDCA) Section 408. Bioban P

- 1487 has not been cleared as a food additive by the US Food and Drug Administration (US FDA) under FFDCA Section 409.


## 1.6 Incidents 1.6.1 Human Health No Bioban P

- 1487 human poisoning incidents have been reported in OPP’s Incident D ata System (IDS) since 1992, based on the search conducted on January 28, 2015.


### 1.6.2 Ecological

T here are no Bioban P

- 1487 ecological incidents reported in OPP’s Incident Data System ( IDS ) as of January 28 , 201 5. 

## 2 A nticipated Data Needs

Several studies were re quired f ollowing the assessment of Bioban P

- 1487 in the 2007 Reregistration Eligibility Decision ( RED ) . In addition to the already

- required RED DCI data, studies listed in Table 7 are expected to be needed for the registration review of Bioban P

- 1487. Tabl e 8 outlines the data required by the post

- RED DCI issued on February 23, 2010 and April 7, 2010. In addition to the parent compound , environmental fate and ecological effects data are expected to be required f or three degradates, 2

- nitropropane, 2

- nitro

- 1

- butanol, and 2

- nitro

- 1

- butene ( s ee S ection 4.1)

. The agency anticipates reviewing data received in response to the post

RED DCI as well as data that will be requ ired for this registration review prior to conduct ing the registration review risk assessments for Bioban P

- 1487

.

Page 13 of 59Docket Number EPA

- HQ

- OPP

- 2014

- 0802 www.regulations.gov
Table 7

– Studies Anticipated as Needed for the Registration Review of Bioban P

- 1487

GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Ri sk Assessment(s)

Data Will Support Use Site(s) Triggering Anticipated Data Requirement Applicable Exposure Scenario

835.3110 1,2 835.3220 835.3240 835.3280 Biodegradability in WWTP D egradates 3 1 2 Environ mental fate and transport

Metalworking fluids/ industrial coatings, preservative in plastic products, fuel/oil storage tank bottom water additive W aste water treatment plant ( WWTP )

850.3300 2 Activated sludge respiration inhibition (ASRI) D egradates 3 12 Environmental fate and transport WWTP

8 35

. 4300 Aerobic aquatic metabolism T GA I 12 E nvironmental f ate and t ransport All

870.3465 90

- day inhalation toxicity TGA I 12 Human Health Exposure All

870.7800 Immunotoxicity TGAI 12 Human Health Exposure All

850.1010 Freshwater invertebrates, acute Degradates 3 12 Aquatic organisms Ecological

850.4500 Algal toxicity, freshwater and saltwater diatoms T GAI and Degrada tes 3 12 Aquatic plants Ecological

850.4550 Cyanobacteria toxicity T GAI and Degradates 3 12 Aquatic organisms Ecological

850. 4400 Aquatic plant toxicity, Lemna sp. T GAI and Degradates 3 12 Aquatic organisms Ecological

850.1075 Freshwater and
e stuari ne/marine fish, acute toxicity TGAI and Degradates 3 , 5 1 2 Saltwater organisms Ecological

850.1025
or 850.1055 Oyster, shell deposition
or Bivalve embryo larval toxicity TGAI and Degradates 3 12 Saltwater organisms Ecological

850.1035 Mysid, acute toxici ty TGAI and Degradates 3 12 Saltwater organisms Ecological

850.1400 Fish, early life stage Degradates 4 2 4 Aquatic organisms Ecological

850.1300 Aquatic invertebrate, life cycle Degradates 4 2 4 Aquatic organisms Ecological

875.1100 Dermal exposure EP 24 Occupational handler Metalworking fluids Fuel Liquid pour

875.1200 Inhalation exposure EP 24 Occupational handler Metalworking fluids Fuel Liquid pour

875.1700 Product use EP 12 Occupational handler Metalworking fluids Fuel Liquid pour Liquid pump

Page 14 of 59GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Ri sk Assessment(s)

Data Will Support Use Site(s) Triggering Anticipated Data Requirement Applicable Exposure Scenario

875. 2400 Dermal exposure EP 24 Occupational post

- application (machinist) Metalworking fluids Occupational post

application (machinist)

875.2500 Inhalation exposure EP 24 Occupational post

- application (machinist) Metalworking fluids Occupational post

applicati on (machinist)

875.2700 Product use EP 12 Occupational post

- application Metalworking fluids Occupational post

application (machinist)

875.2800 Description of human activity EP 12 Occupational post

- application Metalworking fluids Occupational post

applica tion (machinist)

1 A n ASRI study (MRID 47005503) was conducted on P

- 1487 and the IC 50 value was determined to be 306 mg/L, which is greater than the 20 mg/l threshold that would trigger a waste water treatment plant biodegradation simulation test. Althoug h a ready biodegradability study (MRID 4700550 2 ) was conducted, based on the results, it was determined that P

- 1487 was not
r eadily biodegradable. Hydrolysis leads to fairly rapid formation of degradates. Consequently for the degradates , one of the followi ng: a) Biodegradation in Activated Sludge or b) Simulation Test

- Aerobic Sewage Treatment: A. Activated Sludge Units, or c) the Porous Pot study is expected to be required

. 2 An ASRI study is required for the degradates , 2

- nitropropane, 2

- nitro

- 1

- butanol , and 2

- nitro

- 1

- butene

. The results of the Activated Sludge Respiration Inhibition Test (ASRI) study will determine which of these four biodegradation tests would be 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 would be anticipated to be required. If the ASRI test EC50 is greater than 20 mg/L, then the DCI expected to be issued would provide that the registrant would choose 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 Poro us 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 be expected to be required.
3 S tudy is expected to be required for any or all three degradates ( 2

- nitropropane, 2

- nitro1

- 1butanol and/or 2

- nitro

- 1

- butene) unless the registrant can demonstrate from environmental fate data that the degradate will not occur in wastewater discharge d into the aquatic environment or, for chronic studies, that the degradate will not persist in surface water

. 4 Testing should be done with the most sensitive species (either freshwater or estraurine/marine) as determined from the result s of the acute toxicity tests (EC50 freshwater invertebrate, acute LC50/EC50 estuari ne/marine species).
5 Testing is anticipated to be required on degradates only for freshwater species, but the TGAI and degradates for estuarine/marine species.
Table 8

– Data Required by the February 23 and April 7, 2010 Data Call

- In s for the Bioban P

- 1487 RED

G LN Study Name Status of DCI

850.1010 Aquatic Invertebrate Acute Toxicity Test, Freshwater Daphnids Satisfied for the parent.

870.3800 Reproductive and fertility effects Satisfied.

870.4300 Combined Chronic/carcinogenicity No data have been subm itted; th ese studi e s are outstanding

.

Page 15 of 59

## 3 Human Health Risk Assessment

The a gency anticipates the need to conduct a hu man health risk assessment for Bioban P

- 1487

. The agency will evaluate the data required by the RED DCI

. A lso , the a gency anticipates the need to require additional data for the registration review of Bioban P

- 1487 , based on the currently registered use s. These additional studies include mammalian toxicity data for Bioban P

- 1487 from a 90

- day inhalation toxicity study, an immunotoxicity study , and all applicable exposure studies

. A detailed description of the available toxicity studies is provided in Append ix A.


## 3.1 Existing Toxicological Endpoints

The a gency anticipates the need to revise the existing toxicological endpoints , shown in Table 9 , as part of th e registration review. All available information , including existing toxicology studies and valid scientif ic literature, will be considered in establishing the toxicology endpoints to be used in the registration review risk assessment.

Table 9

– Existing Toxicological Endpoints for Bioban P

- 1487 Exposure Scenario Dose Used in Risk Asse ssment (mg/kg/day) Target MOE, UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects
Dietary Risk Assessments Acute Dietary (all populations) NOAEL(maternal) = 10 UF = 100 (10x inter

species extrapolation, 10x intra

- species variati on) FQPA SF = 10 Developmental Toxicity Study in Rats (MRID 416738801, 41978802) LOAEL = 30 mg/kg/day based on excessive salivation and decreased body weight aRfD = 0.1 mg/kg/day aPAD 1 = 0.01 mg/kg/day Chronic Dietary (all populations) NOAEL( maternal) = 10 UF = 300 (10x inter

species extrapolation, 10x intra

- species variation, 3x for lack of chronic data) FQPA SF = 10 Developmental Toxicity Study in Rats (MRID 416738801, 41978802)

LOAEL = 30 mg/kg/day based on excessive salivation and d ecreased body weight cRfD = 0.03 mg/kg/day cPAD 2 = 0.003 mg/kg/day Non

- Dietary Risk Assessments

Page 16 of 59Exposure Scenario Dose Used in Risk Asse ssment (mg/kg/day) Target MOE, UF, Special FQPA SF, for Risk Assessment Study and Toxicological Effects

Incidental Oral Short

- Term (1

- 30days) and Intermediate

Term (1

- 6 months) No endpoint identified due to lack of residential uses

.

Dermal Short

- Term (1

- 30 days) LOAEL (dermal) = 30 (dermal irritation) MOE = 30 (3x inter

species extrapolation, 3x intra

- species variation, 3x for use of a LOAEL value) 90

- Day (Dermal) Subchronic Toxicity Study in Rats (MRID 42440001, 41619302) LOAEL = 30 mg/kg/day based on skin irritation (erythema and edema) at all doses tested. Dermal Intermediate

Term (1

- 6 months) NOAEL (systemic) =300 MOE = 100 (10x inter

species extrapolation, 10x intra

- species variation) 90

- Day (Dermal) Subchronic Toxicity Study in Rats (MRID 424 40001, 41619302) LOAEL = 1000 mg/kg/day based on decreased body weight, chronic inflammation of the urinary bladder in males and females. Dermal Long

- Term (> 6 months) NOAEL (systemic) =300 MOE = 300 (10x inter

species extrapolation, 10x intra

- species v ariation, 3x for use of a subchronic endpoint for the long

- term endpoint) 90

- Day (Dermal) Subchronic Toxicity Study in Rats (MRID 42440001, 41619302) LOAEL = 1000 mg/kg/day based on decreased body weight, chronic inflammation of the urinary bladder in ma les and females. Inhalation (All Durations) NOAEL(maternal) = 10 MOE = 3000 (10x inter

species extrapolation, 10x intra

- species variation, 30x for severe adverse effects observed in the acute inhalation toxicity study, the lack of repeat inhalation expos ure study, severe skin irritation and dermal sensitization, and use of route extrapolation. Developmental Toxicity Study in Rats (MRID 416738801, 41978802) LOAEL = 30 mg/kg/day based on excessive salivation and decreased body weight

Cancer (oral, de rmal, inhalation) No carcinogenicity data available for Bioban P

- 1487 ; such information has been required in the post RED DCI

. 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
Page 17 of 591 aPAD = aRfD ÷ FQPA SF = 0.1 mg/kg/day ÷ 10 = 0.01 mg/kg/day 2 cPAD = cRfD ÷ FQPA SF = 0.03 ÷ 10 = 0.003 mg/kg/day NOTE: The S pecial FQPA Safety Factor recommended by the A ntimicrobials D ivision T oxicity C ommittee (ADTC ) assumes that the exposure databases (dietary food, drinking water, and residential) are complete and that the risk assessment for eac h potential exposure scenar io includes all metabolites and/or degradates of concern and does not underestimate the potential risk for infants and children. 

## 3.2 Dietary Exposure 3.2.1 Food Based on the current labels, the registered uses of Bioban P

- 1487 are not expected to result in direct or indirect d ietary (food) exposure. Therefore, a dietary (food) assessment is not needed for t his registration review and r esidue chemistry data are not anticipated to be required at this time.


### 3.2.2 Drinking Water
EPA anticipates conducting a drinking water assessment as part of this registration review. T he agency has not previously conducted a drinking water assess m e nt for Bioban P

- 1487 and its degradates

. Based on the registered uses, however , the agency can not rule out the potential for exposure of humans to 4

- (2

- nitrobutyl)morpholine (P

- 1447) , one of the components of Bioban P

1487 and degradates of Bioban P

- 1487 including 2

- nitropropane, 2

- nitro

- 1

- butanol, and 2

- nitro

1

- butene in drinking water . There are uncert a in t i es with respect to the residues of concern in drinking water, including the magnitude of residues , mammalian toxicities, persisten ce in the environment , and potential to be removed during wastewater treatment. Therefore, the age ncy anticipates needing additional environmental fate data as noted in Table 7 . These data will be
use d to determine whether and to what extent degradates of Bioban P

- 1487 pass through the WWTP. The agency anticipat es acquiring data and information from other sources such as open literature during the risk assessment stage of registration review to determine the potential of discharged residues of 4

- (2

- nitrobutyl)morpholine (P

- 1447) and degradates of Bioban P

- 1487 to result in human dietary exposure through drinking water which may trigger drinking water assessment. 

## 3.3 Occupational and Residential Exposures 3.3.1 Occupational Handler Exposure EPA anticipate s the need to revise the occupational handler assessment conducted in support of the 200 7 RED (D3 38283 ). Occupational handler dermal and inhalation exposures to Bi oban P

1487 were assessed in the RED for the following applications: liquid pour and liquid pump . For registration review, the liquid pump scenario is anticipated to be negligible. However, t he agency anticipate s the need for a new occupational handler ris k assessment for liquid pour based on the data submitted by the Antimicrobial Exposure Assessment Task Force ( AEATF )

.

Page 18 of 59

### 3.3.2 Occupational Post

- application Exposures Metalworking Exposure The RED assessed the dermal and inhalation exposure when a worker handles treated metalworking fluids with Bioban P

- 1487

. The previous exposure assessment had several
unce rtainties, which are identified below:

• T here are no acceptable re peated dose inhalation toxicity data.

• The toxicological endpoint was based on an oral NOAEL

. • Bioban P

- 1487 is a potential sensitizer and a severe irritant.

T he agency anticipates the need to require inhalation and dermal exposure data to estimate potential risk from exposure to mists and aerosols f or machi nists in industrial settings

. 

### 3.3.3 Residential Handler Exposures Residential exposure is not expected to occur based on current labels and therefore, will not be assessed as part of thi s regis tration review.


### 3.3.4 Residenti al Post

- Application Exposures Residential exposure is not expected to occur based on current labels and therefore, will not be assessed as part of thi s regis tration review.


## 3.4 Aggregate and Cumulative Exposure 3.4.1 Aggregate Exposures

E PA anticipates that an aggregate assessment will not be needed for Bioban P

- 1487. Typically, dietary (food and drinking water) exposures would be aggregated with residential exposures in an assessment, but only drinking water exposures will need to be considered for Bioban P

- 1487.


### 3.4.2 Cumulative Exposures With respect to cumulative exposure, unlike other pesticides for which EPA has followed a cumulative risk appro ach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to Bioban P

- 1487 and any other substances and Bioban P

- 1487 does not appear to produce a toxic metabolite produced by other substances. For the purposes of this registration review, therefore, EPA has not assumed that Bioban P

- 1487 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 evalua te the cumulative effects of such chemicals, see http://www.epa.gov/pesticides/cumulative/

. 

## 4 Environmental Risk Assessment
In September 2007, the agency published its Reregistration Eligibility Deci sion (RED) for Bioban P

- 1487 (EPA739

- R

- 07

- 005). At that time, the agency considered all the registered uses of Bioban P

- 1487 to be “indoor uses” and therefore ruled out the potential for exposure to
Page 19 of 59ecological organisms. Consequently, an ecological risk assessment was not performed. Since that time, the agency has determined that all uses may have the potential to lead to environmental exposure. Specifically, the potential for ecological exposures as a result of registered uses of Bioban P

- 1487 (i.e., in dustrial preservatives incorporated into metalworking cutting fluids, industrial coatings, plastic products, and as fuels/oil storage tank bottom water additives) cannot be ruled out , and the potential for exposure and risk to m ust be evaluated.

The a gen cy has not previously conducted a complete endangered species determination for any of the antimicrobial uses of Bioban P

- 1487 considered as part of this case . The ecological risk assessment planned during registration review will allow the a gency to dete rmine potential acute and chronic risks to aquatic organisms exposed to B ioban P

- 1487 and/ or any of its degradates that are transported from treatment sites into the aquatic environment. The risk assessment will allow the a gency to determine whether each use 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 habit at, the a gency 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
Bioban P

- 1487 is a mixture of two morpholine

- derivatives : 4,4’

- (2

- nitromethylene)d imorpholine (P

- 1490) and 4

- (2

- nitrobutyl)morpholine (P

- 1447)

. According to a hydrolysis study performed under abiotic conditions at pH values of 5, 7, and 9 (MRID 43494001 ) , P

- 1490 is very hydrolytically unstable with a half

- life of 10 minutes. Degradate s formed include d the other morpholine derivative , P

- 1447 , and 2

- nitro

- 1

- butene.

P

- 1447 was determined to have hydrolytic half

- lives of 22 hours at pH 5, 45 hours at pH 7, and 46 hours at pH 9. The hydrolytic degradates of P

- 1447 include 2

- nitropropane, 2

- nitro

- 1

- butanol, and 2

- nitro

- 1

- butene. Although the hydrolytic half

- life of P

- 1447 is relatively short, it is long enough that if a waste stream containing this chemical enters a wastewater treatment plant and is subsequently discharged to surface water , there would be potential for aquatic organisms to be exposed. In addition, aquatic organisms could also potentially be exposed to its hydrolytic degradates , 2

- nitropropane, 2

- nitro

- 1

- butanol, and 2

- nitro

- 1

- butene. Sorption to soil is not expected to be significant for Bioban P

- 1487. T he measured log Koc of 1.7 (50 L/kg) indicates that it prefer entially partitions to water in the presence of soil (MRID 45900901)

. The degradates are also expected to have limited sorption to soil . Of the three degradates , 2

- nitropropane had the hig hest estimated L og Koc , 1 .65 (45 L/kg) (Table 5)

. Based on the Henry’s law constants (HLC) of approximately 10

- 10 and 10

- 15 atm m 3 mol

- 1 for P

1490 and P

- 1447, these chemicals may volatilize from water. Of the degradates, 2

- nitr opropane has highest potential to volatilize from water based on its HLC of approximately 10

- 4 atm m 3 mol

- 1 followed by 2

- nitro

- 1

- butene with an HLC of approximately 10

- 6 atm m 3 mol

- 1 and approximately 10

- 7 atm m 3 mol

- 1 for 2

- nitro

- 1

- butanol (Table 5)

.

Page 20 of 59Bas ed on low estimated log Kow values for P

- 1447 and P

- 1490 (0.18 for the former and

- 0.58 for the latter) using EPI

- WEB 4.11 , these chemicals are not expected to bioaccumulate in aquatic animals.


### 4.1.1 Fate and Effects during Wastewater Treatment Based on the e stimated log Kow of 0.18 for P

- 1487 , it would be expected to have very limited potential to sorb to activated sludge in a wastewater treatment plant. The estimated log Kow values for the degradates also indicate that the potential for sorption to activated sludge would be limited. (The highest estimated log Kow value for 2

- nitropropane is 0.87 ) (Table 5).

Based on an IC 50 value of 306 mg/L (MRID 47005503) , results of a preliminary review of an activated sludge respiration inhibition (ASRI) study indicate that Bioban P

- 1487 must be present in much higher levels than expected to occur in a wastewater treatment plant for microorganism s to be inhibited

. No AS RI test data were found for degradates of Bioban P

- 1487. In a ready biodegradability study (MRID 47005 502), Bioban P

- 1487 was found to be not readi ly biodegradable based on degradation of <60 % within a 10

- day period after the onset of biodegradation

. No test data on biodegradability in wastewater treatment w ere foun d for degradates of Bioban P

- 1487.

In t he absence of data on the degradates of Bioban P

- 1487 with regard to biodegradability during wastewater treatment and effects to wastewater treatment plant microorganisms, the a gency anticipates requiring ASRI and WWTP biodegradation studies for each o f th e degradates

. 

## 4.2 Conceptual Models for Environmental Exposure Pathways
The registered uses for the two chemicals included in Case 3028, 4

- (2

- Nitrobutyl)morpholine and 4,4’

- (2

- e thyl

- 2

- nitromethylene)dimorpholine are as industrial preservatives incorporated i nto metalworking cutting fluids, industrial coatings, plastic products, and as fuels/oil storage tank bottom water additive s (see Table 6 for additional information). Based on these registered industrial uses, physical/chemical properties of the two paren t chemicals and their degradates, and environmental fate information presented in Appendix B, the agency cannot rule out the potential for exposure of aquatic organisms downstream of w astewater treatment plant s that treat wastewater from these uses.

The ag ency has created conceptual models for potential routes of environmental exposure which are included in “Conceptual Models for Environmental Exposure Pathways of Antimicrobial Pesticides” (EPA

- HQ

- OPP

- 2014

- 0638

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

- HQ

OPP

- 2014

- 0638. For metalworking cutting fluids, refer to slide 18 . For in

- service use of industrial coatings , refer to slide 24

. For industrial coatings, there may also be releases to the aquatic environm ent if process water is used to incorporate antimicrobials into coatings and is released to on

- site or off

- site treatment and subsequently discharged to surface water. For Fuels/oil storage tank bottom water additives, refer to slide 23

. Aquatic organis ms potentially at risk include those inhabiting waters adjacent to or downstream from sources of down

- the

- drain discharges (e. g., waste water treatment plants). Water bodies Page 21 of 59might include ponds, lakes, and reservoirs or flowing waterways such as streams and rivers. For uses in coastal areas, aquatic habitat also includes marine ecosystems, including estuaries. Aquatic organisms likely to be exposed include fish, invertebrates, aquatic stages of amphibians, and aquatic and semi

- aquatic plants. The major route of exposure for aquatic animals is likely to be uptake via the respiratory surface (gills) or the integument from surface water that has pesticide residues. The major route of exposure for plants is considered to be uptake from surface water or sed iments.


## 4.3 Ecological Effects Assessment 4.3.1 Mechanism of Action The Agency has no information on the mode of action of B ioban P

- 1487 to terrestrial and aquatic vertebrates and invertebrates.


### 4.3.2 Measure of Effects ( Ecotoxicology Endpoints ) Acute and chronic toxici ty data from registrant

- submitted studies (850 OCSPP Harmonized Test Guidelines) will be used to evaluate the potential effects of B ioban P

- 1487 to aquatic and terrestrial nontarget organisms

. All available ecotoxicity endpoints , data requirements, and dat a gaps are presented in Appendix C. OPP uses the most sensitive of the endpoints for assessing risks. The endpoints currently selected for B ioban P

- 1487 (TGAI) are provided in Table 1 0

. No data are currently available for the degradates (see Table 7 for data requirements).

Table 10

– Available Ecological Effects Endpoints Receptor

Group Test Material Scenario Toxicity Endpoint Reference

Freshwater fish TGAI Acute LC50 = 0.75 mg ai/L 93055005 TGAI Chronic No data

--
Fresh water invertebrates TGAI Acute EC50 = 3.23 mg ai/L 47285301 Chronic No data

--
Estuarine/marine fish TGAI Acute No data

-- Chronic No data

-- Estuarine/marine

invertebrates TGAI Acute No data

-- TGAI Chronic No data

-- Algae TGAI EC50 and NOAE C EC50 = 0.352 mg ai/L NOAEC = 0.049 mg ai/L 47005504

Aquatic vascular plants TGAI EC50 and NOAEC No data

--

Birds TGAI Acute LD50 >1000 mg ai/kg 93055001 TGAI Dietary LC50 >3692 ppm 93055002

Page 22 of 59

### 4.3.3 Open Literature Open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) database. The ECOTOX database will be searched when the risk assessment is prepared. ECOTOX was created and is maintained by the USEPA, Office of Research and Development, and the National Health and Environmental Effe cts Research Laboratory's Mid

- Continent Ecology Division. Any acute or chronic endpoints more sensitive than what are currently available will be evaluated for the risk assessment

. 

## 4.4 Exposure Analysis Plan 4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates To predict the potential for exposures and risks to aquatic organisms downstream of facilities that release 4

- (2

- n itrobutyl)morpholine and 4,4’

- (2

- ethyl

- 2

- nitromethylene)dimorpholine and /or their degradates to surface water, t he agency plans to use the Ge neral Population and Ecological Exposure from Industrial Releases module of E

- FAST (Exposure and Fate Assessment Screening Tool) to determine the number of days of exceedance of concentrations of concern for aquatic organisms.

All end

- uses for this case ar e industrial uses. Since a screening tool to analyze exposures and ecological risk from industrial uses is not currently available, as stated in Appendix D, a screening

- level down

- the

- drain analysis of these uses is not within the scope of this preliminar y work plan. Input data required to run the General Population and Ecological Exposure from Industrial Releases module of E

- FAST include: (1) percent removal of antimicrobial during wastewater treatment; (2) environmental releases of antimicrobial to surf ace water in kg/site/day; (3) annual number of days of release of antimicrobial to surface water; (4) Standard Industrial Classification (SIC) codes to represent the industrial uses being assessed and (5) concentrations of concern for aquatic animals and p lants . The method used to estimate environmental releases of antimicrobial to surface water will be based on the specific end

- use being evaluated. 

## 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 toxicit y. 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 ratio s in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision , for B ioban P

- 1487 , EPA review ed these data and existing hazard database. However, as required by FFDCA section 408(p), Bioban P

1487 is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

Page 23 of 59EPA 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 ED SP screening was published on June 14, 2013 1 and includes some pesticides scheduled for registration review and chemicals found in water

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

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website. 2 

## 6 Optional Label Changes

The agency invites comment on any label amendments that c ould 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. Directions for use for the corrosion inhibiting metal co atings and mold

- releasing agents do not specify an application method. In the absence of updated labels clarifying application method, EPA will assume products are applied by liquid pour or pump

. 

## 7 Guidance for Commenters
7.1 Preliminary Work Plan The public is invited to comment on EPA’s Preliminary Work Plan. The agency will carefully consider all comments as well as any ad ditional information or data provided in a timely manner prior to issuing a final work plan for the B ioban P

- 1487 registration review case.


### 7.1.1 Trade Irritants Through the registration review process, the agency intends to solicit information on trade irritan ts and, to the extent feasible, take steps toward facilitating irritant resolution. The agency

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

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals. 2 http://www.epa.gov/endo/

. Page 24 of 59will 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 Bioban P

- 1487 is not id entified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act

. 3 In addition, no Total Maximum Daily Loads (TMDL) have been developed for the two ingredients of Bioban P

- 1487

. 4 More information on impa ired water bodies and TMDLs can be found at EPA’s website

. 5

The agency invites submission of water quality data for Bioban P

- 1487, P

- 1490, P

- 1447, and the degradates , 2

- nitropropane, 2

- nitro

- 1

- butanol, and 2

- nitro

- 1

- butene

. To the extent possible, data sh ould 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 Process 6 in order to ensure they can be
u sed 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 locat ion, cultural practices, or other factors, may have atypical, unusually high exposure to Bioban P

- 1487 compared to the general population. Please comment if you are aware of any sub

- populations that may have atypical, unusually high exposure compared to th e 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 ap plicant’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 environmen tal 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

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

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

. 5 http://www.epa.gov/owow/tmdl/

. 6 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.ht m

. Page 25 of 59decision

- 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 proper ties 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 p art of a weight

- of

- the

evidence 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 ap propriate 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 submissi on of predicted data can fulfill one of the data needs for the Bioban P

- 1487 ca se, 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 documenta tion 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 . Pre

- submission consultation with the agency is encouraged.


### 7.1.5 Additional Information

S takeholders 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 foll owing 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. Geog raphic limitations on use 2. Use or potential use distribution 3. Use history
Page 26 of 594. 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 2015 , the agency will review and respond to any comments received in a ti mely manner and then issue a F inal W ork P lan for B ioban P

- 1487

.

Page 27 of 59

## 9 References
MRID 43494001. Burke, B, 1994. Hydrolysis of 4

- (2

- nitrobutyl) morpholine and 4,4’

- (2

- ethyl

2

- nitromethylene) dimorpholine. Lab Project # PRT

- 23

- 4 ANN

- 01

- PRT

- 23

- 4ANN

- 01

- 03. Unpublished study prepared by Plant Research Technologies, Inc. 228 pages

. MRID 45900901. Gonsoir, SJ, Rivard, MA, and Stock, MK, 2002. Estimating Soil Koc for a series of Biocides by HPLC Using OECD Method # 121. Biocides TS and D, The Dow Chemical Company, Midland, Michigan

. MRID 47005502. Gonsoir, S, Stock, M, and Rivard, M. 2002: Evaluation of Ready Biodegradability of Bioban P

- 1487 using OECD Method 301F: Manometric Respiratory Test; Project# 011131. Unpublished Study Prepar ed by Dow Chemical Company, 31 pages

. MRID 47005503. Gonsior, S.; Rivard, M.; Stock, M. (2002) Activated Sludge, Respiration Inhibition Test (OECD 209) for Bioban P

- 1487. Project Number: 011177. Unpublished study prepared by The Dow Chemical Company. 16 p

. MRID 47285303. Ponte, M. (2007) Aqueous Photolysis of Bioban P

- 1487 Biocide Under Artificial Sunlight. Project Number: 1625W, 070058. Unpublished study prepared by The Dow Chemical Co., 80 p.

Klin e. 2005

. Kl ine Biocides Report for 2004/2005 for Bioban P

- 1487

. U.S. EPA. 2012. EPI

- Suite 4.11. http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

. U.S. EPA. 2007 . Reregistration Eligibility Decision for Bioban P

- 1487. EPA 739

- R

- 07

- 005. D338283. U.S. EPA. 2007 Occupational and Residential Exposure for Bio ban. Memorandum from S. Mostaghimi, Ph.D. to Mark Hartman. EPA

- HQ

- OPP

- 2007

- 0402

- 0015.

Page 28 of 59

# Appendix A T oxicology Profile

Acute Toxicity for Product Labeling
Adequacy of D atabase for Acute Toxicity : The database for acute toxicity is considered complete. No addition al studies are anticipated to be required.

Bioban P

- 1487 was found to be moderately toxic (Toxicity Category III), with a calculated median lethal dose of 620 mg/kg (combined) in an acute oral toxicity study in rat s (MRID 43558901 ) an d 652 mg/kg (combined) in rabbits (MRID 41677601 )

. Catalepsy and tremors were observed at a dose of 500 mg/kg i n th e rat study, and at 800 mg/kg, lethargy, na s al discharge, and convulsions were observed. The acute dermal LD 50 was determined to be of 420 mg/kg (combined) in rabbits ( Toxicity Category II) (MRID s 41677602 / 41810801 )

. In a n old acute inhalation study (MRID 00094994), utilizing a n one

- hour exposure , estimated a median lethal concentration of 746 mg/L (595

- 936 mg/L) in male rats, in addition to s ignificant clinical toxicity and blood in the urine at concentration of 200 mg/L as well as porphyrin discharge, corneal opacity, and conjunctivitis at 100 mg/L. A newer acute inhalation limit test (MRID 47394701; 4

- hour , nose

- only) reported that one fe male rat died 3 days post

- dosing with hypoactivity, ventral staining, ocular and nasal red color discharge prior to the death. Red urine on the litter paper and around the penis in one surviving male rat, weight loss in the surviving animals in the first week of post

- dosing, and discoloration and distention of the intestines at gross necropsy were also observed. The study author concluded a LC 50 of greater than 2.33 mg/L. Bioban P

- 1 487 i s corrosive to the eyes ( Toxicity Category I ) and severe ly irritatin g to the skin ( Toxicity Category I I ). It is a dermal sensitizer

. Table A1

– Acute Toxicity Profile for Bioban P

- 1487

Guideline Number Study Type/ Test substance (% a.i.) MRID Number/ Citation Results Toxicity Category 870.1100 Acute oral, rat (Purity 81% ) 43558901 LD 50 =620 mg/kg (combined) III

870.1100 Acute oral, rabbit (Purity 92%) 41677601 LD 50 =625 mg/kg (combined) III

870.1200 Acute dermal, rabbit (Purity 92%) 41677602 (duplicate 41810801) LD 50 =420 mg/kg (combined) II

870.1300 Acute inhalation, rat (Purity 94.6%) 47394701 LC 50 >2.33 mg/L (combined) IV

870.2400 Primary eye irritation, rabbit (Purity 92% a.i.) 41677603 Corrosive I

870.2500 Primary dermal irrit ation, rabbit (Purity 92%) 41677604 (duplicate 41810802) Severe irritant II

870.2600 Dermal sensitization, guinea pigs (Purity 90%) 000104805 Sensitizer NA

N/A

– Not applicable

Page 29 of 59

## Subchronic Toxicity
Adequacy of Database for Subchronic Toxicity: The dat abase for subchronic toxicity is considered incomplete. There are several studies in the agency’s hazard database to address subchronic oral toxicity , including subchronic oral toxicity studies in rats as well as in dogs (MRIDs 47213801, 47394702, 4739470 3, 49088901, and 49087501) and 90

- day dermal toxici ty studies in rats (MRIDs 41619 302 /41978801 and 42440001). A brief summary of the reviewed studies is provided below.

B ased on the currently registered uses for Bioban P

- 1487 and i ts high volatility, a route

- specific subchronic inhalation toxicity study in r oden ts is anticipated to be required for registration review risk assessment

. 870.3100 90

- Day (13

- Week) Oral Toxicity

– Rat
(1) In a 90

- day oral toxicity study (MRID 4 7 3 947 0 2 ) , Bioban P

- 1487 [4

- (2

- Nitrobutyl) morpholine; 9 4 .6% active ingredient ; lot # UD1731LAD7 ] in corn oil was administered to Crl:CD(SD) rats (10/sex/dose) via gavage at dose levels of 0, 5, 10, 25 or 50 mg/kg /day , 7 days a week for 13 weeks.

All male rats in t he 50 mg/kg/day dose group were sacrificed in extremis on D ay 32 due to excessive toxicity as evidenced by decreases in body weight (15.2% less than controls) and body weight gain (38.2% less than controls) on Day 29, in addition to one rat (5 mg/kg/day gr oup) being euthanized on Day 88 due to a mechanical injury resulting in a broken muzzle. All other animals survived until study termination (90

- days). Clinical signs for m ales and females in the 50 mg/kg/day dose group and to a lesser extent those in the 25 mg/kg/day dose group had a treatment

- related increase in the incidence of transient, clear perioral soiling (salivation) usually following dosing. At study termination of Day 90, r educed mean body weights and b ody weight gains were observed in males g iven 10 or 25 mg/kg/day test material and females given 10, 25 or 50 mg/kg/day test material. Female rats seemed being affected more than males, with as low as near 10% decrease in body weight and 18% decrease in body weight gain, respectively, were obser ved. Additionally, statistically significant lower feed consumption (12

- 18.9% decrease) was reported for males given 25 or 50 mg/kg/day Bioban P

- 1487 and females given 50 mg/kg/day (10.4%), but only in the first week of the study.

Hematuria occurred i n one male given 25 mg/kg/day and may be a treatment

- related effect of the test material. At the high dose of 50 mg/kg/day, absolute and relative adrenal weights of females were elevated over those of the controls. Gross pathologic observations consisted of thickened nonglandular mucosa of the stomachs of males administered greater than or equal to 10 mg/kg/day and in females administered greater than or equal to 25 mg/kg/day Bioban P

- 1487. Treatment

- related histopathological changes were present in the n asal tissue (olfactory mucosa), stomach, urinary bladder and adrenal glands of treated rats . A majority of females in the 50 mg/kg/day dose group and some females in the
Page 30 of 5925 mg/kg/day dose group had degenerative changes of the olfactory epithelium of the n asal cavity. Hyperplasia, hyperkeratosis and chronic active inflammation of the nonglandular stomach mucosa, as well as necrosis of the nonglandular stomach epithelium, were presented in a majority of males in the 25 mg/kg/day dose group, females in the 2 5 or 50 mg/kg/day dose groups and occasionally in males of the 10 mg/kg/day dose group. Changes in the urinary bladder (very slight, diffuse, hyperplasia of the lining epithelium) occurred in a majority of females in the 50 mg/kg/day dose group; lymphoid cell aggregates were present under the urinary bladder epithelium (lamina propria) of males and females in 10 mg/kg/day and/or greater dose groups, consistent with a mild chronic inflammatory response. Hypertrophy in the adrenal glands (zona fasciculata o f the adrenal cortex), consistent with increased adrenal gland weights, occurred only in the high

- dose (50 mg/kg/day) females.

There were no treatment

- related effects in clinical observations, open

- field observations, functional tests (sensory evaluation s, rectal temperature, grip performance and motor activity), ophthalmic observations, hematology, prothrombin time, or clinical chemistry parameters. The LOAEL is 10 mg/kg/day based on decreased body weight and body weight gain (males and females), decre ased feed consumption (males) and histopathology of the stomach (inflammation, hyperplasia, hyperkeratosis and thickening of the nonglandular mucosa in males) and urinary bladder (mononuclear lymphoid cell aggregates in the lamina propria of males and fema les). The NOAEL is 5 mg/kg/day for male and female rats.

Th is study is classified A cceptable/Guideline

. (2) In a subchronic oral toxicity study (MRID 49088901), Bioban P

- 1487 [purity of 82.95% wt/wt 4

- (2

- Nitrobutyl)morpholine and 4.37% wt/wt 4,4'

- (2

- Ethy l

- 2

- nitro

- l,3

- propanediyl)bismorpholine ; lot# YH1031LAH4 ] was administered to F344/DuCrl rats (10/sex/dose), in diet, at dose levels of 0, 20, 60, or 125 mg/kg/day (time

- weighted average doses of 0, 11.7, 45.9, and 95.2 mg/kg/day for males and 0, 11.5, 45. 3, and 92.3 mg/kg/day for females), for at least 90 days. The study author(s) concluded that “Under the conditions of this study, based on treatment

- related higher reticulocyte counts and cholesterol levels of males at 60 mg/kg/day, the no

- observed

- effect level (NOEL) for male F344/DuCrl rats was the targeted dose of 20 mg/kg/day BIOBANTM P

- 1487 that corresponded to test material intake of 11.7 mg/kg body weight/day. The NOEL for female rats was 60 mg/kg/day that corresponded to test material intake of 45.3 mg/kg/day.” The final conclusion of the study will be available once the agency’s comprehensive review is completed.
(3) In a subchronic oral toxicity study (MRID 49087501), Bioban P

- 1487 [purity of 82.95% wt/wt 4

- (2

- Nitrobutyl)morpholine and 4.37% wt /wt 4,4'

- (2

- Ethyl

- 2

- nitro

- l,3

- propanediyl)bismorpholine ; lot# YH1031LAH4 ] was administered to F344/DuCrl rats (5/sex/dose), in diet, at dose levels of 0, 15, 50, or 150 mg/kg/day (time

- weighted average doses of 0, 8.82, 39.4, and 117 mg/kg/day for males an d 0, 9.08, 39.3, and 114 mg/kg/day for females), for 29 days. The study author(s) concluded that “ Under the conditions of this study, based on the decrements in body weights/body weight gains, feed consumption in males and females given 150 mg/kg/day, and the slightly higher serum cholesterol levels of males given 150 mg/kg/day, the 28

- day dietary No

- Observed

- Effect

- Level (NOEL) for BIOBANTM P

- 1487 in F344/DuCrl rats was the targeted dose of 50 mg/kg/day that corresponded to an actual time weighted average
Page 31 of 59dose of 39.4 mg/kg/day in males and 39.3 mg/kg/day in females.” The final conclusion of the study will be available once the agency’s comprehensive review is completed.
(4) In a subchronic oral toxicity study (MRID 47213801), Bioban P

- 1487 [ 4

- (2

- Nitrobu tyl)morpholine; purity of 94.6%; lot# UD1731LAD7] in com oil was administered to Beagle dogs (2/sex/dose), via oral gavage, at dose levels of 0, 2.5, 10, or 25 mg/kg/day for at least 28 days. The study author(s) concluded that “The lack of incoordination and/or urinary tract lesions in the other animals given Bioban P

- 1487 makes it difficult to make a definitive conclusion as to the potential of P

- 1487 to cause significant toxicity in dogs. However, the prominent incoordination of the hind limbs and the le sions of the urinary tract in one male given 25 mg/kg/day, and the vomiting and blood from the penis in the other male given 25 mg/kg/day may be treatment related. The no

- observed

- effect level (NOEL) was 10 mg/kg/day for males and 25 mg/kg/day for females. ” The final conclusion of the study will be available once the agency’s comprehensive review is completed

. (5 ) In a subchronic oral toxicity study (MRID 473 947 0 3 ), Bioban P

- 1487 [ 4

- (2

- Nitrobutyl)morpholine; purity of 94.6%; lot# UD1731LAD7] in com oil w as administered to Beagle dogs ( 4 /sex/dose), via oral gavage, at dose levels of 0, 2.5, 10, or 25 mg/kg/day for at least 90 days. The study author(s) concluded that “The urinary tract was the primary site of toxicity for males and females given 25 mg/kg/d ay. Alterations in the urinary bladder, occurring with variable incidence in males and/or females, consist ed of: very or slight submucosal hemorrhage, very slight or slight hyperplasia of the transitional epithelium, very slight or slight hyperplasia of t he transitional epithelium, very slight or slight chronic inflammation of the submucosa or transitional epithelium, very slight or slight necrosis of individual transitional epithelial cells, and slight ulceration of the transitional epithelium...... The no

- obs erved

- effect level (NOEL) was 10 mg/kg/day for both sex es.” The final conclusion of the study will be available once the agency’s comprehensive review is completed.

870.3250 Subchronic (90

- day dermal) Toxicity

– Rat

In a 90

- day derma l t oxicity study (MR IDs 41619 302 /41978801 ), g roups of Sprague

- Dawley rats (20/sex/group) received Bioban P

- 1487 (85% a.i.) to the clipped dorsal area at doses of 0 (deionized water), 30, 100, 300 (MRID 41619302), and 1000 mg/kg/day (MRID 42440001), 6 hou rs/day, 5 days/week for 13 weeks. The clipped dorsal area constituted approximately 10% of a total body surface. The appropriate amount of test material was applied evenly over one quarter of the clipped unabraded area, and the application site was rotat ed weekly over the four quadrants to prevent dermal irritation by the test material. Skin reactions (erythema and edema) were evident at all dose levels tested. Hematocrit was slightly reduced in males at 100 and 300 mg/kg/day as was white cell count i n females at 300 mg/kg/day. Creatinine was reduced in males at all dose levels. Body weight was reduced in both sexes, in the absence of any changes in food consumption. Food consumption was slightly increased in males at the 100 and 300 mg/kg/day dose levels in weeks 7, 11, and 12. At the 1000 mg/kg/day dose level, acanthosis was observed at the site of skin application, and histological examination showed chronic inflammation of the urinary bladder in both males and females. T he s ystemic L OAEL i s 10 0 0 mg/kg/day , based on decreased body weight and chronic

Page 32 of 59inflammation of the urinary bladder in both sexes; the s ystemic NOAEL i s 300 mg/kg/day

. The dermal L OAEL was determined to be ≤ 30 mg/kg/day ( the lowest dose tested ), based on skin reactions (erythema and edema) observed at all dose levels tested; the dermal NOAEL was not established. This study is classified Acceptable/Guideline

. 

## Developmental Toxicity
Adequac y of D atabase for Prenatal Developmental Toxicity : The database for prenatal developmental toxicity is adequate. There are developmental toxicity studies, one in the rat ( MRIDs 41673801 and 41978802 ) and another in the rabbit ( MRID 47865701 ) available for Bioban P

- 1487

. 870.3700a Prenatal Developmental Toxicity (Gavage) Study

– Rat In a developmental toxicity study in rats (MRID s 41673801 / 41978802 ), artificially inseminated female Sprague

- Dawley rats (25/group) were administered to Bioban P

- 1487 (79% 4

- (2

- nitrobutyl)morpholine, 4.8% 4, 4’

- (2

- ethyl

- 2

- nitrotrimethylene)dimorpholine), by gavage, at doses of 0, 10, 30, and 100 mg/kg/day in corn oil on gestation days 6 through 15. One materna l rat at 100 mg/kg was sacrificed in extremis on gestation day 11. Excessive salivation was observed in increased incidence at the 30 mg/kg and 100 mg/kg dose levels. Reduced body weight gain (36% reduction from control) was observed in maternal animals at 100 mg/kg for days 0

- 20, and a 12% reduction in weight gain was observed at the 30 mg/kg dose level for the 0

- 20 day time period. Food consumption was significantly affected at 30 and 100 mg/kg for maternal animals during week 2 of the study (decreases of 12% and 30% respectively). There were no significant adverse effects in fetal body weight, crown

- rump length, or external, visceral, or skeletal malformations at any dose tested. At the 100 mg/kg dose, there was a slight reduction in live fetuses p er dam (8.2 vs. 9.1 in control), total implants per dam (9.4 vs. 11.2 in control), but the incidences of these effects were not significantly different from control. The maternal LOAEL is determined to be 30 mg/kg/day , based on increased salivation, accom panied by significantly reduced (p ≤ 0.05) body weight gain (and food consumption) ; the m aternal NOAEL is 10 mg/kg/day . The d evelopmental toxicity NOAEL is determined to be 100 mg/kg/day (the highest dose tested), and the developmental toxicity LOAEL is n ot established. This study is classified Acceptable/Guideline

. 870.3700b Prenatal Developmental Toxicity (Gavage) Study

– Ra bbi t In a developmental toxicity study in rats (MRID 47865701), groups of 26 time

- mated female New Zealand white rabbits were adm inistered BiobanTM P

- 1487 Antimicrobial (94.7% a.i.; Lot# UD 1731 LAD7) in polyethylene glycol 400 ( PEG

- 400 ) , by oral gavage, at targeted dose levels of 0, 15, 50, or 150 mg/kg/day from days 7 through 27 of gestation.

Page 33 of 59The predominant toxicological findings were observed in 150

- mg/kg/day females, including decreased body weight/body weight gains and decrease in food consumption, and resulted in removal of 5 rabbits from the treatment due to 10

- 14% body weight loss. An overall of 52% decrease in body weight gains, compared to controls, was observed through the treatment period (GD 7

- 28), while a decrease of 35

- 88% (of controls) in feed consumption was reported throughout most of the dosing period. Corresponding to these changes, an increased incidences of tr eatment

- related clinical observations included decrease in quantity of feces (including absent), soft feces, and soiling of the perioral (clear), perineal (fecal) and perinasal (clear) regions. In addition, absolute and relative liver weights were increas ed by 12 and 16%, respectively, compared to controls. The maternal toxicity LOAEL is 150 mg/kg/day, based on toxicological findings including significant (p < 0.05) reductions in body weights, body weight gains, and food consumptions and increase in absolu te and relative liver weights. The maternal toxicity NOAEL is 50 mg/kg/day. At 150 mg/kg/day, decreased mean fetal body weights and gravid uterine weights of 16% and 20%, respectively, were observed, along with increased incidences of delayed ossificatio n of the hyroid (reached statistically different), pubis, and talus. The developmental toxicity LOAEL is 150 mg/kg/day, based on significant (p < 0.05) decreases in fetal weights and delayed ossification of the hyroid, pubis, and talus. The developmental toxicity NOAEL is 50 mg/kg/day. The study is classified Acceptable/Guideline

. 

## Reproductive Toxicity
Adequacy of D atabase for Reproductive Toxicity : The database for reproductive toxicity is adequate. The re is a 2

- generation repro ductive toxicity study f or Bioban P

- 1487 (MRID 48126001), submitted in response to the post

- RED data

- call

- in (DCI)

. In a 2

- gene ration reproduction study (MRID 48126001 ) , Bioban TM P

- 1487 (94.6% a.i., l ot # UD1731LAD7 ) was administered to 30 Crl:CD rats /se x/dose , by gavage, at dose levels of 0, 1, 5, or 20 mg/kg /day. For both the F 1 and F 2 generations, there were 8 pups per litter (4 per sex, unless not possible) and 1 litter per successful mating female. Results showed evidence of systemic toxicity in both sexes of P parental and F 1 animals

. The parental systemic LOAEL is identified as 20 mg/kg/day for males and females, based on lowered mean body weights, reduced body weight gains, reduced food consumption (and/or food efficiency), and histopathologic al changes seen in the non

- gland ular area of the stomach . The parental systemic NOAEL is 5 mg/kg/day.

There were no treatment

- related effects in F 1 or F 2 offspring. As a result, the offspring NOAEL is 20 mg/kg /day. Pups did not experience decreases in survival, lowered body weight, reduced body weight gain, or altered food consumption compared to controls. Therefore, a LOAEL cannot be identified for this study.

Page 34 of 59There were no changes in gonadal function, estrous cycles, mating, fertility, pregnancy, weaning, or other reproductive functions in either sex at any dose. The r eproductive NOAEL is 20 mg/kg /day in both sexes, based on a lack of reproductive effects in either sex of offspring. Therefore, a reproductive LOAEL is not established. This study is Acceptable/Guideline

. 

## Chronic Toxicity
Adequacy of D atabase for Chronic Toxicity : The database for chronic toxicity is considered incomplete. There are no chronic toxicity studies in the agency’s hazard database; these studies are anticipated to be required for registration review risk assessment, based on the currently registered uses for Bioban P

- 1487

. The chronic studies were identified as data gaps in the RED and are required by the post

- RED DCI

. 

## Carcinogenicity
Adequacy of D atabase for Carcin ogenicity : The database for carcinogenicity is considered incomplete . There are no carcinogenicity studies in the agency’s hazard database; these studies are anticipated to be required for registration review risk assessment , in order to adequately addre ss the hazardous risks of Bioban P

- 1487 from the currently registered uses . The carcinogenicity study were identified as data gaps in the RED and are required by the post

- RED DCI

. 

## Mutagenicity
Adequacy of D atabase for M utagenicity : The database for muta genicity is considered adequate. Several mutagenicity studies have been submitted and reviewed by the Office of Pesticide Programs (OPP) and found acceptable. The summaries of these studies are provided below.

Gene Mutation (1) In an Ames test ( MRID 4 16 193 01 ), Bioban P

- 1487 (Purity: 85% 4

- (2

- nitrobutyl)morpholine, 10% 4, 4’

- (2

- ethyl

- 2

- nitrotrimethylene)dimorpholine; Lot 8K15

- DF28 ) was assessed in the standard battery of Salmonella his

– strains, TA98, TA 100, TA1535, and TA1537. All four tested strains, in triplicate cultures, were exposed to the graded test material for 65±2 hours, with and without S9 metabolic activation. The dose range (0.007

- 7.5 μg/plate) was determined based on a preliminary range

- finding test. No induction of reverse mutations wa s shown with or without S9 activation in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 up to the highest dose level (7.5 μg/plate). The positive controls substances caused significant increases in reversions, 3 to 5 times higher than the solvent values. It was concluded that B ioban P

- 1487 was not mutagenic in Ames test with or without S9. This study is classified Acceptable

.

Page 35 of 59( 2 ) Bioban P

- 1487 ( 8 0.86 % 4

- (2

- nitrobutyl)morpholine , 4.12 % 4, 4’

- (2

- ethyl

- 2

- nitrotrimethylene)dimorpholine; Batc h # OJ0431LAN7 ) was evaluated for its ability to induce forward mutations at the TK locus in L5178Y +/

- mouse lymphoma cells (MRID 45655301). The dose range (0.25

- 30 μg/mL) was based on a preliminary range

- finding t est. The cell cultures were exposed to t he test article for 4 hours in exposure medium, ±S9

. Bioban P

- 1487 treatments, +S9, resulted in significant increases in mutant frequency and increased mutant indices. A second assay, under the same conditions, confirmed the results of the first experime nt. The sensitivity of the test system was clearly demonstrated by the positive responses elicited by the positive control compounds. In this assay, Bioban P

- 1487 was found to be mutagenic with S9. This study is classified Acceptable/Guideline

. Cytogen etics (1) Bioban p

- 1487 ( 81% 4

- (2

- nitrobutyl)morpholine , 5% 4, 4’

- (2

- ethyl

- 2

- nitrotrimethylene)dimorpholine; Lot # 8K15

- DF28 ) was administered to Chinese hamster ovary (CHO) cells to assess its potential clastogenic effects (MRIDs 41298502 [main study]/ 415 67901 [supplemental study] ) . CHO cell cultures, in duplicates, were exposed to the test article in doses ranging from 1x10

- 8 mL/mL to 1x10
- 4 mL/mL for 8 hours without activation (

- S9) and from 5x10
- 8 mL/mL to 5x10
- 4 mL/mL for 2 hours with activation (+S9 ). All cultures were exposed to colcemid (1x10

- 6 M) during the last 3 hours of incubation. In this assay, B ioban P

- 1487 did not induce chromosomal aberrations with or without S9. This study is classified Acceptable

. (2) In a C D

- 1 m ice bone marrow micronucleus assay (MRID 47005501 ) , 6 male mice/dose were treated by single oral gavage on two consecutive days with Bioban P

- 1487 TM ( 4

- (2

- nitrobutyl)morphine [80.86%]; 4,4’(2

- ethyl

- 2

- nitromethylene)dimorphine [4.12%] , Batch No.: OJ0431 LA N ) in corn oil at doses of 0, 125 , 250 , or 500 mg/kg based upon the results of a range

finding test in which significant mortality was observed in both sexes at 1000 mg/kg body weight. An additional group of 6 mice were treated with 500 mg/kg dose concent ration. Bone
marrow cells were harvested 24

- hours post

- treatment (after second treatment). The positive control was cyclophosphamide monohydrate (120 mg/kg). Clinical signs of toxicity including decreased activity, perioral/periocular soiling, and urine and fecal perineal soiling languid were observed in the 250 and 500 mg/kg animals. No significant increases in micronucleated polychromatic erythrocytes (MN

- PCEs) frequencies were reported in any dose group, whereas, a significant increase in the frequ encies of MN

- PCEs was observed in the positive control group. The mean percent PCE values were significantly reduced at 500 mg/kg and for the positive control groups compared to the corresponding negative controls. Bioban P

- 1487 TM is considered negative in this mice bone marrow micronucleus assay under the test condition. This study is classified Acceptable/Guideline

.

Page 36 of 59Other Genotoxicity (1) In an unscheduled DNA synthesis assay (MRID 46965903), 5 male rats/dose were exposed once by oral gavage to Bi oban TM P

- 1487 (>93% pure; batch No.: OJ0431LAN7 ) in corn oil at doses of 450 or 900 mg/kg based upon the results of a range

- finding test, in which mortality was observed in all females at ≥750 mg/kg and in one male at 750 mg/kg two days post

- dosing. Hepat ocytes were isolated from the liver of 4 male Fischer 344 rats per group by the two

- step in

situ perfusion at 2

- 4 or 14

- 16 hours post

- treatment. The vehicle used was corn oil. There were no unscheduled deaths and all animals appeared normal after dosin g and prior to perfusion at the 2

- to 4

- hour time

- point. Clinical signs of toxicity were observed prior to perfusion in animals at the 14

- to 16

- hour time

- point. No significant increases in mean net nuclear grains (NNG), or in the percent of nuclei with five or more net grains, were reported at any dose level at any time point. This was comparable to the solvent controls. The positive control elicited a clear positive response. There was no evidence of induction of unscheduled DNA synthesis in rat prim ary hepatocytes over the background. This study is classified Acceptable / Non

- guideline

. (2) Bioban P

- 1487 ( 81% 4

- (2

- nitrobutyl)morpholine , 5% 4, 4’

- (2

- ethyl

- 2

- nitrotrimethylene)dimorpholine; Lot No.: 8K15

- D F 28 ) was assayed in another unscheduled DNA sy nthesis assay (MRID 41298503). Following preliminary cytotoxicity testing (range, 1x10
- 3 mL/mL down to 5x10

- 7 mL/mL), coverslip cultures of freshly perfused rat hepatocytes (male Sprague

- Dawley rats) were exposed to test substance, in quadruplicate per tr eatment dose, for 18 hours, followed by a further 18

- hour treatment with 10 μ Ci/mL tritiated

- thymidine ( 3 H

Tdr). Negative and positive controls were used. No significant increases in mean net nuclear grains (NNG) were reported at any dose level at any ti me point. This was comparable to the solvent controls. It is concluded that Bioban p

- 1487 was no t g en o toxic in prom o ting UDS in rat hepatocyte cultures. This study is classified Acceptable

. 

## Immunotoxicity

870.7800 Immunotoxicity Study Adequacy of Datab ase for Immunotoxicity: The database for immunotoxicity is considered incomplete . There are no immunotoxicity studies in the agency’s hazard database. An immunotoxicity study is anticipated to be required for registration review risk assessment , based
o n the currently registered uses for Bioban p

- 1487

. 

## Other Toxicological Effects

Metabolism and Pharmacokinetics

Page 37 of 59In a metabolism study (MRID 48239101), 14 C

- BIOBANTM P

- 1487 and unlabeled BIOBANTM P

1487 (radiolabeled purity 90.2%, Lot No. 3587

- 027; unlabeled purity 94.6%, Lot No. UD1731LAD7) were administered to groups of four Sprague Dawley rats/sex/ treatment group at oral doses of 2.0 mg/kg (Group 1) or 50 mg/kg /day (Group 2), by rep eated oral doses of 2.0 mg/kg /day with unlabeled test material followed by a single oral dose of 2.0 mg/kg radiolabeled material (Group 5), or by dermal application of 2.0 mg/kg radiolabeled test material (Group 6). Groups 1, 2, and 6 were jugular cannulated for pharmaco kinetic analysis. Blood was collected from these rats at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours for Group 1 rats with additional collection at 96, 120, 144, and 168 hours for Groups 2 and 6. Urine and feces were collected up to 72 hours after treatment for Group 1 rats with additional collection of uri ne and feces up to 168 hours after treatment for Groups 2, 5, and 6. CO 2 was collected up to 72 hours after treat

ment for rats in Groups 1, 2, 5, and 6. At the end of the study, the rats were sacrificed and selec

ted tissues collected for radioactivity analysis. In addition to the above treatment groups, two addi tional groups of four Sprague Dawley rats/sex/dose were treat ed with 2.0 mg/kg test material (Groups 3 and 4). Group 3 rats were sacrificed at C max (0.5 hours after treatment as determined fr om Group 1 analysis) and blood and tissues collected. Group 4 rats were sacrificed at 1⁄2C max (8 hours after treatment as determined by Group 1 analysis) and blood, urine, feces and tissues collected. Following oral treatment with 14 C

- BIO BANTM P

- 1487, the t est material was rapidly absorbed without any apparent lag time. Plasma concentrations peaked between 0.25

- 4 hours post

- dos e and were ~0.75 μg/g in rats treated orally with 2.0 mg/kg and ~10 μg/g in rats treated orally with 50 mg/kg. A bi

- modal increas e in plasma concentrations was observed, particularly in high

- dose rats. The 14 C

- BIOBAN TM P

- 1487

- derived radioactivity declined in the plasma in a bi

- phasic manner with faster e limination at the low dose group ( t 1⁄2α 6 hours; t 1⁄2 β ~ 35 hours), compar ed to tho se of the high dose group ( t 1⁄2α ~ 14 hours; t 1⁄2 β ~60 hours). The rates of uptake and elim ina tion (based on the plasma time course) were similar in males and females. Peak plasma con cen

trations were roughly dose

- proportional between high

- and low

- dosed animals (13

- to 17

- fold difference for males and females , respectively ). AUCs were essentially dose

- proportional ( a 23

- fold difference between high

- and low

- dose for males and a 25

- fold difference for females).

Most 14 C

- BIOBANTM P

- 1487 was eliminated in t he urine. The radioactivity re covered in urine from orally dosed animals (Groups 1, 2, and 5) ranged from 77 % to 89% of the administered dose, and most (>90%) was excre ted within 24 hours of treat ment

. Less than 5% of the orally administered radioacti vity was asso ciated with tissues for rats sacrificed >72 hours after treat

ment

. Based on the r adioac tivity recovered in the urine and tissues at sacrifice from the various dose groups, it was estimated that between 83 % and 93% of the oral dose was syst emically absorbed. Peak plasma 14 C concentrations follo wing dermal application of 2 mg /kg test material were lower than those observed following oral treatment; and the time to C max was longer. R adio

activity in plasma peaked between 8 and 12 hours after treatment at a concentration of ~0.03 μ g /g plasma (
~ 4% C max of rats dosed orally with 2 mg/kg test material). Based on the radio ac

tivity recovered in the urine, feces , and tissues of dermally dosed rats, it was estimated that 27% and 38% of the applied dose was systemically absorbed in male and female rats, respec tively.

Page 38 of 59Most of the radioactivity was recovered in the urine with ~20% and ~30% of the adminis tered dose excreted by males and females, respectively.

14 C

- BIOBANTM P

- 1487 was highly metabol ized by both male and female rats following oral or dermal treatment

. No parent compound was identified in the urine or feces. Morpholine repre

sented
~ 65% of the admin istered dose in the urine of the oral treatment groups and ~ 21% of the administered d ose in urine following dermal treatment. It was the only metabolite identified in the feces of all treatment groups

. It accounted for an average of 6.7% of the admin istered dose in the feces of the oral treatment groups , and 1.7% of administered dose in the feces of dermally

treated rats. A minor urinary metabolite representing
~ 1.3% of the admin istered dose of rats in Groups 1 and 2, ~ 9.3% of the administered dose in the repeat dose Group 5, and
~ 0.5% of administered dose in rats from Group 6 was N

- me thyl morpholine N

- oxide. The formation of this metabo lite was through the transient metabolite N

- methylmor pholine, which was not detected in the urine.
This metabolism study in the Sprague Dawley rat is classified Acceptable/Guideline

.

Page 39 of 59Table A 2

– Toxicity Profile for Bioban P

- 1487

Guideline No./

Study Type MRID No./ Study Classification Dosing and Animal Information Results Subchronic Toxicity 870.3100 90

- day Oral (Rat) MRID 47394702 Acceptable/Guideline Purity 94

. 6 %
10 Crl: CD(SD) rats /sex/ dose 0, 5, 10, 2 5, or 50 mg/kg/d in corn oil, gavage , once daily, 7 days/wk, for 13 wks N OAEL = 5 mg/kg/d LOAEL = 10 mg/kg/d , based on ↓ body weight and body weight gain ( both ♂ and ♀ ), ↓ feed consumption ( ♂ ) and histopathology of the stomach , including inflammation, hyperplasia, hyperkeratosis and thickening of the nonglandular mucosa in ♂ and urinary bladder (mononuclear lymphoid cell
a ggregate s in the lamina propria of ♂ and ♀ ) 870.3100 90

- day Oral (Rat) MRID 49088901
In the Agency’s review Purity 83 %
10 F344/DuCrl r ats / sex/ d o se 0, 20, 6 0, or 12 5 mg/kg/d ( time

weighted average doses ♂ : 0, 1 1

. 7 , 4 5

. 9 , or 9 5.2 mg/kg/d; ♀ : 0, 1 1. 5 , 4 5

. 3 , or 92. 3 mg/kg/d) , in diet, for at least 90 days The study author concluded:

N OAEL male = 20 mg/kg/d (corresponding to test material intake of 11.7 mg/kg/d) N OAEL fem ale = 60 mg/kg/d (corresponding to test material intake of 45.3 mg/kg/d) , based on trea tment

- related higher reticulocyte counts and cholesterol levels of ♂ at 60 mg/kg/d 870.30 50 28

- day Oral (Rat) MRID 49087501 In the Agency’s review Purity 8 3 %
5 F344/DuCrl r ats / sex/ d o se 0, 15, 50, or 150 mg/kg/day (time

- weighted average doses ♂ : 0, 8.82, 39.4, or 117 mg/kg/d ; ♀ : 0, 9.08, 39.3, or 114 mg/kg/d, in diet , for 29 days The study author concluded:

N OAEL = 50 mg/kg/d (corresponding to test material intake ♂ : 39.4 mg/kg/d and ♀ : 39.3 mg/kg/d ) , based on the decrements in body weights/body weight gains, feed consumption in ♂ and ♀ given 150 mg/kg/d, and the sli ghtly higher serum cholesterol levels of ♂ given 150 mg/kg/day

Page 40 of 59Guideline No./ Study Type MRID No./ Study Classification Dosing and Animal Information Results
Non

- guideline (range

finding study) 28

- day Oral ( Dog ) MRID 47213801
In the Agency’s review Purity 9 4 .6% 2 Beagle dogs/ sex/ d o se 0, 2.5 , 1 0, or 25 mg /kg/d in corn oil, oral gavage, for at lea st 28 days NOAEL male = 10 mg/kg/d NOAEL female = 25 mg/kg/d , based
on the prominent incoordination of the hind limbs and the lesions of the urinary tract in one male given 25 mg/kg/d, and the vomiting and blood from the penis in the other male given 25 mg/ kg/d

870.3 1 50 90

- day Oral Subchronic (Dog ) MRID 4739470 3
In the Agency’s review Purity 9 4 .6% 2 Beagle dogs/ sex/ d o se 0, 2.5 , 1 0, or 25 mg /kg/d in corn oil, oral gavage, for at least 90 days NOAEL male = 10 mg/kg/d NOAEL female = 25 mg/kg/d , based
on the a lterations in the urinary bladder , including very or slight submucosa l hemorrhage, very slight or slight hyperplasia of the transitional epithelium, very slight or slight hyperplasia of the transitional epithelium, very slight or slight chronic inflammati on of the submucosa or transitional epithelium, very slight or slight necrosis of individual transitional epithelial cells, and slight ulceration of the transitional epithelium
870.3250 90

- day Dermal Subchronic (Rat ) MRID 41618302/42440001
Acceptable/Gui deline Purity 85%
20/sex/group
0 (deionized water), 30, 100, 300 (MRID 41619302), and 1000 mg/kg/d (MRID 42440001), 6 hrs/d, 5 days/wk , for 13 wks LOAEL dermal ≤ 3 0 mg/kg/day ( low est dose tested [ L DT]), based on skin reactions (erythema and edema) observe d at all dose levels tested NOAEL dermal not established

NOAEL systemic = 30 0 mg/kg/d LOAEL systemic = 1000 mg/kg/d , based on ↓ body weight and chronic inflammation of the urinary bladder in both sexes 870.3465 90

- day inhalation Subchronic A subchronic inhalation study is not available for Bioban P

- 1487.

Developmental Toxicity

Page 41 of 59Guideline No./ Study Type MRID No./ Study Classification Dosing and Animal Information Results 870.3700a Developmental Toxicity (Rat) MRID 41673801/41978802 Acceptable/Guideline Purity 7 9 %

2 5 /dose
0, 1 0, 3 0, or 10 0 mg/kg/d, GD 6

- 15 NOAEL maternal = 1 0 mg/kg/d LOAEL mater nal = 3 0 mg/kg/d , based
on ↑ salivation, accompanied by significantly ↓ (p ≤ 0.05) body weight gain (and food consumption)

NOAEL developmental ≥ 10 0 mg/kg/d (highest dose tested [HDT]). LOAEL developmental not established

. 870.3700b Developmental Toxicity (Ra bbi t) MRID 47865701

Acc eptable/Guideline Purity 9 4

. 7 %

2 6 NZ white ra bbit s/group
0, 15 , 5 0 or 150 mg/kg/d, GD 7

- 27 NOAEL maternal = 5 0 mg/kg/d LOAEL maternal = 150 mg/kg/d , based
on significant (p < 0.05) ↓ in body weights, body weight gains, and food consumptions and ↑ in absol ute and relative liver weights

NOAEL developmental = 50 mg/kg/d LOAEL developmental = 1 50 mg/kg/d , based on significant (p < 0.05) ↓ in fetal weights and delayed ossification of the hyroid, pubis, and talus Reproduction Toxicity 870.3800 Reproduction MRID 48126001
Acceptable/Guideline Purity 9 4 .6%

30 Crl:CD rats /sex/dose ; 8 pups/litter (4 per sex, unless not possible) for both F 1 & F 2 and 1 litter/successful mating female

0 , 1, 5, or 20 mg/kg /d , oral gavage NOAEL parental = 5 mg/kg/d LOAEL parental = 20 m g/kg/d , based
on lowered mean body weights, reduced body weight gains, reduced food consumption (and/or food efficiency), and histopathological changes seen in the non

- glandular area of the stomach

NOAEL offspring ≥ 20 mg/kg/d (highest dose tested [HDT]); LOAEL parental not established

NOAEL reproductive ≥ 20 mg/kg/d (HDT); LOAEL reproductive not established Chronic Toxicity 870.4100 Chronic Toxicity A chronic toxicity study is not available for Bioban P

- 1487

. Carc inogenicity 870.4200 Carcinogenicity A carcinogenicity study is not available for Bioban P

- 1487

. Mutagenicity 870.5100 Bacterial reverse mutation test MRID 41619301 Acceptable/Guideline Purity 85%
TA1535, TA1537, TA98, or TA100

0.007

- 7.5 μg/plate w ith and without S9 metabolic activation Negative

Page 42 of 59Guideline No./ Study Type MRID No./ Study Classification Dosing and Animal Information Results 870.5300 Mammalian cell gene mutation test MRID 45655301
Acceptable/Guideline Purity 81 % mouse lymphoma cells (L5178Y TK +/

- )
0.25

- 30 μg/mL ± S9; for a period of 4 hours Posi tive (+S9)

870.5300 Mammalian cell gene mutation test MRIDs 41298502 [main study] /41567901 [supplemental study]
Acceptable Purity 81 % Chinese hamster ovary (CHO) cells

1x10

- 8

- 1x10

- 4 mL/mL for 8 hours , - S9 ; 5x10

- 8

- 5x10

- 4 mL/mL for 2 hours , +S9 Negative

870.5385 In vivo mammali an bone marrow chromosome aberration test (mouse) MRID 47005501
Acceptable/Guideline Purity 8 1 %

6 male mice 0, 125, 250, or 500 (12 mice) mg/kg Negative

870.5550 ( I

n vivo ) Unscheduled DNA synthesis MRID 46965903
Acceptable/ Non

Guideline Purity > 9 3 % Rat hepatocyte cells
0, 4 5 0 , or 90 0 mg/kg , 5 male rats, oral gavage Negative

870.5550 Unscheduled DNA synthesis MRID 41298503

A cceptable Purity 81 %

Rat (male) hepatocyte cells
5x10

- 7

– 1x10

- 3 m L/mL Negative

Metabolism

Page 43 of 59Guideline No./ Study Type MRID No./ Study Classification Dosing and Animal Information Results 870.7485 M etabolism and Pharm acokinetics MRID 48239101
Acceptable/Guideline Purity 90 .2% (radiolabeled); 9 4.6 % (non

- radiolabeled)

4 SD rats/sex/ group
O ral doses 2.0 mg/kg (Group 1) or 50 mg/kg (Group 2), by rep eated oral doses of 2.0 mg/kg /day with unlabeled test material followed by a single oral dose of 2.0 mg/kg radiolabeled test material (Group 5), or by dermal application of 2.0 mg/kg radiolabeled test material (Group 6) . A ddition ally, two addi tional groups of four Sprague Dawley rats/sex/dose were treat ed with 2.0 mg/kg tes t material (Groups 3 and 4) ; Group 3 rats were sacrificed at C max (0.5 hours after treatment as determined from Group 1 analysis) and blood and tissues collected ; Group 4 rats were sacrificed at 1⁄2C max (8 hours after treatment as determined by Group 1 analy sis) and blood, urine, feces and tissues collected

. 14 C

- BIOBANTM P

- 1487 was rapidly absorbed (estimated 83%

- 93%) following oral administration. Plasma concentrations peaked between 0.25

- 4 hours post

- dose and were ~0.75 and ~10 μg/g in rats treated oral ly with 2.0 and 50 mg/kg, respectively. A bi

- modal increase in plasma concentrations was observed, particularly in high

- dose rats. The 14 C

BIOBANTM P

- 1487

- derived radioactivity declined in the plasma in a bi

- phasic manner with faster elimination at the lo w dose group ( t 1⁄2α 6 hours; t 1⁄2β ~ 35 hours), compar ed to those of the high dose group ( t 1⁄2α ~14 hours; t 1⁄2β ~60 hours). The rates of uptake and elim ina tion (based on the plasma time course) were similar in males and females. Peak plasma con cen

trations were roughly dose

- proportional between high

- and low

- dosed animals (13

- to 17

- fold difference for males and females, respectively). AUCs were essentially dose

- proportional (a 23

- fold difference between high

- and low

- dose for males and a 25

- fold difference for females). Most 14 C

- BIOBANTM P

- 1487 was eliminated in the urine (77%

- 89%).

It was estimated that 27% and 38% of the applied dose was systemically absorbed in male and female rats, respec tively , following dermal application of 2 mg/kg test materia l. Peak plasma 14 C concentrations were lower than those observed following oral treatment; the time to C max was longer. Most of the radioactivity was recovered in the urine with ~20% and ~30% of the adminis tered dose excreted by males and females, respe ctively.

14 C

- BIOBANTM P

- 1487 was highly metabolized by both male and female rats following oral or dermal treatment. No parent compound was identified in the urine or feces. Morpholine repre sented ~65% of the admin istered dose in the urine of the ora l treatment groups and ~21% of the administered dose in urine following dermal treatment. It was the only metabolite identified in the feces of all treatment groups.

Page 44 of 59Reference s for Mammalian Toxicity

MRID

000 94994 Goldenthal, E.I.; Wazeter, F.X.; Dea n, W.P. (1973) Acute Inhalation Toxicity Study (LC 50 ) in Albino Rats: 267

- 009; Report No. PLR

- 11. (Unpublished study received Jan 14, 1981 under 271

- 30; prepared by International Research and Development Corp., sub

- mitted by International Minerals & Chem ical Corp., Terre Haute, Ind.; CDL:244383

- F)

. 00104805 Wilbur, S. (1978) P

- 1487 Skin Sensitization: SW78/11. (Unpublished study received Apr 25, 1979 under 271

- 30; submitted by Inter

- national Minerals & Chemical Corp., Terre Haute, IN; CDL: 238693

- A)

. 412 98501 Desai, L. (1989) Ames Bacterial/microsomal Plate Incorporation Assay: Bioban P

- 1487 Antimicrobial Agent: Project Number 89G

- 0093. Unpublished study prepared by Toxikon Corp. 12 p.

41298502 Desai, L. (1989) Chromosome Aberrations in Chinese Hamster O vary (CHO) Cells: Bioban P

- 1487 Antimicrobial Agent: Lab Project Number 89G

- 0095. Unpublished study prepared by Toxikon Corp. 15 p.

41298503 Desai, L. (1989) Unscheduled DNA Synthesis in Rat Liver Primary Cell Cultures: Bioban P

- 1487 Antimicrobial Agent: L ab Project Number 89G

- 0094. Unpublished study prepared by Toxikon Corp. 12 p.

41567901 Desai, L. (1989) Chromosome Aberration in Chinese Hamster Ovary (CHO) Cells: Lab Project Number: 89G

- 0095. Unpublished study prepared by Toxikon Corp. 6 p.

41619301 Lynn , S. (1990) Ames Mutagenicity Assay: Bioban P

- 1487: Lab Project Number: 90G/0526. Unpublished study prepared by Toxikon Corp. 14 p.

41619302 Griffin, T. (1990) Subchronic 90

- Day Dermal Toxicity Study of Bio

- ban P

- 1487 in Rats: Lab Project Number: 890202. Unpublished study prepared by Coulston International, Inc. 311 p.

41677601 Kreuzmann, B. (1990) Acute Oral Toxicity in Rats

- Median Lethal Dos

- age Determination: Lab Project Number: 90

- 4091

- 21 (A). Unpub

- lished study prepared by Hill Top Biolabs, Inc. 16 p.
41677602 Kreuzmann, B. (1990) Acute Dermal Toxicity in Rabbits

-- Median Leth

- al Dosage Determination: Lab Project Number: 90

- 4091

- 21 (B). Unpublished study prepared by Hill Top Laboratories, Inc. 109 p.

41677603 Kreuzmann, B. (1990) Primary Eye Irritati on Study in Rabbits: Bioban P

- 1487: Lab Project Number: 90

- 4091

- 21 (D). Unpublished study prepared by Hill Top Laboratories, Inc. 14 p.
Page 45 of 5941677604 Kreuzmann, B. (1990) Primary Skin Irritation Study in Rabbits: Bio

- ban P

- 1487: Lab Project Number: 90

- 4091

- 21 (C). Unpublished study prepared by Hill Top Laboratories, Inc. 14 p.

41810801 Kreuzmann, J. (1990) Acute Dermal Toxicity in Rabbits

- Median Lethal Dosage Determination: Lab Project Number: 90

- 4091

- 21 B. Unpub

- lished study prepared by Hill Top Biolabs, Inc. 84 p.

41810802 Kreuzmann, J. (1990) Primary Skin Irritation Study in Rabbits: Lab Project Number: 90

- 4091

- 21 C. Unpublished study prepared by Hill Top Biolabs, Inc. 31 p.
41949403 Paika, I. (1991) Chromosome Aberrations in Chinese Hamster Ovary (CHO) Cell s: Lab Project Number: 90

- G

- 0536. Unpublished study prepared by Toxikon Corp. 56 p.

41949404 Paika, I. (1991) Unscheduled DNA Synthesis in Rat Liver Primary Cultures: Lab Project Number: 90

- G

- 0535. Unpublished study prepared by Toxikon Corp. 63 p.

41978801 Griffin, T. (1991) Supplemental Data to MRID No. 41619302: A Subchronic 90

- Day Dermal Toxicity Study of Bioban P

- 1487 in Rats. Unpublished study prepared by Coulston International, Inc. 5 p

. 42440001 Griffin, T. (1992) Subchronic 90

- day Dermal Toxicity St udy of Bioban P

- 1487 in Rats (Limit Test): Lab Project Number: 910302. U npublished study prepared by Cou l st on Research, Inc. 228 p.

43558901 Fitzgerald, G (1995) Acute Oral Toxicity Study (in Rats): Bioban P

- 1487: Final Report: Lab Project Number: 94G

- 1937 . Unpublished study prepared by Toxikon Corp. 18 p.

45655301 Linscombe, V.; Schisler, M.; Treadway, K. (2002) Evaluation of Bioban P

- 1487 in the Mouse Lymphoma (L5178Y TK+/

- ) Forward Mutation Assay: Lab Project Number: 011110. Unpublished study prepared by The Dow Chemical Company. 39 p.
46965903 Cifone, M. (2002) In Vivo/In Vitro Unscheduled DNA Synthesis in Rat Primary Hepatocyte Cultures at Two Time points with a Dose Range finding Assay with Bioban P

- 1487. Project Number: 23633/0/494/OECD, 021036. Unpu blished study prepared by Covance Laboratories, Inc. 52 p.

47005501 Spencer, P. (2003) Evaluation of Bioban p

- 1487 in the Mouse Bone Marrow Micronucleus Test. Project Number: 020146. Unpublished study prepared by The Dow Chemical Company. 74 p.

47213801 St ebbins, K.; Dryzga, M. (2007) P

- 1487 Antimicrobial: 28

- Day Oral Gavage Toxicity Study in Beagle Dogs. Project Number: 061185. Unpublished study prepared by The Dow Chemical Co. 131 p.
Page 46 of 5947394702 Thomas, J.; Andrus, A. (2007) Bioban P

- 1487 Biocide: 90

- day Ora l Gavage Toxicity Study in CRL:CD(SD) Rats. Project Number: 061155. Unpublished study prepared by Dow Chemical Co. 459 p.

47394701 Durando, J. (2007) Acute Inhalation Toxicity Study in Rats

- Limit Test: Bioban P

- 1487. Project Number: P330/DOW, 21611, 0701 27. Unpublished study prepared by Product Safety Laboratories. 35 p.

47394702 Thomas, J. and Andrus, A.K. (2007) Bioban P

- 1487TM Biocide: 90

- day oral gavage toxicity study in CRL:CD(SD) rats. Toxicology & Environmental Research and Consulting, t he Dow Chemi cal Company, Midland, Michigan 48674, Laboratory Project Study ID 061155, June 19, 2007. Unpublished.

47394703 Stebbins, K.; Brooks, K. (2007) P

- 1487 Antimicrobial: 90

- day Oral Gavage Toxicity Study in Beagle Dogs. Project Number: 071059. Unpublished study prepared by Dow Chemical Co. 266 p.

47865701 Carney, E.; Marshall, V.; Ellis

- Hutchings, R. (2009) BIOBAN P

- 1487 Antimicrobial: Oral Gavage Developmental Toxicity Study in New Zealand White Rabbits. Project Number: 081134. Unpublished study prepared by The Dow Chemical Company. 334 p.

48126001 Knapp, J. (2008) An Oral Gavage Two

- Generation Reproductive Toxicity Study of Bioban P

- 1487 Biocide in CRL:CD(SD) Rats: Final Report. Project Number: WIL/410006, 070157. Unpublished study prepared by WIL Research Labo ratories, Inc. 3056 p.

48239101 Rick, D.; Clark, A.; Markham, D.; et al. (2008) Bioban P

- 1487 Antimicrobial Pharmacokinetics and Metabolism in Crl:CD(SD) Rats. Unpublished study prepared by The Dow Chemical Company. 122 p.

49087501 Thomas, J.; Murray, J.; Hukkanen, R. (2012) Bioban P

- 1487: 28

- Day Dietary Toxicity Study in F344/DuCrl Rats. Project Number: 101196. Unpublished study prepared by Dow Chemical Company. 252p.

49088901 Thomas, J.; Murray, J. (2012) Bioban P

- 1487: 90

- Day Dietary Toxicity Study in F3 44/DuCrl Rats. Project Number: 111065. Unpublished study prepared by The Dow Chemical Company. 332p.

Page 47 of 59

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of Bioban P

- 1487

Water and Sediment Hydrolysis

A h ydrolysis stud y (MRID 43494001) w as performed on both derivatives of the Bioban P

- 1487 mixture: Bioban P

- 1447 and Bioban P

- 1490

. The study consisted of two individual studies for each active ingredient in the product at 25 o C

. For P

- 1490, the significant degradates formed were the active ingredient P

- 1447 and the degradate 2

- nitro

- 1

- butene after 10 minutes of hydrolysis. Bi oban P

- 1447 hydrolyzed with half

- lives of 22 hour s at pH 5, 45 hours at pH 7, and 4 6 hours at pH 9 in a study conducted for up to 73 hours. For P

- 1447, the significan t ( present at >10 % of applied parent compound) degradates were 2

- nitro

- 1

- butanol, 1

- nitro

- propane, and 2

- nitro

- 1

- butene, all of which were either stable in the study or demonstrated enough persistence to be present throughout the wastewater treatment proc ess. Table B1. Hydrolysis Results for P

- 14 4 7

Degradate formation and decline (maximum formation at end of study unless stated) Active ingredient Half

- life (hours) 2

- nitro

- 1

- butanol 2

- nitropropane 2

- nitro

- 1

- butene

P

- 1447 22 (pH 5) 31 % 19 % 36 % (3 2

- 48 hours), decline to 22 % (end of study) 46 (pH 7) 21 % 18 % 19 % (6 hours), decline to 4 % (end of study) 46 (pH 9) 9 % 19

- 20 % 15 % Table B2. Hydrolysis Results for P

- 1490

Degradate formation and decline (maximum formation at end of study unle ss stated) Active ingredient Half

- life ( minutes ) P

- 1447 2

- nitro

- 1

- butene

P

- 14 90 <10 (pH 5) 15 % 64 %

<10 (pH 7) 61 % 28 %

Page 48 of 59<10 (pH 9) 40 % 25 %

Aqueous Photolysis The registrant submitted a photodegradation in water study (MRID 47285303) for P

- 1 487. The half

- lives were 14 hours for the irradiated treatment and 19 .4 hours for the dark control , with a dark

- control adjusted half

- life of 50 hours. Hydrolysis degraded P

- 1487 2.6X faster than photolysis. Due to the rapid hydrolysis of P

- 1447 and P

- 1 490 , these two chemicals are not expected to persist long enough for aqueous photolysis to be an important competing environmental fate process. The study did not quantify the formation percentages of the degradates 2

- nitropropane, 2

- nitro

- 1

- butanol and 2

- nitro

- 1

- butene , but did state that the degradates formed in the dark controls, which represent hydrolysis, were the same as those in the irradiated treatments. There is no record of review of this study, which will be formally

reviewed in Registration Re view.
Octanol

- Water Partition Coefficient Log Kow values can indicate the potential for aquatic animals to bioaccumulate a chemical and for the potential for sorption of a chemical by activated sludge. The estimated log Kow is 0.18 for 4

- (2

- nitrobutyl) morpholine (P

- 1447) and

- 0.54 for 4,4

- (2

- ethyl

- 2

- nitromethylene) dimorpholine (P

- 1490) . The estimated log Kow values for the degradates of 4

- (2

- nitrobutyl)morpholine are 0.87 for 2

- nitropropane,

- 0.101 for both 2

- nitro

- 1

- butanol and 2

- nitro

1

- butene (Epi

- Suite 4.11) . Based on these low estimated values, bioaccumulation by aquatic animals and sorption by activated sludge would not be expected to be important environmental process es

. Aerobic Aquatic Metabolism

No information was found on the aerobic aquati c metabolism potential of P

- 1447 and its hydrolytic degradates . Since these chemicals appear to be highly soluble in water (Table E1 , Appendix E ) , data are needed to determine whether or not they are persistent enough for aquatic organisms to be exposed t o them.

A na erobic Aquatic Metabolism Based on the estimated log Kow values for P

- 1447 and its hydrolytic degradates (Table E1 , Appendix E ) , these chemicals are not expected to be likely to have a very high potential to sorb to suspended and benthic sedime nt . As a result, anaerobic aquatic metabolism data are not needed for these chemicals.

Soil Soil Leaching/Adsorption/Desorption Batch Equilibrium

Page 49 of 59P

- 1487 is not expected to sorb strongly to soil and sediments based on t he measured log Koc of 1.7 (Koc of 50 ml/g) . As a result, any P

- 1487 present in water will be associated with water and not soil and sediment (MRID 4590 0901)

. Aerobic and Anaerobic Soil Metabolism Data on aerobic and anaerobic soil metabolism are not required for P

- 1487 and its degradates b ecause environmental pathways of release to soil are not expected from uses in metalworking fluids and fuels

. In the event of a spill, the high mobility (MRID 45900901) of P

- 1487 and its degradates (MRID 43494001) preclude the soil compartment as a potent ial sink. T he rapid hydrolysis of P

- 1487 and its degradates (MRID 43494001) is expected to prevent surface water or ground water contamination from any potential exposure from spills.

Fate and Transport in WWTP 835.1110. Activated Sludge Sorption Isoth erm (ASSI)

Data on sorption to activated sludge is not required because of the low log Kow values for the two morpholine derivatives of P

- 1487 and their degradates , which precludes the potential for sorption to activated sludge as a significant transport p athway. The highest estimated log Kow value was 0.18 for P

- 1447. 850.3300: Activated Sludge Respiration Inhibition (ASRI)
The registrant submitted an ASRI study (MRID 47005503) in which an IC 50 value of 306 mg/L was determined for Bioban P

- 1487. The study appears to be valid, based on the IC 50 of 21 mg/L for the reference compound, 3,5

- dichlorophenol, and low variability in the controls (<15 %). There is no record of review for this study, which will be formally

- reviewed during registration review

. Biodegradation in a WWTP In a ready biodegra da bility study (MRID 47005502), Bioban P

- 1487 was found to be not readily biodegradable in a 28

- day study . It did not degr ade >60% within the 10

- day period after the start of biodegradation process

. Since n o ASR I and WWTP biodegradability data were found for the degradates, 2

- n itropropane, 2

- nitro

- 1

- butanol, and 2

- nitro

- 1

- butene , ASRI and WWTP biodegradability data are expected to be required for these degradates

. Results of the ASRI studies will determine whet her a ready biodegradability study or a simulation test will be required.

Page 50 of 59Reference s for Environmental Fate of Bioban P

- 1487

MRID 43494001

. Burke, B, 1994. Hydrolysis of 4

- (2

- nitrobutyl) morpholine and 4,4’

- (2

- ethyl

2

- nitromethylene) dimorpholine. Lab Project # PRT

- 23

- 4ANN

- 01

- PRT

- 23

- 4ANN

- 01

- 03. Unpublished study prepared by Plant Research Technologies, Inc. 228 pages

. MRID 45900901

. Gonsoir, SJ, Rivard, MA, and Stock, MK, 2002. Estimating Soil Koc for a series of Biocides by HPLC Using OECD Method # 1 21. Biocides TS and D, The Dow Chemical Company, Midland, Michigan

. MRID 47005502

. Gonsoir, S, Stock, M, and Rivard, M. 2002: Evaluation of Ready Biodegradability of Bioban P

- 1487 using OECD Method 301F: Manometric Respiratory Test; Project# 011131. Unpub lished Study Prepared by Dow Chemical Company, 31 pages

. MRID 47005503. Gonsior, S.; Rivard, M.; Stock, M. (2002) Activated Sludge, Respiration Inhibition Test (OECD 209) for Bioban P

- 1487. Project Number: 011177. Unpublished study prepared by The Dow Che mical Company. 16 p.

MRID 47285303. Ponte, M. (2007) Aqueous Photolysis of Bioban P

- 1487 Biocide Under Artificial Sunlight. Project Number: 1625W, 070058. Unpublished study prepared by The Dow Chemical Co., 80 p.

U.S. EPA. 2012. EPI

- Suite 4.11. http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

. U.S. EPA. September, 2007. Reregistration Eligibility Decision for Bioban P

- 1487. EPA 739

- R

- 07

- 005.

Page 51 of 59

# Appendix C Ecotoxicology Profile

Toxicity to Te rrestrial Organisms
Birds, acute oral and dietary

The available acute

- oral and dietary studies categorize technical

- grade Bioban P

- 1487 as being no more than slightly toxic to birds. No additional avian toxicity data are anticipated to be needed. The gui delines (850.2100, 850.2200) are satisfied.
Avian Acute

- oral and Dietary Toxicity
Test Species Test Material (% ai) Toxicity Toxicity Category EPA Study ID

Mallard ( Anas platyrhynchos ) 90 LD50 >1000 mg ai/kg bw Slightly toxic at most 93055001 Supplemen tal

90 LC50 >3692 ppm Slightly toxic at most 93055003 Supplemental Northern bobwhite ( Colinus virginianus ) 90 LC50 >3692 ppm Slightly toxic at most 93055002 Supplemental



### Toxicity to Aquatic Organisms
Freshwater Fish, acute

The available acute tox icity studies categorize technical

- grade BIOBAN P

- 1487 as being highly toxic to freshwater fish. The guideline (850.1075) for acute toxicity testing is satisfied for the TGAI

. Data anticipated to be needed for any or all three degradates (2

- nitropropane, 2

- nitro1

- 1butanol and/or 2

- nitro

- 1

- butene) unless the registrant can demonstrate from environmental fate data that each degradate will not occur in wastewater discharged into the aquatic environment. Acute Toxicity to Freshwater Fish
Test Species Test Mat erial (% ai) 96

- h LC50 (mg ai/L) Toxicity Category EPA Study ID Rainbow Trout ( Oncorhynchus mykiss) 90 0.75 Highly toxic 93055005 Acceptable Bluegill ( Lepomis macrochirus ) 90 0.83 Highly toxic 93055004 Acceptable

Page 52 of 59Freshwater Invertebrates, acute
The o ne available study categorizes technical

- grade BIOBAN P

- 1487 as being moderately acutely toxic to freshwater invertebrates. The guideline (850.1010) for acute toxicity testing is satisfied for the TGAI. Data are anticipated to be needed for any or all t hree degradates (2

- nitropropane, 2

- nitro1

- 1butanol and/or 2

- nitro

- 1

- butene) unless the registrant can demonstrate from environmental fate data that each degradate will not occur in wastewater discharged into the aquatic environment. Acute Toxicity to Fres hwater Invertebrates
Test Species Test Material (% ai) 48

- h EC50 (mg ai/L) Toxicity Category EPA Study ID Water flea ( Daphnia magna) 94.6 3.23 Moderately toxic 47285301 Acceptable

Estuarine/Marine Fish and Invertebrates, acute
No data are available. B ecause BIOBAN P

- 1487 may reach the estuarine/marine environment from discharges from WWTPs, acute toxicity data are anticipated to be needed. Acute toxicity studies anticipated to be needed for the TGAI include tests for a fish sp. (850.1075), a bivalve s p. (850.1025 or 850.1055), and one additional invertebrate sp. (850.1035). Data also are anticipated to be needed for any or all three degradates (2

- nitropropane, 2

- nitro1

- 1butanol and/or 2

- nitro

- 1

- butene) unless the registrant can demonstrate from enviro nmental fate data that each degradate will not occur in wastew ater discharged into the estuarine/marine environment. Fish and Aquatic Invertebrates, chronic No chronic data are available. Because parent Bioban P

- 1487 degrades rapidly, any significant chro nic exposure in waste water discharge would be to one or more degradates (2

- nitropropane, 2

- nitro1

- 1butanol and/or 2

- nitro

- 1

- butene ) . If the outstanding environmental fate studies identify any degradates likely to occur and persist in waste water discharg e waters, chronic data will be expected to be needed for one fish species (850.1400) and one invertebrate species (850.1300 or 850.1350)

. T esting sh ould be done with the most sensitive species (either freshwater or estuarine/marine) as determined from the results of the acute toxicity tests (acute EC50 freshwater invertebrates; acute LC50 freshwater fish; LC50/EC50 estuarine/marine species).
Aquatic Plants Toxicity data are available for the green algae. Becau se that study shows that the EC50 is less than 1 mg ai/L, additional studies are triggered. To support the TGAI, Tier II testing is anticipated to be needed with a vascular species (850.4400), freshwater and marine diatoms (850.4500), and cyanobacteria (8 50.4550). Data also are anticipated to be needed for any or all three degradates (2

- nitropropane, 2

- nitro1

- 1butanol and/or 2

- nitro

- 1

- butene) unless the registrant

Page 53 of 59can demonstrate from environmental fate data that each degradate will not occur in wastewate r discharged into the aquatic environment. Toxicity to Aquatic Plants
Test Species Test Material (% ai) Toxicity (mg ai/L) Toxicity Category EPA Study ID Green algae ( Selanastrum capricornutum ) 90 EC50 = 0.352 NOAEC = 0.049 NA 47005504 Acceptable

Bent hic Invertebrates Sediment toxicity tests for benthic invertebrates (850.1735, 850.1740) are not anticipated to be needed. The available environmental fate data indicate that BIOBAN P

- 1487 will partition into the water column (K oc = 3.4 and 12.4 L/kg) and will not accumulate in aquatic sediments.
Ecotoxicity References:

93055001 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00083017. BIOBAN P

- 1487: Single Oral Dose LD50 in Mallard Duck: Project No. 170

- 103. Prepared by Wildlife International, LTD. 13 p.

93055002 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00069609. BIOBAN P

- 1487: Eight

- Day Dietary LC50 in Bobwhite Quail: Project No. 170

- 101. Prepared by Wildlife International. 13 p.
93055003 Trueblood , A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00083018. BIOBAN P

- 1487: Eight

- Day Dietary LC50 in Mallard Duck: Project No. 170

- 102. Prepared by Wildlife International. 12 p.

83017 Fink, R.; Beavers, J.B.; Brown, R.; et al. (1980) Final Repor t: Acute Oral LD50

-- Mallard Duck: Project No. 170

- 103. (Unpub

- lished study, including submitter summary, received Jan 14, 1981 under 271

- 30; prepared by Wildlife International, Ltd. and Wash

- ington College, submitted by International Minerals & Chemical Corp., Terre Haute, Ind.; CDL:244373

- B)

. 69609 Fink, R.; Beavers, J.B.; Brown, R.; et al. (1980) Final Report: Eight

- day Dietary LC50

-- Bobwhite Quail: Project No. 170

- 101. (Unpublished study, including submitted summary and letter dated Apr 29, 1980 from C.P. Bouchard to C. Parekh, received Jan 14, 1981 under 271

- 30; prepared by Wildlife International, Ltd. and Washington College, submitted by International Minerals & Chemi

- cal Corp., Terre Haute, Ind., CDL:244373

- D)

. 83018 Fink, R.; Beavers, J.B.; Bro wn, R.; et al. (1980) Final Report: Eight

- day Dietary LC50

-- Mallard Duck: Project No. 170

- 102. (Un

- published study, including submitter summary and letter dated Apr 29, 1980 from C.P. Bouchard to C. Parekh,

Page 54 of 59received Jan 14, 1981 under 271

- 30; prepared by Wildlife International, Ltd. and Washington College, submitted by International Minerals & Chemi

- cal Corp., Terre Haute, Ind.; CDL:244373

- C)

. 69610 Griffen, J.; Thompson, C.M. (1980) Acute toxicity of Bioban P

- 1487 to Bluegill Sunfish (~Lepomis macrochi rus~): Static Renewal Acute Bioassay Report # 25061. (Unpublished study, including submitter summary and letter dated Apr 29, 1980 from C.P. Bou

- chard to C. Parekh, received Jan 14, 1981 under 271

- 30; prepared by Analytical Bio Chemistry Laboratories, Inc ., submitted by International Minerals & Chemical Corp., Terre Haute, Ind.; CDL: 244373

- E)

. 69611 Griffen, J.; Thompson, C.M. (1980) Acute Toxicity of Bioban P

- 1487 to Rainbow Trout (Salmo gairdneri): Static Renewal Acute Bioassay Report # 25145. (Unpubl ished study, including submitter summary and letter dated Apr 29, 1980 from C.P. Bouchard to C. Parekh, received Jan 14, 1981 under 271

- 30; prepared by Analytical Bio Chemistry Laboratories, Inc., submitted by International Minerals & Chemical Corp., Terre Haute, Ind.; CDL:244373

- F)

. 93055004 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00069610. BIOBAN P

- 1487: Acute Toxicity Effects on Bluegill Sunfish Ninety

Six Hour LC 50: Project No. 25061. Prepared by Analytical Bio

- Chemical L abs. Inc. 12 p. 93055005 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00069611. BIOBAN P

- 1487: Acute Toxicity Effects on Rainbow Trout Ninety

- Six Hour LC50: Project No. 25145. Prepared by Analytical Bio

- Chemical Labs. Inc. 11 p. 47005504 Kirk, H.; Staley, J.; McClymont, E.; et al. (2002) Bioban P

- 1487: Growth Inhibition Test with the Freshwater Green Alga, Selenastrum capricornutum Printz. Project Number: 021001. Unpublished study prepared by The Dow Chemical Company. 45 p. 47285 301 Marino, T.; Najar, J.; Arnold, B. (2007) Bioban P

- 1487 Antimicrobial: An Acute Toxicity Study with the Daphnid, Daphnia magna . Project Number: 071054. Unpublished study prepared by The Dow Chemical Co., 43 p.

Page 55 of 59

# Appendix D Screening Level Down

- the

Drain Analysis

No screening

- level Down

- the

- Drain analysis was performed for this case since all uses for this case are industrial uses. Results from the Down

- the

- Drain module of E

- FAST are only applicable for chemicals that are incorporated in products that are releas ed down

- the

- drain to domestic wastewater treatment facilities. Such results are not applicable for releases to surface water from industrial uses.

Page 56 of 59

# Appendix E Product Chemistry

The Biob an P

- 1487 product chemistry information is summar ized in Table E1 and Table E2 contains the product chemistry information for the degradates of P

- 1487.

Table E1

– Product Chemistry of Bioban P

- 1487

Guideline No. Parameter 4

- (2

- nitrobutyl) Morpholine (P

1447) 4,4’

- (2

- ethyl

- 2

- nitromethylene)dimor pholine (P

- 1490) Source (MRID unless

sp ecified)

830.1800 Enforcement analytical method Gas Chromatography and Reverse phase HPLC Gas Chromatography and Revers Phase HPLC 41995101C

830.6302 Color Yellow to brown Yellow to brown 41995101C 830.6303 Physical State Liquid Liquid 41995101C

830.6304 Odor Mild fish like odor characteristics of amines Mild fish like odor characteristics of amines 41995101C

830.6313 Stability Indefinitely stable at room temperature Indefinitely stable at room temperature 41995101C
830.7000 pH 9.5

- 10.0 9.5

- 10. 0 41995101

830.7050 UV Visible absorption Sorption below 210 nm (acid and neutral)

and below 275 nm (basic) Sorption below 210 nm (acid and neutral) and below 275 nm (basic) 48511302

830.7220 Boiling point ( o C) 199

- 225 o C 199

- 215 o C 41995101 830.7300 De nsity 1.075 g/cc 1.075 g/cc 41995101

830.7550 Octanol

- water partition coefficient at 25 o C (Log K ow ) 0.18

- 0.54 EPI Suite / EPWEB 4.1
830.7840 Solubility in water (mg/L) 11 ,000 m g/L 11 ,000 m g/L 41995101

830.7950 Vapor pressure (mmHg) 20

- 43 mm Hg at 90 o C

Estimated: 7.5 x 10

- 3 mm Hg at 25 o C 20

- 43 mm Hg at 90 o C

Estimated: 5.07 x 10

- 6 mm Hg at 25 o C 41995101

----------------- EPI Suite/EPWEB 4.1
Henry’s Law (atm m 3 mol

- 1 ) 1.1 x 10

- 10 1.51 x 10

- 1 5 EPI Suite /EPWEB 4.1

o C = d egrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury; Henry’s Law in atm m 3 mol

- 1

Page 57 of 59Table E2: Estimated Physical/Chemical Properties of Bioban P

- 1487 Degradates Based on EPI

Suite 4.11

P/Chem and Environmental Fate Property Degrada te 2

- Nitropropane

CAS# 79

- 46

- 9 2

- Nitro

- 1

- Butanol CAS# 609

- 31

- 4 2

- Nitro

- 1

- Butene CAS# 2783

- 12

- 2 Structure

MP/BP ( o C) 101 (BP) 28 (MP) 28 ( MP ) Molecular weight (g/mol) 89.9 119.2 101.12
Log Kow 0.87

- .101

- 0.101 Solubility in water (mg/L) 8 , 1 8 0 50 , 3 00 50 ,300
Ready Biodegradability NO Yes Yes

Half

- life in air (days) 84 10.4 10.4
Log Koc 1.65 0.73 0.73 % removal in WWTP 7.5 1.85 1.85
Vapor pressure (mm Hg) 15.5 0.056 0.43
Henry’s Law (atm
m 3 mol

- 1 ) 2.2 x 10

- 4 1.7 x 10

- 7 1.1 x 10

- 6

Page 58 of 59References for Product Chemistry of Bioban P

- 1487 MRID 41995101. Bollimer, A, 1990. Product chemistry for Bioban P

- 1487. Unpublished study prepared by Angus Chemical Company, 28 pages

. MRID 48511302. O'Connor, B.; Woolley, S. (2011) Bioban P

- 1487: De termination of Physico

Chemical Properties. Project Number: 41005027, 24P/2010/036, GLP/2011/030. Unpublished study prepared by Harlan Laboratories, Ltd. 73 p.

U.S. EPA. 2012. EPI

- Suite 4.11. http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

.

Page 59 of 59