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Page 2 of 52 1, 2

- Benzisothiazolin

- 3

- one (BIT) Registration Review Team

Human Health & Environmental Effects William Erickson Srinivas Gowda Najm Shamim Siroos Mostaghimi Jonathan Chen Timothy Dole Zoë Cavinder

Risk Management Donna Kamarei James Parker

Office of General Counsel Philip RossDocket Number EPA

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Page 3 of 52 TERMS, 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

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

- of

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

- water partition coefficient Kd s oil

- water partition coefficient Kow o ctanol

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

- o bserved

- a dverse

- e ffect

- c oncentration LOEC l owest

- o bserved

- e ffect

- c oncentration LOAEL lowest

- observed

- adverse

- e ffect

- l evel Log K ow l ogarithm of the octanol

- water partition coefficient
μg m 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 a y mg/L m illigram p er l iter mm Hg m illimeter of mercury MOE m argin of e xposureDocket Number EPA

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Page 4 of 52 MRID 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 Chemical Safety and Pollution Prevention OECD Organization for Economic Co

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

- 10 logarithm of the acid

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

- a ctivity r elationship RED Rere gistration Eligib ility Decision SAR s tructure a ctivity r elationship SF s afety f

actor TEP t ypical e nd

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

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Page 5 of 52 

### Table of Contents
1 Introduction

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

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

................................ ................................ ................................ ................. 9 1.3 Chemical Identification and Properties

................................ ................................ ............ 9 1.4 Use/Usage Description

................................ ................................ ................................ ... 10 1.4.1 Registrations

................................ ................................ ................................ ........... 10 1.4.2 Summary of Registered Uses

................................ ................................ .................. 11 1.5 Regulatory History

................................ ................................ ................................ ......... 11 1.5.1 Tolerance Information

................................ ................................ ............................ 11 1.6 Incidents

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

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

................................ ................................ ................................ ............... 13 2 Anticipate d Data Needs

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

................................ ................................ ........................... 17 3.1 Existing Toxicological Endpoints

................................ ................................ .................. 17 3.2 Dietary Exposure

................................ ................................ ................................ ............ 19 3.2.1 Fo od

................................ ................................ ................................ ........................ 20 3.2.2 Drinking Water

................................ ................................ ................................ ....... 20 3.3 Occupational and Residential Exposures

................................ ................................ ....... 21 3.3.1 Occupational Handler Exposure

................................ ................................ ............. 21 3.3.2 Residential Handler Exposures

................................ ................................ ............... 22 3.3.3 Residential Post

- Application Exposures

................................ ................................ . 22 3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 23 3.4.1 Aggregate Exposures

................................ ................................ .............................. 23 3.4.2 Cumulative Exposures

................................ ................................ ............................ 23 4 Environmental Risk Assessment

................................ ................................ ........................... 23 4.1 Environmental Fate Assessment

................................ ................................ .................... 23 4.1.1 Leaching [Wood/Paint/Antifoulant Paint/Plastic/Textiles/e.g., treated article]

...... 24 4.1.2 Water and Sediment

................................ ................................ ................................ 24 4.1.3 Soil

................................ ................................ ................................ .......................... 24 4.1.4 Air

................................ ................................ ................................ ........................... 24 4.1.5 Water Quality

................................ ................................ ................................ .......... 24 4.2 Envi ronmental Exposure Pathways

................................ ................................ ................ 24 4.3 Ecological Effects Assessment

................................ ................................ ....................... 26 4.3.1 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 26 4.4 Exposure Analysis Plan

................................ ................................ ................................ .. 27 4. 4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............ 27 4.4.2 Screening Level Down

- the

- Drain Analysis

................................ ............................ 27 4.5 Effects Analysis Plan

................................ ................................ ................................ ..... 28 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 28 6 Optional Label Changes

................................ ................................ ................................ ........ 29 7 Guidance for Commenters

................................ ................................ ................................ .... 29 7.1 Preliminary Work Plan

................................ ................................ ................................ ... 29 7.1.1 Trade Irritants

................................ ................................ ................................ .......... 29 7.1.2 Water Quality

................................ ................................ ................................ .......... 30Docket Number EPA

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Page 6 of 52 7.1.3 En vironmental Justice

................................ ................................ ............................. 30 7.1.4 Additional Information

................................ ................................ ........................... 30 8 Next Steps

................................ ................................ ................................ ............................. 31 9 References

................................ ................................ ................................ ............................. 32

Appendix A T oxicology Profile

................................ ................................ ............................... 33 Appendix B Environmental Fate

................................ ................................ ............................. 41 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 44 Appendix D Screening Level Down

- the

- Drain Analysis

................................ ........................ 50 Appendix E Product Chemistry

................................ ................................ ............................... 51

List of Tables Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registration Review BIT 8 Table 2

– Anticipated Registration Review Schedule

................................ ................................ .......... 8 Table 3

– Chemical Identification of BIT

................................ ................................ ............................. 9 Table 4

– Physical

- Chemical and Environmental Fate Properties for BIT

................................ ........... 9 Table 5

– Summary of BIT Registered Uses

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

– Summary of BIT Food Con tact Notifications

................................ ................................ ..... 13 Table 7

– Studies Anticipated as Needed for the Registration Review of BIT

................................ ... 15 Table 8

– Data Needs Required by the March 2008 Data Call

- In for the BIT RED

.......................... 16 Table 9

– Existing Toxicological Endpoints

................................ ................................ ....................... 17 Table 10

– Occupational Han dler Scenarios to be Assessed During Registration Review

................. 21 Table 11

– Residential Handler Scenarios to be Assessed During Registration Review

..................... 22 Table 12

– Residential Post

- Application Scenarios to be Assessed During Registration Review

..... 22 Table 13

– Ava ilable Ecological Effects Endpoints

................................ ................................ ............ 27 Table 14

– Summary of Screening Level Down

- the

- Drain Analysis Results for Aquatic Organisms 29

List of Figures Figure 1

- Conceptual Model for Ecological Exposure and Effects of BIT to Aquatic and Terrestrial Organisms

................................ ................................ ................................ .................... 25Docket Number EPA

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## 1 Introduction

This document is the United States Environmental Protection Agency ’s ( USEPA, EPA or “the
agency ”) Preliminary Work Plan (PWP) for 1,2

- Benzisothiazolin

- 3

- one (BIT)

. The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about BIT
, highlighting anticipated data and assessment needs, identifying the types of information that would be especially useful to the agency in conducting the review, and providing an anticipated timeline for completing BIT’s review

. The registration review pr ocess was designed to include a public participation component to solicit input from interested stakeholders. The agency intends, by sharing this information in the docket, to inform the public of what it knows about BIT and what types of new data or other information would be helpful for the agency to receive as it moves toward a decision on BIT

. The agency encourages all interested stakeholders to review the PWP and to provide comments and additional information that will help the agency ’s decision

- makin g process for this chemical.



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

.
The agency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standa rd for registration. The regulations governing registration review begin at 40 CF R 155.40. The agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for eac h case. The docket is the
agency ’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. After reviewing and responding to comments an d data received in 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 BIT case

. Documents associated with this registration review can be viewed at http://www.regul ations.gov in docket EPA

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. Tables 1 and 2 b elow summarize the issues relevant to this registration review case and the anticipated registration review schedule

.Docket Number EPA

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Page 8 of 52 Table 1

– Summary of Anticipated Risk Assessments and Data Needs for Registra tion Review : BIT

Risk Assessment Assessment Necessary to Support Registration Review Date of Most

Recent Assessment Type of

Assessment Required (New/Updated) Data Anticipated as Needed (See Table 7 and 8 for detail s)

Dietary (food) Yes 7/11/ 20 05 Updated Product use information Dietary (drinking water) Yes N/A New Product use information

Occupational Handler Yes 9/01/2005 Updated Product use information, 90

- day inhalation toxicology, i mmunotoxicity

Residential Handler Yes 9/01/2005 Updated Product use information, 90

- day inhalation toxicology, i mmunotoxicity Residental Post Application

- Incidental Oral and Dermal Yes 9/01/2005 Updated Indoor surface residues, p roduct use information

Residental Post Application

- Inhalation No 9/01/2005 Updated Product use information

Aggregate Yes 9/01/2005 Updated Product use information

Cumulative No N/A None None

Tolerance Review No N/A None None

Ecological Yes N/A New Product use information, Aquatic plants

, Leaching study, Ready biodegradability or one of three biodegradation in activated sludge simulation tests, Aerobic aquatic metabolism, Activated sludge, respiration inhibition test N/A = Not applicable * Table 1 is a summary of the anticipated risk assessments and data needs for Registration Review. For data called in through the post

- RED DCI, see Table 8

. Table 2

– Anticipated Registration Review Schedule

Anticipated Activity Target Date * Completion Date Phase 1: Opening the Docket Open Docket and 60

- Day Comment Period for Preli minary Work Plan 2014

- 06 2014

- 06

- 25
Close Public Comment Period 2014

- 08 Phase 2: Case Development
Issue Final Work Plan 2014

- 12
Issue Data Call

- In (DCI) 2015

- 12
Receive Data to be Considered in Risk Assessment 2017

- 12 Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 2019

- 06
Close Public Comment Period 2019

- 07 Phase 3: Registration Review Decision and Implementation Open 60

- Day Public Comment Period for Pro posed Decision 2019

- 12
Close Public Comment Period 2020

- 02
Issue Final Decision 2020

- 06 Begin Post

- Decision Follow

- up 2020 Total (years) 6Docket Number EPA

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Page 9 of 52 * The anticipated schedule will be revised as necessary ( e.g ., need arising under the Endocrine Disruptor Screening Program with respect to the active ingredients in this case).


## 1.2 Case Overview

The docket for the BIT case ( c ase 3026 ) has been established at http://www.regulations.gov in docket number EPA

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. 

## 1.3 Chemical Identification and Properties

Table 3 presents the active ingredient to be assessed in case 3026 : 1,2

- Benzisothiazolin

- 3

- one (PC Code 098901 )

.

Table 3

– Chemical Identification of BIT

Chemical Name 1,2

- Benzisothiazolin

- 3

- one (BIT) Chemical Classification Isothiazolone
PC Code 098901
CAS N umber 2634

- 33

- 5 Molecular Formula C 7 H 5 NOS Molecular Weight (grams/mole) 151.19

Molecular Structure

The BIT product chemistry information (MRID Nos. 43584001, 41927501, 43584001, 42908201 ) relevant to risk assessment is summarized in Table 4 , and the details of the environmental fate and product chemistry information are discussed in Appendix B and E, respectively

.

Table 4

– Physical

- Chemical and Environmental Fate Properties for BIT

Guideline No. P arameter 1,2

- Benzisothiazolin

- 3

- one (BIT) Physical/Chemical Properties 830.7000 pH 4.25

- 1% slurry 830.7050 UV/Visible Absorption Stable with respect to sunlight 830.7200 Melting point ( o C) 159.5

- 160 o C 830.7220 Boiling point ( o C) Not applicable 830.7300 Density 1.36±0.02 g/ cm 3

830.7370 Dissociation c onstant (pKa) Acid dissociation constant 9.12 x 10

- 8 moles/L (PAI) pKa 7.04 at 25 o C

830.7550 Octanol

- water partition coefficient

at 25 o C (Log K ow ) Log Kow 1.4 (PAI)

830.7840 Solubility in water (mg/L) 1118 ppm at 20 o C 1380 ppm at 24 o C 830.7860 Solubility in organic solvents n

- H e xane: 100 ppm at 23 o CDocket Number EPA

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Page 10 of 52 Guideline No. P arameter 1,2

- Benzisothiazolin

- 3

- one (BIT) Ethyl acetate: 23000 ppm at 23 o C Methanol: 67000 ppm at 24 o C Acetonitrile: 13000 ppm at 23 o C Acetone: 42000 ppm at 24 o C Dichloromethane: 31000 ppm at 23 o C Toluene: 5000 ppm at 24 o C Heptane: 135 ppm at 20 o C DMSO

830.7950 Vapor pressure (mmHg) 4.4 x 10

- 7 mm Hg at 20 o C (PAI) 9.8 x 10

- 7 mm Hg at 25 o C (PAI) Environmental Fate Properties Mobility Organic Carbon Partitioning Coefficient (K oc ) From the K d values, K oc were estimated: values range from 254

- 728 mg/g Persistence in Water (half

- life) Hydrolysis at 25 o C: pH 5, 7 &9 (days) It is Hydrolytically stable at pHs 5, 7, and 9 under buffered conditions (MRID # 41199101, 44182101)

Aqueous photolysis at 25 o C (days) The h alf

- life of BIT at pH 5= 9 hours; pH 7 = 0.7 hours and at pH 9, the half

- life is 0.7 hours. A number of photodegradates were identified: 1) ortho sulfbenzamide + 2

- sulfobenzoic acid ; 2) 1,2

- benzthiazolin

- 2

- one; 3) hydroxy

- 1,2

- benzthiazolin

- 3

- one and 4) sacchrin + 1,2

- benzthiazolin

- 3

- one

- 1,1

- dioxide ; 5) dihydroxy

- 1,2

- benzthiazolin

- e

- one. Two more degradates w ere observed (called degradate E, and M). these were not identified (MRID# 47329402) Aerobic aquatic metabolism (days) No study was submitted Anaerobic aquatic metabolism half

- life (days) No study was submitted

Persistence in Soil (half

- lifes)

Aerobic soil metabolism at 25 o C (days) Half

- life was measured between 0.4 to 3.6 days. It is not stabl e in aerobic soils and the degradates identified were: 1) ortho sulfbenzamide (same as in aqueous photolysis study; 2)BIT

- s

oxide ;3) 1,2

- benzthiazolin

- 3

- one dioxide; 4) 2

- carbamylbenzenesulfonic acid. (MRID# 41199102, 41199103, 93053102) Anaerobic soil metabolism (days) No study was submitted Persistence in WWTP (% removed) Ready biodegradation No study was submitted

atm

- m 3 /mol = atmosphere cubic meter per mole; o C = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury.


## 1.4 Use/Usage Description

1.4.1 Registrations

There are 68 EPA

- registered products that contain BIT as an active ingredient (a.i.). Two of the regis tered products are technical, ten are registered as intermediate formulations, and 5 6 are registered as end use products. There are currently fourteen companies that have active products containing BIT.Docket Number EPA

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Page 11 of 52 

### 1.4.2 Summary of Registered Uses

Table 5 presents a summary of all registered uses of BIT , all of which will be assessed in this registration review. BIT can be applied by the follow ing application methods: p aint brush, roller, airless sprayer (for paints containing BIT), wiping, mopping (for cleaning products containing BIT), open pour and meter pump injection (for incorporation as a material preservative and treatment of industrial processes and water systems).

Table 5

– Summary of BIT Registered Uses

Use Application Method Application Rate
Industrial Processes and Water Systems

A ir washer water systems C ommercial/industrial water cooling systems I ndustrial waste disposal systems P ulp/paper mill water systems R everse osmosis water system S econdary oil recovery injection water Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump 1 to 4 ppm 1 to 4 ppm 1 to 4 ppm 35 to 950 ppm 3 ppm 1 to 308 ppm

Material Preservative

A dhesives, industrial Automotive Evaporator Cores C oatings, industrial E mulsions, resin/latex/polymer L eather processing liquors

Leather and Leather Products Metalworking Fluids O il recovery drilling muds/packer fluids P aints (in

- can) P aper/paper products

P lastic products R ubber products Household and Janitorial Cleaning Products Laundry and Dishwashing Detergents T extiles (carpets, canvas, drapes, mattress covers ) Open Pour, Meter Pump Dip Open Pour, Meter Pump Open Pour, Meter Pump Open Pour

Open Pour Open Pour Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump

Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump 25 t o 2000 ppm 1770 ppm (in dip solution) 25 to 950 ppm 25 to 2900 ppm 60 to 950 ppm

475 to 4920 ppm 25 to 1760 ppm 1 to 9200 ppm 25 to 950 ppm 25 to 490 ppm

2000 ppm 162 to 500 ppm 25 to 1025 ppm 25 to 1025 ppm 25 to 2000 ppm



## 1.5 Regulatory Histor y The first product containing BIT as an active ingredient was r egistered in the United States o n April 16, 1973 . The agency completed a Reregistration Eligibility Decision (RED) for BIT in September of 2005 ( 9/29/2005) . The post

- RED Data Call

- In s (DCI s )

, PDCI

- 098901

- 27549 and GDCI

- 098901

- 27548 were issued in March of 2008

. 

### 1.5.1 Tolerance Information

For the active ingredient BIT, no pesticide tolerances or exemptions from tolerances have been established. BIT currently has one inert ingredient exemption from t he requirement of a tolerance for residues as required under the Food Quality Protection Act (FQPA) section 408. The existing inert exemption is for use on growing crops under 40 CFR part 180.920.Docket Number EPA

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Page 12 of 52 BIT is listed as a food contact substance by FDA

, eight food contact notifications (FCNs) have been granted (FFDCA Section 409) . See Table 6 below. These FCNs are only effective for the manufacturer or supplier identified in the notification.

Tabl e 6

– Summary of BIT Food Contact NotificationsDocket Number EPA

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Page 13 of 52 

## 1.6 Incidents

1.6.1 Human Health

There are eight incidents listed in the OPP Incident Data System for the period 1 / 01 /2005

, to 4/14/2014, when the data system was queried. All eight of these incidents were rated as minor and skin irritation was the most common ly reported effect

. One incident also resulted in swollen lips in addition to skin irritation.



### 1.6.2 Ecological No ecological incidents are in the Incident Data System (IDS, v. 1.8) a s of April 1, 2014.


## 2 A nticipated Data Needs

Several studies were required from the assessment of BIT in the 2005 RED . In addition to the already

- required RED DCI data, the following studies as listed in Table 7 are expected to be needed for the registration review of BIT . Table 8 outlines the data requirements required by the post

- RED DCI issued on March 3, 2008

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

- RED DCI as well as data requested for this registration review prior to conducting the registration review risk assessments for BIT

.Docket Number EPA

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Page 14 of 52 Table 7

– Studies Anticipated as Needed for the Registrati on Review of BIT

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

Anticipated Data Requirement Applicable Exposure Scenario

Studies Anticipated to be Required through the Registration Review DCI
Non

Guideline Leaching Study EP 12 Ecological Risk Assessments Treated wood Soil/water

Non

Guideline Leaching Study EP 12 Ecological Risk Assessments Treated Textiles Aquatic medium

835.3110 1 835.3220 2 835.3240 3 835.3280 4 Ready

biodegradability or one of three biodegradation in

a ctivated sludge simulation tests TGAI/ DEGR 12 Ecological Risk Assessments

- Fate and persistence in WWTPs Down the drain assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Aquatic environment

835.4400 Aerobic aquatic

metabolism PAI 24 Ecological Risk Assessments Metalworking Fluids, once through cooling towers Aquatic medium

850.3300 5 or OECD 209 Activated sludge,

respiration inhibition
test TGAI/ DEGR 12 Ecological Risk Assessments

- Fate and persistence in WWTPs Down the drain assessment Paints, Material Preservatives, Drilling Muds and Flooding Fluids, Textiles Toxicity to WWTP organisms

850.4400 Aquatic plant toxicity,

Lemna sp. TGAI 12 Ecological Risk Assessments All Aquatic environment

850.4500 6 Algal toxicity (3 spp.) TGAI 12 Ecological Risk Assessments All Aquatic environment

850.4550 6 Cyanobacteria TGAI 12 Ecological Risk Assessments All Aquatic environment

875.1700 875.2700 Product Use

Information (Applicator/Post

application) TGAI or EP 12 All Risk Assessments All use sites All exposure scenarios

875.2300 Indoor Surface

Residues TGAI 24 Residential Post Application Carpet fibers, Leather, Mattress Covers, Plastics, Floor cleaners See footnote 7

870.3465 90

- day Inhalation

Toxicology TGAI 24 Occupational and Residential All All potential
exposures
870.7800 Immunotoxicity TGAI 24 Occupational and Residential All All potential
exposuresDocket Number EPA

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Page 15 of 52 TGAI = Technical Grade Active Ingredient; TGAI/DEGR = Technical Grade of the Active Ingredient and Degradates; EP = End Use P roduct; PAI = Pure Active Ingredient.

1 EPA has a published final guideline for this study: http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0152

- 0017 . The required biodegradation study required is based on results of an Activated Sludge Respiration Inhibition test.

2 EPA has a published final guideline for this study: http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0152

- 0024 . The required biodegradation study required is based on results of an Activated Sludge Respiration Inhibition test.

3 EPA has a published final guideline for this study: http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0152

- 0034 . The required biodegradation study is based on results of an Activated Sludge Respiration Inh ibition test.

4 EPA has a published final guideline for this study: http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0152

- 0036 . The required biodegr adation study required is based on results of an Activated Sludge Respiration Inhibition test.

5 EPA published draft guidance under guideline 850.6800 and has since published final guidance for this study under guideline 8 50.3300: http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

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

- ilibrary.org/content/book/9789264070080

- en . The results of the Activated Sludge Respiration Inhibition Test (ASRI) will determine which of these four biodegradation tests is/are required. If the ASRI test EC50 is less than or equal to 20 mg/L, then either the (i)Biodegradation in Activated Sludge Study or (ii) Simulation Test

- Aerobic Sewage Treatment: A. Activated Sludge Units or (iii) the Porous Pot Test is required. If the ASRI test
EC5 0 is greater than 20 mg/L, then the registrant must conduct either: (i) Ready Biodegradability or (ii) a) Biodegradation in A ctivated Sludge or b) Simulation
Test

- Aerobic Sewage Treatment: A. Activated Sludge Units or c) the Porous Pot Test. If the Ready Biodegradability study is conducted and passes, then no further testing is required. If, however, the antimicrobial fails the Ready Biodegradability study, then the a) Biodegradatio n in Activated Sludge or b) Simulation
Test

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

6 Results for studies conducted for (i) the freshwater green alga, Selenastrum capricornutum, (ii) the freshwater diatom, Navic ula pelliculosa, (iii) the marine diatom, Skeletonema costatum, and (iv) the cyanobacteria species Anabaena flos

- aquae, must be submitted to satisfy this requirement. Final 850 guidelines for the algal testing were posted in June 2012. The Public Draft OPPTS 850.5400 Algal Toxicity guideline was split into two separat e guidelines and renumbered with the cyanobacteria species separated into OCSPP 850.4550 and the other three species under OCSPP 850.4500.

7 Exposure scenarios include dermal and/or incidental oral exposures to carpet fibers, clothing, leather, mattress co vers, plastics, and floors preserved with BIT or cleaned with BIT preserved cleaning products.Docket Number EPA

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Page 16 of 52 Table 8

– Data Needs Required by the March 2008 Data Call

- In for the BIT RED

GLN Study Name Test Substance Status

Studies Required through the Post

- RED DCI

870.13 00 Acute Inhalation

toxicity TGAI Data have been submitted

870.42 00 Carcinogenicity TGAI Data have been w aived

875.12 00 Indoor Dermal

Exposure TGAI or

surrogate Awaiting data submission

875.14 00 Indoor Inhalation

Exposure TGAI or

surrogate Awaiting data submission

875.16 00 Applicator

Exposure Monitoring Data Reporting TGAI or

s urrogate Awaiting data submission

875.28 00 Description of

Human Activity TGAI or EP Awaiting data submission (Post Application)Docket Number EPA

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## 3 Human Health Risk Assessment

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

. The agency expects to require additional data for use in conducting the registration review

. 

## 3.1 Existing Toxicological Endpoints
On August 28, 2002 the Antimicrobials Division’s Toxicology Endpoint Selection Committee (ADTC) reviewed the available toxicology data for BIT with regard to the acute and chronic Reference Doses (RfDs) and the toxicological endpoint selection fo r use as appropriate in occupational/residential exposure risk assessments. The potential for increased susceptibility of infants and children from exposure to BIT was also evaluated as required by the FQPA of 1996. On February 8, 2005, the ADTC met agai n to consider additional data submitted by the registrant in response to the conclusions reached from the first meeting and as discussed in the September 2002 ADTC memo. On May 17, 2012, the ADTC met again for several purposes: (1) to consider results of additional data submitted since the issuance of the RED for BIT in 2005 and its impact on the previously selected endpoints; (2) to re

- evaluate the conclusions reached previously on neurotoxicity; (3) to re

- evaluate the impact of the lack of a developmenta l toxicity study in the rabbit for BIT; and (4) to update the mutagenicity and carcinogenicity sections of the ADTC memo. The toxicological end

- points selected are summarized in Table 9

. A detailed description of the toxicity studies is provided in Appendix A

.

Table 9

– Existing Toxicological Endpoints

Exposure Scenario Dose Used in Risk Assessment (mg/kg/day) Target MOE, UF, Special FQPA SF, for Risk Assessment S tudy and Toxicological Effects
Dietary Risk Assessment s

Acute Dietary

General population

, including infants and children NOAEL= 5

mg/kg/day UF = 100 (10x inter

- species

extrapolation, 10x intra

- species variation)

FQPA SF= 1

DB UF = 1

Acute RfD =0.05 mg/kg/day Co

- Critical studies:

Subchronic toxicity (dog) NOAEL = 5 mg/kg/day based on increased incidence of emesis and clinical chemistry alterations at 20 mg/kg/day.

Subchronic toxicity (rats) NOAEL = 8.42 mg/kg/day based on macroscopic and microscopic lesions in the

non

- glandular andDocket Number EPA

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Page 18 of 52 Exposure Scenario Dose Used in Risk Assessment (mg/kg/day) Target MOE, UF, Special FQPA SF, for Risk Assessment S tudy and Toxicological Effects glandular regions of the stomach.

Chronic Dietary

All populations NOAEL =5

mg/kg/day UF = 300 (10x inter

- species

extrapolation, 10x intra

- species variation)

FQPA SF = 1

DB UF = 3 (for extrapolation from subchronic to chronic)

Chronic RfD = 0.017 mg/kg/day Co

- critical studies:

S ubchronic toxicity (dog) NOAEL = 5 mg/kg/day based on increased incidence of emesis and clinical chemistry alterations at 20 mg/kg/day.

Subchronic toxicity (rats) NOAEL = 8.42 mg/kg/day ba sed on macroscopic and microscopic lesions in the

non

- glandular and glandular regions of the stomach.

Non

- Dietary Risk Assessments

Incidental Oral

(short and intermediate term) NOAEL =5

mg/kg/day MOE = 1 00 (10x interspecies

extrapolation, 10x intraspecies variation) Co

- critical Studies:

Subchronic toxicity (dog) NOAEL = 5 mg/kg/day based on increased incidence of emesis and clinical chemistry alterations at 20 mg/kg/day.

Subchronic toxicity (rats) NOAEL = 8.42 mg/kg/day based on macroscopic a nd microscopic lesions in the

non

- glandular and glandular regions of the stomach.Docket Number EPA

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Page 19 of 52 Exposure Scenario Dose Used in Risk Assessment (mg/kg/day) Target MOE, UF, Special FQPA SF, for Risk Assessment S tudy and Toxicological Effects

Dermal

All time periods

(occupational and residential) LOAEL = 100

mg/kg/day MOE =1000 (10x interspecies

extrapolation, 10x intraspecies variation, 10x for lack of NOAEL) Subchronic dermal toxicity (rat)

LOAEL = 100 mg/kg/day, based on macroscopic and microscopic changes in the stomach.

NOAEL not established.

Inhalation

All time periods

(occupational and residential) NOAEL = 5

mg/kg/day MOE = 100 (10x interspecies

extr apolati on, 10x intraspecies variation,).

An additional 10x factor for route extrapolation is used based on the use of an oral endpoint (route

- to

- route extrapolation). Co

- critical studies:

S ubchronic toxicity (dog) NOAEL = 5 mg/kg/day based on increased in cidence of emesis and clinical chemistry alterations at 20 mg/kg/day.

Subchronic toxicity (rats) NOAEL = 8.42 mg/kg/day based on macroscopic and microscopic lesions in the

non

- glandular and glandular regions of the stomach.

Ca rcinogenicity N/A Cancer stud y waived because risk assessment endpoints are protective of irritation effects.



## 3.2 Dietary Exposure

The agency plans to update the dietary exposure (food and drinking water ) assessment s for BIT in order to support registration review . The food assessment must be updated to include uses that may result in exposure to food but were not previously assessed in support of the 2005 RED. The specific uses that need to be assessed are household and janitorial cleaning products and dishwashing detergents

. Additi onally, a drinking water assessment was not conducted as part of the 2005 RED , and will be included in the updated dietary exposure assessment.

Antimicrobial uses of BIT that may result in dietary exposure (food) include use in home and janitorial cleaning products, dishwashing detergent, as a slimicide in paper manufacturing, and as a preservative in coatings, adhesives, emulsions , paper/paper products, and plastics. All of these uses are considered indirect food uses because, although BIT is not intended to be applied directly to food, the use pattern may result in food contact. With respect to drinking water exposure, several approved uses including use as a mat erial preservative and in industrial waterDocket Number EPA

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Page 20 of 52 systems may result in BIT being discharg ed into wa ste water or leached from preserved materials and subsequently running off into surface water.



### 3.2.1 Food

BIT was previously evalua ted as part of the U.S. EPA ’s 2005 RED

. All of the uses that may result in dietary exposure were evaluated except household and ja nitorial cleaning products and dishwashing detergents. As part of the 2005 RED, the agency conducted a dietary exposure and risk assessment for the use of BIT as a pulp and paper mill slimicide, and as a preservative in paper coatings and adhesives. For both the acute and chronic dietary exposure, the risk is highest for children (21.8% of the acute and chronic PAD). For an adult, the acute and chronic dietary exposure is 9.4% of the acute and chronic PAD. All dietary exposures calculated are below the
ag ency ’s level of concern (100% of aPAD or cPAD) for non

- cancer risk

. Since the 2005 RED, new uses as cleaning products and dishwashing detergents were granted and FCNs became effective for wet state preservatives, biocides in uncured liquid rubber latex used to manufacture repeat

- use rubber gloves, and for can

- end cements. Since these can contribute to dietary (food) exposure, the agency will need to conduct bo th acute and chronic dietary exposure assessments for all population subgroups to support registration review. In an effort to determine if additional residue data will be required to conduct these assessments, a screening level analysis was conducted for both the dish detergent use and the household cleaning products use. Both of these screens used FDA methodology (FDA, 1993) where appropriate as well as relied on high

- end assumptions to be protective of human health. The toxicological points of departur e used for the analyses were from a subchronic toxicity study with a NOAEL of 5 mg/kg/day. For the acute RfD a 100x uncertainty factor was applied in order to account for intr a

- and interspecies variation. For the chronic RfD a 300x uncertainty factor was applied in order to account for intra

- and interspecies variation and for extrapolation from subchronic to chronic.

The previous risk assessment conducted in support of the RED as well as the screening level assessment conducted for dishwashing detergent and household cleaning product uses indicate that no further residue data will be required when the current toxicological information available is used to conduct the assessment. The exposure contributions from these two scenarios will be considered in th e aggregate assessments conducted during registration review. It is important to note that if the toxicological point of departure for either the acute or chronic scenario changes based on data received during the registration review process, additional r esidue chemistry data may be required.



### 3.2.2 Drinking Water A drinking water assessment has not been conduc ted for BIT in the past. However, for several approved uses (including some plastics, household cleaners, textile, paints , adhesives, oil recovery drilling fluids and water cooling systems ) the agency cannot rule out the potential for BIT to enter surface water and to subsequently be present in drinking water

. Since drinking water risk is a function of many unknown factors including (1) the residues of conc ern in drinking water, (2) the magnitude of these potential residues of concern, (3) the persistence of BIT in water, and (4) if residues of BIT are likely to pass through a wastewater treatment plantDocket Number EPA

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Page 21 of 52 (WWTP)

, the agency anticipates needing certain environm ental fate data listed in Section 4 of this PWP . These data will be useful to determine whether, and to what extent, residues of BIT will pass through a WWTP. Upon receipt and review, these data and/or other sources of information will be used during the r isk assessment stage of this Registration Review to determine the potential for discharged or leached residues of BIT to result in human dietary exposure via drinking water, which may trigger a drinking water assessment.



## 3.3 Occupational and Residential Exposu res

T he agency anticipates the need to revise the Occupational Residential Exposure (ORE)
assessment (EPA, 2005) that was written for the B IT RED. The ORE assessment will need to be revised to account for the toxicology studies that were submitted after the RED and to utilize the
exposure and surface residue data that were required by the post

- RED DCI’s or are anticipated to be required for r egistration review of BIT

.


### 3.3.1 Occupational Handler Exposure EPA anticipates the need to revise the occupational handler assessment conducted in support of the 200 5 RED. The exposures assessed include liquid pouring for industrial water systems treatment, o il and gas drilling fluids and material preservation and use of preserved materials such a s cleaning products and paint. Both dermal and inhalation exposures were assessed and were considered to be of short to intermediate term in duration

. The dermal M OEs ranged from 90 (airless sprayer application) to 450,000 and were generally not of concern because they exceeded the target MOE of 100. The inhalation MOEs ranged from 1,700 to 7,000,000 and were not of concern because they exceeded the target MOE of 1 000. Based on these MOEs , the RED did not specify any risk mitigation.

The exposure to machinists using metal working fluids treated with BIT was assessed as a long term exposure using the air concentration approach for inhalation exposures and a thin fil m approach for the dermal exposure. The MOE for inhalation exposure was 31,000 which exceeded the target MOE of 1000 and the MOE for dermal exposure was 200 which exceeded the target MOE of 100.

Handler Exposures to Assessed during Registration Review

The occupational handler scenario s that will need to be assessed for registration review are listed in Table 10

.
Table 10

– Occupational Handler Scenarios to be Assessed During Reg istration Review

Scenario Exposure Route(s) Duration Open pour application for material preservation and industrial process and water system treatment Dermal

, Inhalation Short and Intermediate T erm

Brush/ r oller and airless sprayer application of B IT preserved paints Dermal

, Inhalation Short and Intermediate Term

Machinist exposure to BIT preserved MWF Dermal

, Inhalation Long TermDocket Number EPA

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Page 22 of 52 Scenario Exposure Route(s) Duration Mop wipe and trigger sprayer application of BIT preserved cleaning products. Dermal

, Inhalation Short and Intermediate Term



### 3.3.2 Residential Handler Exposures EPA anticipates the need to revise the residential handler assessment conducted in support of the 200 5 RED. Residential handler dermal and inhalation exposures to B IT were assessed in the RED for moping and wiping using BIT preserved cleaning products and for brush/roller and airless sprayer application of B IT preserved paints. The dermal MOEs ranged from 140 ( airless sprayer application ) to 48,000 and were not of concern because they exceeded the target MOE of 100. The inhalation MOEs ranged from 5

, 600 to 590,000 and were not of concern because they exceeded the target MOE of 1000

. Based on these MOEs , the RED did not specify any risk mitigation.

The residential handler scenario s will need to be assessed for registration review are listed in Table 1 1

.

Table 1 1

– Residential Handler Scenarios to be Assessed During Reg istration Review

Scenario Exposure Route(s) Duration
Mop, wipe and trigger spray application of BIT preserved cleaning products Dermal, Inhalation Short and Intermediate Term
Brush/Roller and airless sprayer application of B IT preserved paints Dermal, Inhalation Short and Intermediate Term



### 3.3.3 Residential Post

- Application Exposures EPA anticipates the need to revise the residential post

- application assessment conducted in support of the 200 5 RED. Residential post

- application dermal and incidental oral exposures to residues arising from contact with vinyl flooring cleaned with BIT preserved floor cleaning products and clothing laundered with BIT preserved laundry detergent were assessed. The MOEs for dermal exposure ranged from 7,200 to 11,000 and they were not of concern because the exceeded the target MOE of 100. The MOEs for incidental oral exposures ranged from 1,700 to 65,000 and were not of concern because they exce eded the target MOE of 300.

The residential post application scenario s that will need to be assessed for the registration review of BIT are listed in Table 1 2

.

Table 1 2

– Residential Post

- Application Scen arios to be Assessed During Registration Review

Scenario Exposure Route(s) Duration
C arpet fibers

- child Dermal and Incidental Oral Short and Intermediate Term Clothing

– child and adult Dermal and Incidental Oral Short and Intermediate Term

Leather

– child and adult Dermal and Incidental Oral Short and Intermediate Term

Mattress Covers

– child and adult Dermal Short and Intermediate TermDocket Number EPA

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Page 23 of 52 Plastics

– child Incidental Oral Short and Intermediate Term Flooring cleaned with BIT preserved cleaners

– child Dermal and Incidental Oral Short and Intermediate Term



## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

EPA anticipates the need to revise the aggregate assessment conducted in support of the 2005 RED. Upon a reevaluation and selection of toxicolo gical endpoints, combined with the human health exposure assessments expected as a part of this registration review case, aggregate exposures will need to be assessed. This assessment will include dietary (food) exposures and residential exposures.



### 3.4.2 Cumul ative Exposures

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to BIT and any other substances and BIT d oes not appear to produce a toxic metabolite produced by other substances. For the purposes of this registration review, therefore, EPA has not assumed that BIT has a common mechanism of toxicity with other substances. For information regarding EPA’s effor ts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see http://www.epa.gov/pesticides/cumulative/

. 

## 4 Environmental Risk Assess ment

No ecological risk assessment was conducted for the RED (EPA 2005 ). In 2013, the agency completed an environmental risk assessment for the new use of BIT for industrial use in the manufacture of roofing membranes. The agency conclude d that this new use of BIT did not exceed any acute or chronic level of concerns ( LOCs ) for listed or nonlisted aquatic organisms that might be exposed to BIT leached from roofing membranes and transported to the aquatic environment

. Other uses have not been assessed for ecological risks.

The ecological risk assessment planned during registration review will allow the agency to determine potential risks to aquatic organisms exposed to BIT and its transformation products
t hat may be transported to the aquatic environment. T he risk assessment will allow the agency to determine whether each use of BIT 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 pest icide’s use 'may affect' a listed species or its designated critical habitat, the
agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services), as appropriate.



## 4.1 Environmental Fate Assessment

BIT is wat er soluble and is not likely to volatilize from water surfaces . In aqueous photolysis process, the half

- life of BIT is 0.7 hours at pH 7 and 9

. The six identified photodegradates areDocket Number EPA

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Page 24 of 52 not stable

, and in the 30 day study the concentrations decreased to low percentages in the aqueous medium. Under aerobic conditions BIT degrades quickly with a maximum half

- life of 3.6 days. Due to water solubility and moderate mobility in soils, and fast de gradation on soil surfaces, the degradates are likely to reach the sediments. Any potential water con tamination is likely due to degradates and not parent BIT. The agency anticipates requiring a number of fate studies based on the various use scenarios including ae robic and anaerobic aquatic metabolism and leaching from wood and textiles studies. The agency will conduct a full risk assessment

.


### 4.1.1 Leaching [Wood/Paint/ Antifoulant Paint/

Plastic/ Textiles/ e.g., treated article] No leaching data are available. Leaching dat a are anticipated to be needed to assess potential exposures from wood preservative and textile use s

.


### 4.1.2 Water and Sediment

BIT is water soluble and partitions into soils/sediments. No aerobic or anaerobic aquatic studies were submitted for assessment; h owe ver, in the aqueous system it photolyzes quickly at all three pHs , and it forms a number of photodegradates as indicated above.



### 4.1.3 Soil

BIT degrades quickly in aerobic soils

, with a half

- life of 3.6 days (MRID# 4119102, 41199103)

.


### 4.1.4 Air

BIT has a low vapor pressure (4.4 x 10

- 7 mmHG, see Table 4) and it is not likely to volati lize in air.



### 4.1.5 Water Quality

BIT is not identified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act, based on i nformation provided at the agency ’s National Pesticides Cause of Impairment of Wat ers website (searched April , 201 4 ) 1 . In addition, no Total Maximum Daily Loads (TMDL) have been developed for BIT , based on information provided at the agency ’s National Pes ticide TMDL web site (searched April, 2014 ) 2 . More information on impaired water bodies and TMDLs can be found at http://www.epa.gov/owow/tmdl/

. 

## 4.2 Environmental Exposure Pathways
Aquatic organisms potentially at risk from exposure to BIT include those inhabiting water bodies adjacent to or downstream from sources of down

- the

- drain discharges (e. g., waste water treatment plants) , cooling tower direct discharge, or from environmental transport of BIT leached from application of paints and coatings to exterior surfaces. Water bodies might include impounded bodies (e. g., ponds, lakes, reservoirs) or flowing waterways (e. g., streams, rivers). For uses in coastal areas, aquatic habitat also includes marine ecosystems, including estuaries.

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

2 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_ group_name=PESTICIDESDocket Number EPA

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Page 25 of 52 Aquatic organisms likely to be acutely exposed include fish, invertebrates, aquatic stages of amphibians, and aquatic and semi

- aquatic plants. Chronic exposure is possible due t o continuous or repeated exposures from residential and industrial down

- the

- drain discharges. Exoposure from the use in cooling towers is represent ed in the conceptual diagram be low.

Figure 1

- Conceptual Model for Ecological Exposure and Effects of BIT to Aquatic and Terrestrial OrganismsDocket Number EPA

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Page 26 of 52 

## 4.3 Ecological Effects Assessment

4.3.1 Measures of Effect (Ecotoxicology Endpoints) Ecological effects data are used as measures of direct and indirect effects to aquatic and terrestrial organis ms. Acute and chronic toxicity data from registrant

- submitted studies conducted in accordance with the 850 OCSPP Harmonized Test Guidelines are used to evaluate the potential direct and indirect effects to plants and animals. Relevant data from the open literature also may be used if available.

4.3.1.1 Submitted data All data requirements and available ecotoxicity endpoints from studies submitted by registrants are tabulated in Appendix C. OPP uses the most sensitive of these endpoints for assessing risk to

eac h terrestrial and aquatic receptor group. The available endpoints selected for the risk
assessment for BIT are provided in Table 1 3

. Data gaps exist for aquatic plants.

Table 1 3

- Available Ecological Effects Endpoints
Receptor Group Test

Material Risk

Scenario Toxicity Endpoint Reference

Freshwater fish TGAI Acute LC50 = 0.54 mg ai/L 443649

- 13

Chronic NOAEC = 0.28 mg ai/L 477598

- 15

Freshwater invertebrates TGAI Acute EC50 = 1.5 mg ai/L 455346

- 01

Chronic NOAEC = 0.91 mg ai/L 477598

- 14

Estuarine/marine fish TGAI Acute LC50 = 12.2 mg ai/L 429450

- 01

Chronic N ot required --

Estuarine/marine invertebrates TGAI Acute EC50 = 0.047 mg ai/L 429524

- 01

Chronic Not required

-- Aquatic plants

- Lemna TGAI EC 50 NOAEC Data gap --

Aquatic plants

- algae TGAI EC 50 NOAEC Data gap --

Cyanobacteria TGAI EC 50 NOAEC Data gap --

Birds TGAI Acute oral LD50 = 453 mg ai/kg bw 409913

- 01Docket Number EPA

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Page 27 of 52 

## 4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available OPP models will be used to determine the estimated environmental concentration (EECs) in the aquatic environment

. Resulting exposure estimates will be compared to the toxicity endpoints to determine if levels of concern are exceeded for each receptor group.



### 4.4.2 Screening Level Down

- the

- Drain Analysis

The Down

- the

- Drain (DtD) module of E

- FAST (Exposure and Fate Assessment Screening Tool) was used to determine the potential for aquatic organisms downstream of domestic wastewater treatment plants that receive discharges from end

- u se of BIT to be exposed to BIT and its degradates. The results of the DtD module runs are expressed as number of days of exceedance of concentrations of concern (COC) for aquatic organisms. A detailed description of derivation of data for input parameter s selected to run the DtD module and of the theoretical basis for this model is presented in Appendix E. A conservative assumption of no removal during wastewater treatment was used in DtD model runs.

The DtD analysis for BIT is intended to serve two purp oses: (1) to demonstrate the maximum WWTP influent volume of BIT that would trigger potential concerns for aquatic organisms exposed to BIT or its degradates downstream of domestic wastewater treatment plants and (2) to evaluate potential exposures based on the assumptions that the total production volume of BIT enters domestic wastewater treatment plants. A key purpose of the DtD analysis for BIT is to determine the lowest maximum annual WWTP influent volumes of BIT that would trigger potential concerns for aquatic organisms downstream of domestic WWTPs.

Table 1 4 presents results of a screening

- l evel DtD analysis for BIT which was based on laboratory toxicity data for freshwater organisms

. Based on these aquatic toxicity data and the total annual product ion volume of BIT, t he DtD model predicted exceedances of concentrations of concern for acute and endangered aquatic organisms. In addition, a DtD analysis predicted that over 150000 kg/yr of BIT would have to enter domestic wastewater treatment plants to result in an exceedance for one day of the concentration of concern (COC) for endangered freshwater fish and invertebrates.

Table 1 4

– Summary of Screening Level Down

- the

- Drain Analysis Results for Aquatic Organisms

WWTP Influent Volume Freshwater Fish , Acute

(COC = 270 ug ai /L) Fresh water Invertebrates , acute (COC = 75 ug ai /L) Endangered species

- aquatic plants (COC = 400 ug ai /L)

High

- End Scenario

2800000 kilograms/year Exceeded 4 days per year Exceeded 40 days per year Exceeded 2 days per year
150000 kilograms/year No exceedances Exceeded < a day No exceedancesDocket Number EPA

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Page 28 of 52 Average Scenario

2800000 kilograms/year Exceeded < 1 day Exceeded 4 day Exceeded < 1 day

150000 kilograms/year No exceedance Exceeded < 1 day No exceedance
This screening level analysis assumes that BIT and salts are released to domestic wastewater treatment plants. Based on registered uses of BIT and salts presented in Table 8 of this PWP, there are some use s , such as commercial and industrial cooling water systems and paper mill water systems, for which discharges may enter industrial WWTPs rather than domestic WWTPs prior to entering surface water. Different methods and tools for assessing potential exposures and associated ecological risks will be applied for these other types of uses. There is considerable uncertainty regarding the amount of BIT that could be expected to enter domestic wastewater treatment plants. There is also uncertainty about the potential for exposure to aquatic organisms from BIT ente ring industrial wastewater treatment plants as a result of industrial uses of BIT . The agency does not have high quality data on the toxicity of BIT to activated sludge microorganisms in wastewater treatment plants and does not have high quality data on bi odegradation of BIT during wastewater treatment. Consequently, the agency anticipates requiring data addressing toxicity to activated sludge microorganisms and biodegradation of BIT during wastewater treatment

. 

## 4.5 Effects Analysis Plan

The ECOTOX database wil l be searched during the risk assessment phase and the data will be reviewed following the agency ’s policy for reviewing public literature for use in assessing risks from pesticide s ( http://www.epa.gov/pesticides/science/literature

- studies.html )

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

- Conti nent Ecology Division.


## 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine t arget organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its 2005 reregistration decision

, for BIT, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), BIT is subject to the endocrine screening part of the Endocrine Disru ptor Screening Program (EDSP).Docket Number EPA

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Page 29 of 52 EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical subs tance 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 a ctive ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 3 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should b e 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 web site. 4


## 6 Optional Label Changes

The agency invites comment s on any label amendments that could be considered to eliminate the anticipated need for EPA to require certain data, reduce the possibility that EPA’s planned risk assessments overestimate risk due t o reliance on conservative assumptions, and/or improve label clarity , registrants may consider amending product labeling

. 

## 7 Guidance for Commenters

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



### 7.1.1 Trade Irritants Through the registration review process, the agency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The agency will work to harmonize tolerances and international maximum residue limits (MRLs) and may

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

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of chemicals.

4 http://www.epa.gov/endo/Docket Number EPA

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Page 30 of 52 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 th e concern.



### 7.1.2 Water Quality

The agency invites submission of water quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body an d Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 5 in order to ensure they can be used quantitatively or qualitatively in pesticide risk assessments.



### 7.1.3 Environmental Justice EPA seeks to achieve environmental jus tice, 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 enviro nmental justice issues, the agency seeks information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to BIT compared to the general population. Please comment if you are aware of any sub

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



### 7.1.4 Additional Information

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

- specific ecological effects determinations. The agency is interested in receiving the following information:

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

5 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htmDocket Number EPA

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Page 31 of 52 8. Monitoring data



## 8 Next Steps

After the 60

- day comment period closes in August 2014 , the agency will review and respond to any comments received in a timely manner, and then issue a Final Work Plan for the BIT case.Docket Number EPA

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Page 32 of 52 

## 9 References

U.S. Enviro nmental Protection Agency (EPA). 2002. ECOTOX User Guide: ECOTOXicology Database System. Version 3.0. Available: http://www.epa.gov/ecotox/ U.S. Environmental Protection Agency. High Production Volume Information System (HPVIS). http://www.epa.gov/hpvis/Docket Number EPA

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Page 33 of 52 

# Appendix A T oxicology Profile

Acute Toxicity for Product Labeling

As summarized in Table 1 6 , acute toxicity data show that 1,2

- benzisothiazolin

- 3

- one is moderately toxic by the oral and dermal routes (Toxicity Category III for both studies); however, this chemical is a severe eye irritant. Irritation to the skin from acute data show only mild skin irritation. This response could be related to the ability of this chemical to cause a moder ate skin sensitization response.

Table 1 6

– Acute Toxicity Studies for BIT

Guideline Number Study Type MRID Numbers Results Toxicity Category

870.1100 Acute Oral 41022101; 42858101 LD 50 = 670 mg/kg (M);

784 mg/kg (F) III

870.1200 Acute Dermal 41022102; 42858102 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation

--- --- See footnotes a,b

870.2400 Primary Eye

Irritation 42905102 severe eye irritant I

870.2500 Primary Skin

Irritation 42905101 slight irritant IV

870.2600 Dermal

Sensitization 41750001;

42858103 moderate dermal

sensitizer N/A

a On the basis of the recently published waiver guidance for conduct of acute toxicity studies ( http://www.epa.gov/pesticides/science/acute

- data

- waiver

- guidance.pdf ), a waiver can be granted for the acute inhalation toxicity test for the technical test material. In MRID 42905103, the registrant showed that the majority of particles generated from Proxel Press paste are greater than 15 um aerodynamic diameter, and are thus larger than the 1

- 4 um diameter targeted for acute inhalation toxicity tests with solids.

b Data waivers were not granted for any of the aqueous

- based formulations. Thus, aqueous solutions of 1, 2

- benzisothiazolin

- 3

- one will require acute inhalation toxicity data. 

## Subchronic Toxicity

There are two subchronic dog studies. In a subchronic oral toxicity study in dogs (MRID 42205701) BIT (94.6% a.i ., w/w) was administered to 4 beagle dogs/sex/dose by capsule at dose levels of 0, 5, 20, or 50 mg/kg/day for 92 days. No animals died during the study. The only
treatment

- related clinical observation was an increased incidence of emesis in both sexes of d ogs, primarily at the higher dose levels. Treatment with resulted in no differences in body weight or total body weight gain compared to controls. Hematological alterations were sporadic and not considered to be dose

- related. Clinical chemistry parameters that were alteredDocket Number EPA

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Page 34 of 52 significantly from controls (p# 0.05 or 0.01) at the high dose in both sexes for one or more weeks include plasma albumin (9

- 11% decrease), total protein (7

- 13% decrease), alanine transaminase (26

- 30% decrease), and triglycerides (30

- 49% increase). These results were accompanied by increased absolute liver weight in high

- dose dogs of both sexes (17%) and mid

- dose females (12%), and are consistent with an adverse effect on liver function. There were no treatment related effects on gross or microscopic pathology, food consumption, or ophthamology. The LOAEL is 20 mg/kg/day for both male and female dogs, based on the incidence of emesis and clinical chemistry alterations at this dose. The NOAEL is 5 mg/kg/day.

In the second subchronic dog ora l toxicity study (MRID 47759802), BIT ( 89.8% a.i; Lot #: 2005

- 051) was administered to 4 beagle dogs/sex/dose in diet at dose levels of 0, 300, 1000, or 3000 ppm (equivalent to 0, 11, 37, and 106 mg a.i./kg bw/day for males; and 0, 11, 38, 89 mg a.i./kg bw /day for females). There was no mortality or signs of clinical toxicity observed in either male or female dogs treated at any dose level. There were no toxicologically significant effects on hematological, clinical chemistry, organ weights, gross or histop athology by oral administration of 1,2

- benzisothiazolin

- 3

- one. In the 3000

- ppm dose group, mean cumulative body weight/mean cumulative body weight gain was significantly lower in male dogs during weeks 0

- 4 of the study and in females throughout the study p eriod. During week 13, mean body weights of the 3000

- ppm male and female dogs were 6.6% and 18.7% lower than the corresponding control animals. Decreases in mean food consumption correlated with the decreased body weight. Although there were several chang es in organ weights in high

- dose females, these were all secondary to the reduced body weight. Based on the effects on food consumption and body weight, the LOAEL is 3000 ppm (106 mg a.i/kg bw/day

– male; 89 mg a.i./kg/day

– female). The NOAEL is 1000 pp m (37 mg a.i./kg bw/day

– male; 38 mg a.i./kg bw/day

– female)

. This 90

- day oral toxicity study in the dog is Acceptable Guideline and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3150; OECD 409) in non

- rodent species.

T here are two subchronic rat oral studies. In a subchronic oral toxicity study in rats (MRID 46346201), BIT (84.2% a.i., Batch # 22001 014), suspended in carboxymethyl

- cellulose, was administered to 10 HsdCpb: WU conventionally bred (inhouse random bred) Wistar rats/sex/dose by oral gavage at dose levels of 0, 10, 30, and 75 mg/kg bw/day (0, 8.42, 25.26, and 63.15 mg a.i./kg/day, respectively). In addition, 10 rats/sex/dose were administered 0 and 75 mg/kg/day (63.15 mg a.i./kg/day) for 90 days, followed b y a 28

- day recovery period. The LOAEL is identified as 30 mg/kg/day (25.26 mg a.i./kg/day), based on the incidence of macroscopic and microscopic lesions in both sexes. The NOAEL is 10 mg/kg/day (8.42 mg a.i./kg/day). This subchronic toxicity study in the rat is acceptable

- guideline and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in rats.

In the second 90

- day rat oral toxicity study (MRID 47759801) 1, 2

- benzisothiazolin

- 3

- one (89.8% a.i., batch/lot #2005

- 051) was administered to 10 Sprague

- Dawley (Crl:CD) rats/sex/dose by gavage of 5 mL/kg at initial dose levels of 0, 10, 25, or 65 mg/kg/day once a day for 91 or 92 concurrent days. The initial dose of 65 mg/kg/day was lowered to 50 mg/kg/day on day 15 due to mortality and negative health effects.

Mortality was observed in three males and four females in 65/50 mg/kg/day group. Clinical signs of cardiopulmonary distress and/or behavioral/CNS related toxicity were observed at 65/50Docket Number EPA

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Page 35 of 52 mg/kg/day during a week pr ior to death. Upon examination extensive gastric lesions, including hyperplasia and hyperkeratosis of the mucosa of the forestomach, erosions, ulcers, mucosal hemorrhage and/or submucosal inflammation in the glandular and/or nonglandular areas, were found and considered to be the cause of death. Additionally, one male in the 10 mg/kg/day group died on day 47. This rat showed mild necrosis of the laryngeal mucosa and disseminated necrosis of the tracheal mucosa, presumably due to aspiration of the treatme nt substance, which is thought to have been a factor in the death of this animal.

Other observations included a decrease in mean body weight gain in the 65 mg/kg/day group during weeks 1 and 2, as compared to controls, although no effects on food consumpt ion were noted. No neurotoxic effects (week 11) or ophthalmic toxicity (week 12) were found in any of the treatment groups. Hematological evaluations indicated lowered albumin and globulin levels resulting in a significantly lower total protein in the 65 /50 mg/kg/day males and females, which was consistent with the lesions found in the stomach including ulceration and erosions, submucosal inflammation and areas of superficial hemorrhage or hyperplasia of the glandular mucosa in this treatment group.

Tre atment

- related dose

- dependent microscopic findings in the stomach, most commonly thickening of the nongladular (forestomach) mucosa resulted from hyperplasia and hyperkeratosis of the squamous mucosa, ranging from minimal in the low

- dose group to marked di ffuse in the high

- dose animals, were observed in all treatment levels in both male and female rats. Additional changes, including superficial mucosal erosions or ulcers and submucosal inflammation in the nonglandular area of the stomach, were found only i n the mid and high dose
groups.
The LOAEL is 10 mg/kg/day, based on microscopic findings in the stomach. The NOAEL could not be determined. This 90

- day oral toxicity study in the rat is ACCEPTABLE GUIDELINE and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in rats.

There is one acceptable rat dermal 90

- day study. In the study (MRID 45184601), BIT (98.71% a.i., lot #579) was applied to the shaved dorsal skin of 10 Wistar albino rats/sex/dose at dose levels o f 0, 100, 300, or 1000 mg/kg

- d, 6 hours/day for 5 days/week during a 90

- day period. The application site was occluded.

No mortality or clinical signs of systemic toxicity were observed during this study. No effects were observed on body weight or food co nsumption. Treatment

- related skin abnormalities and microscopic changes to the stomach mucosa were observed in rats from all treatment groups. The most common microscopic changes were thickening of the epidermis and nonglandular mucosa of the stomach d ue to hyperplasia and hyperkeratosis. No other treatment

- related gross or microscopic changes in pathology were found. Hematological evaluations indicated a significant increase in the white blood cell count of females treated with 1000 mg/kg

- d when
compa red to controls. Slight changes in clinical chemistry were observed with a significant increase in triglycerides for 300

- mg/kg

- d females and significant decreases in albumin and total protein levels in 1000

- mg/kg

- d females. The mean relative liver weight of males treated with 1000 mg/kg

- d was significantly higher than controls. The systemic LOAEL is 100 mg/kg

- d, based on macroscopic and microscopic changes to the stomach mucosa. A NOAEL for theDocket Number EPA

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Page 36 of 52 systemic effects cannot be determined. The LOAEL for local effects is 100 mg/kg

- d, based on macroscopic and microscopic changes in the treated skin. A NOAEL for local effects cannot be determined. This 90

- day dermal toxicity study in the rat is ACCEPTABLE / GUIDELINE and satisfies the guideline requirement for a 90

- day dermal toxicity study (OPPTS 870.3250) in rodents.

There is no subchronic inhalation study. A 90

- day repeat

- dose inhalation toxicity study is identified as a data gap to properly assess inhalation risks from all uses of this active ingredient, as extrapolation from an oral toxicity study may underestimate inhalation risk. 

## Developmental Toxicity

There were two developmental toxicity studies conducted in rats with 1,2

- benzisothizolin

- 3

- one. One study (MRID 43663008) used 100% a.i. in carboxymeth ylcellulose by gavage, while the other study (MRID 40961201 and 42858104) used a paste of 73.4% purity administered by gavage in 0.5% hydroxy methyl propyl cellulose that was diluted in 0.1% polysorbate 80. Although the dose levels in these two studies we re similar (0, 10, 30, and 90 mg/kg/day for the first study, and 0, 10, 40, and 100 mg/kg/day for the second study [doses corrected for % a.i.]), the maternal toxicity LOAELs were not similar and similar effects were not observed at these doses. In MRID 4 3663008, the maternal toxicity LOAEL was 30 mg/kg/day based on mortality and clinical signs, while in MRID 40961201, the maternal toxicity LOAEL was 100 mg/kg/day based on decreased body weight gain and food consumption. Neither of these two studies indic ated any evidence of sensitivity of offspring to the toxicity of 1,2

- benzisothizolin

- 3

- one in
rats. 

## Reproductive Toxicity

There are two reproduction and fertility effects studies are currently available for BIT. The
agency has reviewed these studies and t heir respective executive s ummaries are presented below.

In a 2

- generation reproduction study (MRID 46097101), BIT (~ 93% pure) was administered to 24 rats (Crl:WI[Glx/BRL/Han]BR)/sex/dose via diet at concentrations of 0, 250, 500, or 1000 ppm (equivalent to18.5

- 24.0, 37.2

- 48.0, and 75.1

- 97.8 mg/kg/day for males and 21.7

- 27.4, 43.0

- 55.6, and 86.3

- 115.7 mg/kg/day for females). The test material was administered to P males and females for 10 weeks prior to mating. Dosing continued throughout the 2

- week ma ting period, as well as during the resulting pregnancies and throughout lactation until weaning of the F 1 offspring. The F 1 generation was randomly selected on lactation day 21 to consist of 24 animals from each sex, direct treatment continued throughout the F 1 maturation period (10 weeks). F 1 animals also were administered the test material throughout the mating period, as well as during the resulting pregnancies and throughout lactation until weaning of the F 2 offspring.

Parental toxicity from exposur e to BIT via diet was evident at 1000 ppm (75.1

- 97.8 mg/kg/day for males and 86.3

- 115.7 mg/kg/day for females) and 500 ppm (37.2

- 48.0 mg/kg/day for males and 43.0

- 55.6 mg/kg/day for females). Toxicity at 1000 ppm consisted of decreased mean body weight gai ns (F 1 males and females), limiting ridge hyperplasia of the stomach (P and F 1 males and females), squamous cell hyperplasia (P and F 1 females), forestomach gastritis (F 1 females),Docket Number EPA

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Page 37 of 52 keratosis (F 1 females), and erosion/ulcer (F 1 females). Toxicity at 500 ppm consisted of limiting ridge hyperplasia in the stomach (P and F 1 males and females). Therefore, the parental toxicity NOAEL is determined to be 250 ppm (18.5

- 27.4 mg/kg/day for males and females), and the parental toxicity L OAEL is determined to be 500 ppm (37.2

- 48.0 mg/kg/day for males and 43.0

- 55.6 mg/kg/day for females).

There was evidence for toxicity in offspring of animals exposed to 1000 ppm (75.1

- 97.8 mg/kg/day for males and 86.3

- 115.7 mg/kg/day for females). At thi s dose, preputial separation in F1 male offspring and impaired growth and survival of pups of both sexes was observed. Therefore, th e offspring LOAEL is determined to be 1000 ppm, and the offspring NOAEL is determined to be 500 ppm

. This study is classi fied as acceptable

- non - guideline. Concentration analyses of the diets administered to the second generation indicate that animals did not receive adequate doses of the test article during weeks 34 to 38 and/or the test diets may have contained an unknown contaminant. However, the study does not need to be repeated because an additional study of this magnitude is unlikely to reveal reproductive toxic effects beyond those that were reported. The study can therefore be used for regulatory purposes, as diet ary errors were not present until the last 4 weeks of the study, thus allowing sufficient time for the manifestation of reproductive effects that could be attributed to the test compound.

In the second two

- generation reproduction study (MRID 47759803 )

, 1 , 2 b enzisothiazolin

- 3

- one (BIT; 89.8% a.i

, batch/lot 2005

- 051) was administered to three groups of male and female Crl:CD(SD) rats (30/sex/group) daily by oral gavage at dose levels of 0, 10, 25, and 65/50 mg/kg bw/day

. Mortality, clinical signs of excessive irritation

, and reductions in food consumption and body weight gain were observed at 65 mg/kg/day, indicat ing that this dose exceeded the maximum tolerated dose. The high

- dose was reduced to 50 mg/kg/day after the first 21 days of dosing, and wa s maintained at this lower level for the remainder of the F 0 generation. This dosage level was also used as the high

- dose for the F 1 generation. One litter per dam was produced in each generation.

F 0 animals were approximately 8 weeks of age at the initi ation of test article administration. BIT was administered to offspring selected as the F 1 parental generation following weaning (starting postnatal day [PND] 21). F 0 and F 1 parental males continued to receive the test article throughout mating and throu gh the day prior to euthanasia. F 0 and F 1 parental females continued to receive the test article throughout mating, gestation and lactation, and through the day prior to euthanasia.

Test article

- related deaths occurred in the 25

- and 65/50

- mg/kg/day gro ups in the F 0 generation and in the 50

- mg/kg/day group in the F 1 generation. Clinical findings for the majority of animals found dead or euthanized in extremis consisted of those related to the irritant properties of BIT, including gasping, rales, labored respiration, red material around the mouth, nose and/or eyes, and/or salivation. Microscopic findings of stomach lesions consisted mainly of hyperplasia and hyperkeratosis of the non

- glandular (forestomach) mucosa in both F 0 and F 1 males and females at

a ll dose level groups . These treatment

- related changes were in a dose

- related manner for incidence and severity. Other changes in the non

- glandular mucosa that occurred in the high

dose rats included submucosal inflammation, keratinous cysts, erosions, an d ulcers. In theDocket Number EPA

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Page 38 of 52 glandular mucosa of the stomach, test article

- relate changes included hyperplasia in the surface epithelium, erosions, and submucosal inflammation. Based on the test article

- related deaths observed at 25

- mg/ kg/day and 65/50

- mg/kg/day, the adverse clinical signs observed in surviving animals and an imals prior to death, and micro scopic findings in the stomach in both F 0 and F 1 males and females at all dose levels , the parental systemic L OAEL for the F 0 and F 1 generations was 10 mg/kg/day. A NOAEL was not observed.

Lower mean F 0 body weight gains, food consumption, and food efficiency were observed in the 65/50

- mg/kg/day group males and females during the first 3 weeks of dosing at 65 mg/kg/day. Improvement was noted after the dosage lev el was lowered to 50 mg/kg/day; however, these early reductions in mean body weight gains resulted in lower overall mean body weight gains when the pre

- mating period (males and females) and entire generation (males only) were evaluated. A test article

- rel ated lower mean body weight gain was also noted in the 50

- mg/kg/day F 1 females during PNDs 22

- 29.

F 0 and F 1 reproductive parameters were not affected by BIT administration at any dosage level. There were no test article

- related microscopic changes in any of the reproductive organs evaluated from the F 0 and F 1 generation rats at any dosage level. Based on the lack of effects on F 0 and F 1 reproductive parameters , a dosage level of 50 mg/kg/day was considered to be the NOAEL for parental reproductive toxicity

.
Mean numbers of F 1 and F 2 pups born, mean live litter sizes on PND 0, and offspring sex ratio

were una ffected by BIT administration in both generations. Lower F 1 postnatal survival was observed in the 65/50

- mg/kg/day group, due in part to 2 F 0 females with total litter loss. However, t here were no test article

- related eff ects on F 2 postnatal survival in this group (offspring of females administered 50 mg/kg/day th roughout the generation). No effects of parental test a rticle administra tion w ere observed on the general physical condition of the pups in both generations or me an body w eights and body weight gains. For pups found dead or euthanized in extremis , no test article

- related macroscopic findings were noted. There were no
t est article

- related effects on the organ weights of F 1 or F 2 pups on PND 21, or on the attainment of sexu al developmental landmarks in F 1 weanlings

. Based on the lower F 1 postnatal survival at the 65/50

- mg/kg/day level , t he NOAEL for neonatal toxicity was considered to be 25 mg/kg/day

. This study is classified as A cceptable G uideline and satisfies the guideline requirement s ( OPPTS 870.3800; OECD 416 ) for a two

- generation reproduction study in the rat.



## Chronic / Carcinogenic Toxicity

There are currently no data on file describing carcinogenicity of 1, 2

- benzisothiazolin

- 3

- one. However, based on extensive discussions with the registrants and with the Health Effects Division’s Hazard and Science Policy Council (HASPOC), the following co nclusions are reached regarding the carcinogenicity of BIT (from the HASPOC memo dated May 3, 2012):

“ The HASPOC recommends , based on a weight of evidence ( WOE) approach, that the chronic toxicity/carcinogenicity study for BIT is not required at this time if the risk assessment is protective of irritation. This recommendation was based on the following considerations: 1)Docket Number EPA

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Page 39 of 52 available cancer studies for the isothiazolone pesticides are negative; 2) there is a lack of mutagenicity concern for BIT and the othe r isothiazolone pesticides; 3) BIT and the other i sothiazolones are irritants following oral, dermal, and inhalation exposures and produce similar effects following subchronic exposures; 4) the isothiazolones as a group have a known mode of action for anti microbial activity; 5) irritation is the predominant effect and is the basis of the PODs; 6) although the metabolism study for BIT showed an increased half

- life and accumulation of radioactivity in thyroid compared to other isothiazolone chemicals, these o bservations were determined to be not of toxicological significance, as the toxicological effects of BIT up to 90 days were not different than the effects observed with the o ther isothiazolone chemicals.”

HASPOC also recommended that AD evaluate the available data to inform the need for a n uncertainty factor to account for extrapolation from subchronic

- to

- chronic exposure durations for BIT . As long as the risk assessment addresses the potential irritation

- like effects, chronic/ca ncer study requirements can be waived. 

## Mutagenicity

Several mutagenicity studies are available for BIT, including a Salmonella typhimurium reverse mutation assay (MRID 4775980 4), an in v itro mammalian cells in culture gene m utation assay in Chinese hamst er ovary (CHO cells ; MRID 47759805), an in v itro mammalian c ytogenetics chromosome aberration a ssay MRID 47759806), and an in v ivo mammalian cytogenetics (erythrocyte m icronucleus assay ) in ICR mice (MRID 47759807). There was no evidence of mutagenicity f

or BIT in any of these studies. 

## Immuntoxicity

There is currently no existing immunot oxicity study for B IT. This is a required study and has been identified as a data gap. The agency anticipates requiring this study.



## M etabolism Study

In a metabolism study (MRID 47759808), 14C

- 1,2

- Benzisothiazolin

- 3

- one ([BIT] radiolabeled at the benzene ring (Lot #s 1069.0003 and 1069.0004) was administered to (1) Sprague

- Dawley rats (4/sex/dose) via single oral gavage at dose levels of 10 or 100 mg/kg and sacrificed at 96 hours post

- dosing; (2) another group of rats (3/sex) via oral gavage at dose level of 10 mg/kg 14C

- BIT and sacrificed at 1 hour post

- dosing; (3) a repeat

- dose group at dose level of 10 mg/kg 14C

- BIT once per day for 5 days and sacrificed at 96

- hours after the final dose. One male rat and one female rat served as controls without being dosed with 14C

- BIT.

In the single

- dose groups, the majority of 14C

- BIT was excreted within 24 hours (89.30

- 94.59%), mostly through urine (94.17

– 97.19% recovery in ur ine plus cage rinse) with a lesser amount found in the feces (1.87

– 4.18%). In the single dose 100 mg/kg group, the highest tissue concentrations of radioactivity (μg equivalents of BIT/g tissue) were found in adrenals, thyroids, and bone marrow, with hi gher concentrations (in these tissues) in females than males. In contrast, only the thyroid contained higher than the lower limit of quantitation (LLOQ) for radioactivity in the sin gle low dose (10 mg/kg) group.Docket Number EPA

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Page 40 of 52 In the 10 mg/kg dose group, mean time to m aximum concentration (Tmax) of radioactivity was 1.7 hr in blood and 1 hr in plasma in both males and females. In the 100 mg/kg group, mean Tmax was 2.3 hr in blood and plasma for females and 3.0 hours in blood and plasma for males. Mean T1/2 values in bl ood were 3.7 and 4.7 hrs in the low dose males and females, respectively, and were 3.8 and 6.0 in high dose males and females, respectively. T1/2 values in plasma were 2.3 and 2.6 hrs in the low dose males and females, respectively, and were 3.4 and 5.0 h rs in high dose males and females, respectively. These results indicated that high dose females had higher exposure to BIT

- derived radioactivity compared to males. Concentration of radioactivity was similar in blood and plasma, indicating that there was n o preferential difference in red blood cells.

BIT was extensively metabolized and primarily excreted through urine in the single

- dose animals. Parent compound was not detected in urine or feces. Three metabolites, M1, M2, and M3, were identified in urine , with M3 having the highest proportion. In the feces, metabolites M1, M2, M3, and M4 were identified for the single

- dose group. Proposed metabolic pathway includes a thiazolin

- ring opening (between sulfur and nitrogen atoms) precursor (not detected), fo llowed by glucuronyl (M1) or methyl (M4) conjugates, then di

- oxidation of thioanisole (M4) resulted in the formation of M3 (sulfoxide), whereas mono

- oxidation of M4 resulted in the formation of M2 (sulfone). The data presented for the single

- dose groups sa tisfy the guideline requirement for a metabolism study OPPTS 870.7485, OECD 417 in rats.

There are uncertainties for the repeated

- dose group (group 6). The study report indicated that the majority of the radioactivity was recovered in the urine and cage rinse (90.92

– 91.50%) with the amount in feces ranging from 4.96

- 5.90%, and tissues contained less than 0.1% radioactivity at 192 hours post

- dose, which brought the total mean recovery of radioactivity to the range of 96.47

– 96.83%. However, the data s howed that the total identified percent distribution (% dose) of BIT metabolites in urine and feces for Group 6 was 16.38% and 15.78% for males and females, respectively, which was significantly lower than those for Group 1 (single low

- dose) and Group 3 (s ingle high

- dose). 

## Toxicological Effects of Degradates.

See Appendix B, a number of degradates have been identified and characterized for the parent BIT. Structurally, these degrades are similar to the metabolites identified in the in vivo metabolism stu dies. There i s no information indicating degradates can be more toxic than the parent compound. Therefore, the parent compound, BIT

, will be used to assess the toxicity concern of its degradates.Docket Number EPA

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Page 41 of 52 

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of Benzisothazolin

- 3

- one and its degradate(s)

Water and Sediment

Hydrolysis

BIT is hydrolytically very stable for > 30 days under abiotic and buffered conditions at the three environmentally important pHs: 5, 7, and 9 (MRID# 4119901, 4418210).

Aqueous Photolysis

In aqueous ph oto lysis, BIT is not stable and breaks down at pH 5, the half

- life is 9 hours, whi le at pH 7, and 9, the half

- life is 0.7 hours. Six photodegradation products were identified. In the 30 day study, it was shown that these ph otodegradates also degrade to very low percentages by day 30. The photodegrates are oxidative metabolites, and f orm sulfur derived side chains (MRID# 47329402)

.
Octanol

- Water Partition Coefficient

The measured value of log K ow has been reported as 1.4. The value is much lower than the risk conern level (log K ow of 3.2) . BIT is not likely to be bioaccumulative in aquatic species.

Soil

Soil Leaching/Adsorption/Desorption Batch Equilibrium

Adsorption/desorption study showed that K d were in the range of 1.3

- 12.3 mg/g, which makes BIT to be mobile to moderately mobile i n soils. Corr e spondingly, K oc were estimated at 254

- 728 mg/g which shows similar trend as the K d This tendency of mobility will take BIT move downward in soils, and pos sibly contaminate ground water. However, since BIT is also not stable on soil surfaces, and its half

- life is 3.6 days, it the degradates rather than the parent that are likely to reach the ground water (MRID# 41687102)

.
Aerobic Soil Metabolism

BIT metaboli zes in soils under aerobic conditions with a short half

- life of 3.6 days. A Three major metabolites were identified These metabolites are also oxidative metabolites. The Benzene skeleton of the parent is kept intact (MRID# 41199102, 41199103, 93053102)

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Page 42 of 52 A number of degradates have been identified and characterized for the parent BIT.

The degradates of BIT are characterized through photolysis and soil metabolism studies:

BIT (1,2

- benzisothiazol

- 3(2H)

- one)

2

- sulfobenzamide

1,2

- benzthiazolin

- 2

- one

Hydroxy

- 1,2

- benzisothiazol

- 3

- oneDocket Number EPA

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Page 43 of 52 Saccharin (1,2

- benzisothiazolin

- 3

- one

- 1,1

- dioxide)

The soil metabolism degradates include: 2

- cabroamoylbenzene sulfonic acid, 1,2

- benzisothaizolin

- 3

- one

- 1,1

- dioxide and 1,2

- ben zthiazolin

- 3

- one

- 1

- oxide.

A number of similarities are evident with these degradates:

1. These are all oxidative degradates. 2. Benzene part of the structures remains intact. 3. 3. The changes in the thiazolo part of the molecule is sulfonation, or sulfur oxidation. 4. Sulfonates, sulfoxides are known to degrade fast in the environmental media. 5. Due to structural similarities of the degradates to the parent, the reactivity and toxicity of the degradates should be equal to or less than the parent. These degradates are not likely
to have additional adverse impact in the environmental media.

The agency anticipates that environmental fate data other than those studies anticipated as required for waste water treatment will not be required for these degradates.

If , however , sta keholders believe that submission of additional environmental fate data on the degradates can streamline the environmental fate risk assessment of BIT, then the agency invites submission of this information. The submitter would be expected to supply a rationale describing the utility of the information and provide documentation on the scientific validity of the information.Docket Number EPA

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Page 44 of 52 

# Appendix C Ecotoxicology Profile

Toxicity to Terrestr ial Organisms

Birds

One acceptable acute

- oral (LD50) study categorizes BIT as being moderately toxic to birds. The guideline (850.2100) is satisfied. Avian dietary studies (850.2200) are not required for BIT. However, one study was previously submitted and indicates that BIT is practically nontoxic when administered in the diet. No additional avian toxicity data are anticipated to be needed

.
Avian Acute

- oral and Dietary Toxicity

Test Species Test Material (% ai) Toxicity Toxicity Category EPA Study

ID

Northern bobwhite ( Colinus virginianus ) 99 LD50 = 453 mg ai/kg bw Moderately toxic 409913

- 01 Acceptable

72.2 LC50 >5620 ppm Practically non

toxic 417320

- 01

Acceptable

Nontarget Insects

Toxicity data for beneficial insects (850.3020, 850.3030) are not needed to support the current use patterns , because BIT is not registered as a wood preservative

. 

### Toxicity to Aquatic Organisms

Freshwater Fish , acute

Th e available acute toxicity studies categorize technical

- grade BIT as being moderately to highly toxic to freshwater fish

. The guideline (850.1075) for acute toxicity testing is satisfied.Docket Number EPA

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Page 45 of 52 Acute Toxicity to Freshwater Fish

Test Species Test Material

(% ai) Toxicity Endpoint

(mg ai/L) Toxicity

Category EPA Study

ID

Rainbow Trout ( Oncorhynchus mykiss) 73.62 LC50 = 1.3 Moderately toxic 455346

- 02 Acceptable

93 LC50 = 1.6 Moderately toxic 416871

- 01 Acceptable

89.9 LC50 = 1.9 Moderately toxic 473190

- 10 Acceptable Bluegill ( Lepomis macrochirus ) 93.2 LC50 = 0.54 Highly toxic 443649

- 13 Acceptable

Freshwater Invertebrates , acute

Four available acute toxicity studies categorize technical

- grade BIT as being moderately to very highly toxic to freshwater invertebrates. The guideline (850.1010) for acute toxicity testing is satisfied

. Acute Toxicity to Freshwater Invertebrates

Test Species Test Material (% ai) Toxicity Endpoint

(mg ai/L) Toxicity

Category EPA Study

ID

Water flea ( Daphnia magna ) 73.62 EC50 = 1.5 Moderately toxic 455346

- 01 Acceptable

76.1 EC50 = 3.3 Moderately toxic 429490

- 01 Acceptable

89.8 EC50 = 3.7 Moderately toxic 473190

- 11 Acceptable

Freshwater Fish and Invertebrates, chronic

Two studies are available

. NOAECs have been determined for both fish and aquatic invertebrates. No additional chronic data are expected to be needed for freshwater organisms (850.1300, 850.1400)

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Page 46 of 52 Chronic Toxicity to Freshwater Organisms

Species Test material

(% ai) Toxicity

(mg ai/L or kg) Endpoint Status/ MRID

Water column:

Fathead minnow ( Pimephales promelas ) 89.8 NOAEC = 0.28 LOAEC = 0.59 Growth 477598

- 15 Acceptable

Water flea ( Daphnis magna ) 89.8 NOAEC = 0.91 LOAEC = 1.9 EC50 = 2.4 No. offspring ;

Immobility 477598

- 14

Acceptable

Estuarine/Marine Fish and Invertebrates , acute
The available studies categorize technical

- grade BIT as being slightly toxic to estuarine/marine fish and moderately to very highly toxic to invertebrates. The guidelines for acute toxicity to estuarine/marine fish (850.1075 ) and invertebrates ( 850.1025, 850.1035) are satisfied

. No additional acute data are expected to be needed.

Acute Toxicity to Estuarine/Marine Invertebrates

Test Species Test Material (% ai) Toxicity Endpoint

(mg ai/L) Toxicity

Category EPA Study

ID Sheepshead minnow (Cyprinodon variegatus) 76.1 LC50 = 12.2 Slightly toxic 429450

- 01 Acceptable

89.9 LC50 = 19 Slightly toxic 477598

- 13 Acceptable

Mysid shrimp (Mysidopsis bahia) 76.1 LC50 = 0.99 Highly toxic 429490

- 02 Acceptable

89.8 L C50 = 1.8 Moderately toxic 477598

- 11

Acceptable Pacific oyster ( Crassostrea gigas) 76.1 EC50 = 0.047 Very highly toxic 429524

- 01

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Page 47 of 52 Estuarine/Marine Fish and Invertebrates , chronic

No chronic data are available for estuarine/marine fish (850.1400) or mysids (850.1350). Because the acute toxicity to the estuarine/marine fish is less than that of the freshwater fish and the mysid is comparable to the daphnid, the agency can use the acute: chronic ratio (ACR) from the freshwater species and the acute data to e xtrapolate the chronic NOAECs for the estuarine/marine organisms if values are needed for risk assessment.

Aquatic Plants

One supplemental study is available for a non

- vascular species

. A toxicity test using a vascular species ( Lemna sp.) is anticipate d to be needed (850.4400) to support all use patterns. To support Industrial Process and Water Systems use, toxicity tests also are anticipated to be needed for a green algae and freshwater diatom (850.4500) and for cyanobacteria (850.4550). If the green algae EC50 from a Tier II test is less than 1 mg ai/L, the freshwater diatom and cyanobacteria tests would also be anticipated to be needed to support the Materials Preservative use pattern.

Toxicity to Aquatic Plants
Species Test material (% ai) Toxicity

(mg ai/L) Status/ MRID

Vascular:

Duckweed ( Lemna sp.) TGAI No data Outstanding

Non

- Vascular:
Green algae (Pseudokirchniriella subcapitata ) 89.8

-- 477598

- 17 Una cceptable 1

Marine diatom ( Skeletonema costatum ) 89.8 EC50 = 0.4 477598

- 18 Supplemental 2

Freshwater diatom ( Navicula pelliculosa ) TGAI No data Outstanding

Cyanobacteria ( Anabaena flos

- aqua ) TGAI No data Outstanding

1 BIT ai concentration was not provided; concentrations were based on nominal values

2 cell density in the control group was below guideline recommendations

Benthic Organisms

Based on the environmental fate properties of BIT (i.e., K d <50 L/kg, K oc <1000), sedime nt toxicity testing (850.1735, 850.1740) is not anticipated to be required.Docket Number EPA

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Page 48 of 52 Appendix C References

40991301 Roberts, N.; Phillips, C.; Howlett, C.; et al. (1988) The Acute Oral Toxicity of Proxel Press

Paste to the Bobwhite Quail: Report No. ISN 164/88278. Unpublished study prepared by Huntingdon Research Centre. 37 p.

41732001 Long, R.; Foster, J.; Hoxter, K.; et al. (1990) A Dietary LC50 Study With the Northern

Bobwhite: Lab Project No. 123

- 16 2. Unpublished study prepared by Wildlife International LTD. 16 p.

41687101 Brown, D. (1979) Proxel Press Paste: Determination of the Acute Toxicity to Rainbow

Trout Salmo gairdneri : Lab Project Number: BL/B/1986. Unpublished study prepared by ICI Brixha m Laborato

- ry. 22 p.

45534602 Scheerbaum, D. (1998) Fish (Rainbow trout), Acute Toxicity Test, 96 h, Semi

- Static:

Acticide BIT: Lab Project Number: 98702TS: FAR59991: FAR5999

- . Unpublished study prepared by Dr U. Noack Laboratorium Fuer Angewandte Biolo gie. 50 p. {OPPTS 850.1075}

42949001 Kent, S.; Roberts, G.; Grinell, A. (1993) Proxel Press Paste: Acute Toxicity to Daphnia

magna : Lab Project Number: BL4847/B: X060/B. Unpublished study prepared by Zeneca Ltd.'s Brixham Environmental Lab. 20 p.

45534601 Noack, U. (1998) Aquatic Invertebrate Acute Toxicity Test (48 h), Freshwater Daphnids:

Daphnia magna Straus: Acticide BIT: Lab Project Number: 9807012TS: DAI59991: DAI5999

- . Unpublished study prepared by Dr. U. Noack Laboratorium fuer Angewandte B iologie. 55 p. {OPPTS 850.1010}

42945001 Roberts, G.; Caunter, J.; Grinell, A. (1993) Proxel Press Paste: Acute Toxicity to

Sheepshead minnow ( Cyprinodon variegatus ): Lab Project Number: BL4869/B: X060/A. Unpublished study prepared by Zeneca Limited, Bri xham Environmental Lab. 20 p.

42949002 Kent, S.; Roberts, G.; Stanley, R. (1993) Proxel Press Paste: Acute Toxicity to Mysid

Shrimp ( Mysidopsis bahia ): Lab Project Number: BL4797/B: X060/C. Unpublished study prepared by Zeneca Ltd.'s Brixham Environmenta l Lab. 20 p.

42952401 Roberts, G.; Caunter, J.; Johnson, P. (1993) PROXEL PRESS PASTE: Acute Toxicity to

Larvae of the Pacific Oyster ( Crassostrea gigas ): Lab Project Number: BL4917/B. Unpublished study prepared by Brixham Environmental Lab, ZENECA Limit ed. 21 p.

47319011 Palmer, S; Kendall, T.; Krueger, T.; et al. (2006) 1,2

- Benzisothiazolin

- 3

- one: A 48

- Hour

Flow

- Through Acute Toxicity Test with the Cladoceran ( Daphnia magna ): Preventol BIT 85 1,2

- Benzisothiazolin

- 3

- one. Project Number: 12A200, 06RC/08 4. Unpublished study prepared by Wildlife International, Ltd. 60 p.Docket Number EPA

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Page 49 of 52 47759811 Palmer, S.; Kendall, T.; Krueger, H. (2007) 1,2

- Benzisothiazolin

- 3

- One: A 96

- Hour Flow

Through Acute Toxicity Test with the Saltwater Mysid ( Americamysis bahia ): Final Report. Pr oject Number: 129A/202, 06RC/085, 129/041806/MYS/96H2/100P/608. Unpublished study prepared by Wildlife International, Ltd. 60 p.

47319010 Palmer, S.; Kendell, T.; Krueger, H. (2006) 1,2

- Benzisothiazolin

- 3

- one: A 96

- Hour Flow

Though Acute Toxicity Test wit h the Rainbow Trout ( Oncorhynchus mykiss ): Preventol BIT 85 1,2

- Benzisothiazolin

- 3

- one. Project Number: 129A/201, 06RC/082. Unpublished study prepared by Wildlife International, Ltd. 60 p.

47759814 Palmer, S.; Kendall, T.; Krueger, H. (2007) 1,2

- Benzisothiazolin

- 3

- One: A Flow

- Through

Life

- Cycle Toxicity Test with the Cladoceran ( Daphnia magna ): Final Report. Project Number: 129A/204, 06RC/091. Unpublished study prepared by Wildlife International, Ltd

. 83 p.

47759815 Palmer, S.; Kendall, T.; Kruger, H. (2007) 1,2

- Benzisothiazolin

- 3

- One: An Early Life

- Stage

Toxicity Test with the Fathead Minnow ( Pimephales promelas ): Final Report. Project Number: 129A/205, 06RC/090. Unpublished study prepared by Wildli fe International, Ltd. 96 p.

44364913 Gilbert, J.L., Roberts, G.C. (1996) Acute Toxicity to Bluegill Sunfish ( Lepomis macrochirus ):

Lab Project Number BL5701/B. Unpublished study prepared by Brixham Environmental Lab, ZENECA Specialties.Docket Number EPA

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Page 50 of 52 

# Appendix D Screening Level Down

- the

Drain Analysis

The Down

- the

- Drain (DtD) module of E

- FAST (Exposure and Fate Assessment Screening Tool), [version 2] was used to screen for the potential for aquatic organisms downstream of domestic wastewater treatment plants to be exposed to BIT. The Down

- the

- Drain module uses daily per capita release of household wastewaters, stream dilution factors, and wastewater treatment plant removal efficiency to provide both high

- end and median (average) time

- averaged surface water concentrations of chemicals discharged by domestic wastewater treatment plants. The high

- end scenario uses surface water concentrations downstream of domestic wastewater treatment plants based on the 10 th percentile stream dilution factor (SDF); the average scenario uses surface water concentrations based on the 50 th percentile SDF. SDF is defined as the ratio of the stream flow downstream of a wastewater treatment plant to the wastewater treatment plant flow. Inputs used to run the DtD module included concentrations of concern (COCs) for aquatic organisms, percent removal during wastewater treatment, and hypothetical wastewater treatment plant influent volumes. The results of the DtD module are expressed as number of days of exceedance of COCs for aquatic organisms. COCs for acute effects were determined by dividing LC 50 values (or EC 50 values, if appropriate) from acute toxicity tests on aquatic vertebrates and invertebrates by 2. COCs for listed endangered and threatened aquatic organisms were determined by dividing LC 5 0 values from acute toxicity tests on aquatic vertebrates and invertebrates by 20

. COCs for chronic effects for non

- listed and listed species were based on NOAEC values fr om tests on aquatic vertebrates and invertebrates . COCs for non

- listed and listed a quatic plant species were determined by using the IC 50 and NOAEC, respectively, from aquatic plant tests

. In the absence of data on removal of BIT during wastewater treatment, no removal of BIT during wastewater treatment was assumed.

The Down

- the

- Drain module was first run using a high

- end scenario to determine whether the model predicted exceedances of concentrations of concern. If the high

- end scenario predicted exceedances of the concentration of concern, the model was also run using the average sce nario.Docket Number EPA

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Page 51 of 52 

# Appendix E Product Chemistry

The 1,2

- Benzisothiazolin

- 3

- one (BIT) product chemistry information is summa rized in Table E1 (source: MRIDs 43584001, 41927501, 43584001, 42908201 ).

Table E1

– Product Chemistry of 1,2

- Benzisothiazolin

- 3

- one (BIT)

.

Guideline Numbers Physical and Chemical Properties 1,2

- Benzisothiazolin

- 3

- one

830.1550 Product identity and composition Refer to Table 3 830.1600 Description of materials used to produce the

product Confidential Business Information (CBI)

830.1620 Description of production process CBI 830.1650 Description of Formulation Process CBI 830.1670 Discussion of Formation of Impurities CBI 830.1700 Preliminary analysis CBI 830.1750 Certified limits CBI 830.1800 Enforcement analytical method NMR; HPLC 830.1900 Submittal of samples CBI 830.6302 Color Off white to brown 830.6303 Physical State Solid 830.6304 Odor Little or no odor

830.6313 Stability Stability to normal and elevated temperature,

metals/metal ions Stable with respect to sunlight. Stable with respect to normal and elevated temperatures. Stable at 55 o C for 14 days Unstable with respect to copper metal and iron (III) ion.

830.6314 Oxidation/Reduction Neither an oxidizing nor a reducing agent. Incompatible with strong oxidizers. 830.6315 Flammability Not Flammable 830.6316 Explodability Not Explodable

830.6320 Corrosion Characteristic No corrosion or discoloration was observed on packaging (Tests done with manufactured product) 830.7000 pH at25 °C 4.25

- 1% slurry 830.7050 UV/Visible Absorption Stable with respect to sunlight 830.7100 Viscosity Not applicable 830.7200 Melting point (°C) 159.5

- 160 o C 830.7220 Boiling point (°C) Not applicable 830.7300 Density ( g/cm 3 ) 1.36±0.02 g/cm 3

830.7370 Dissociation Constant pKa(s) Acid dissociation constant 9.12 x 10

- 8 moles/L (PAI) pKa 7.04 at 25 o C

830.7520 Particle size, fiber length, & diameter

distribution Not reported

830.7550 Partition coefficient ( n

- octanol/water) Log Kow 1.4 (PAI)

830.7840 Solubility in water (mg/L) at 25 o C 1118 ppm at 20 o C 1380 ppm at 24 o CDocket Number EPA

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Page 52 of 52 Guideline Numbers Physical and Chemical Properties 1,2

- Benzisothiazolin

- 3

- one

830.7860 Solubility in organic solvents n

- He xane: 100 ppm at 23 o C Ethyl acetate: 23000 ppm at 23 o C Methanol: 67000 ppm at 24 o C Acetonitrile: 13000 ppm at 23 o C Acetone: 42000 ppm at 24 o C Dichloromethane: 31000 ppm at 23 o C Toluene: 5000 ppm at 24 o C Heptane: 135 ppm at 20 o C DMSO

830.7950 Vapor pressure (mm Hg) at 25 °C Test done with PAI: 4.4 x 10

- 7 mm Hg at 20 o C 9.8 x 10

- 7 mm Hg at 25 o C