Docket Number EPA

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Page 2 of 63 1,2

- Benzisothiazol

- 3(2H)

- one, 2

- butyl Registration Review Team

Human Health & Environmental Effects William Erickson James Breithaupt Patricia Jennings Jenny Tao Timothy Dole Kristin R ickard

Risk Management Rachel Ricciardi Rose Kyprianou Julie Chao

Office of General Counsel Philip RossDocket Number EPA

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Page 3 of 63 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 bioconcentration factor BBIT 1,2

- Benzisothiazol

- 3(2H)

- one, 2

- butyl °C degrees Celsius CAS Chemical Abstracts Service CFR Code of Federal Regulations CHO Chinese h amster o vary CMA Chemical Manufacturers Association CO 2 c arbon dioxide COC c oncentration

- of

- c oncern 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 ET Extrathoracic FDA Food and Drug Administration F FDCA 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 GSD Geometric Standard Deviation HEC Human Equivalent Concentration 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 etha l 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 ilogramDocket Number EPA

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Page 4 of 63 mg/kg/day m illigram p er k ilogram p er d ay mg/L m illigram p er l iter mm Hg m illimeter of mercury MMAD Mass Median Aerodynamic Diameter MOE m argin of e xposure 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 Eco nomic Co

- operation and Development OPP Office of Pesticide Programs PAD p opulation a djusted d ose PAI p ure active i ngredient PDM Probabilistic Dilution Model % p ercent PC Code Pesticide Chemical Code PCF p ounds p er c ubic foot pH power of h ydrogen or power of the con centration of the hydrogen ion PHED Pesticide Handler’s Exposure 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 Eligibility Decision RDDR Regional Dose Deposition Ratio SAR s tructure a ctivity r elationship SF s afety f

actor SSTS Section Seven Tracking System TEP t ypical e nd

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

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Page 5 of 63 

### Table of Contents 1 Introduction

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

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

................................ ................................ ................................ ................. 8 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

................................ ................................ .................. 10 1.4.3 Usage Information

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

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

................................ ................................ ............................ 12 1.6 Incidents

................................ ................................ ................................ ......................... 12 1.6.1 Human Health

................................ ................................ ................................ ......... 12 1.6.2 Ecol ogical

................................ ................................ ................................ ............... 12 2 Anticipated Data Needs

................................ ................................ ................................ ........ 12 3 Human Health Risk Assessment

................................ ................................ ........................... 14 3.1 Toxicological Endpoints

................................ ................................ ................................ 14 3.2 Dietary Exposure

................................ ................................ ................................ ............ 17 3.2.1 Food

................................ ................................ ................................ ........................ 17 3.2.2 Drinking Water

................................ ................................ ................................ ....... 18 3.3 Occu pational and Residential Exposures

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

................................ ................................ ............. 18 3.3.2 Residential Handler Exposures

................................ ................................ ............... 19 3.3.3 Residential Post

- Application Exposures

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

................................ ................................ ............. 20 3.4.1 Aggregate Exposures

................................ ................................ .............................. 20 3.4.2 Cumulative Exposures

................................ ................................ ............................ 20 4 Environmental Risk Assessment

................................ ................................ ........................... 20 4.1 Environmental Fate Assessment

................................ ................................ .................... 21 4.1.1 Water and Sediment

................................ ................................ ................................ 23 4.1.2 Soil

................................ ................................ ................................ .......................... 23 4.2 Water Quality

................................ ................................ ................................ ................. 23 4.3 Conceptual Models for Environmental Exposure Pathways

................................ .......... 23 4.4 Ecological Effects Assessment

................................ ................................ ....................... 24 4.4.1 Measures of Effect

................................ ................................ ................................ .. 24 4.5 Exposure Analysis Plan

................................ ................................ ................................ .. 25 4.5.1 Screening Level Down

- the

- Drain Analysis

................................ ............................ 25 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 25 6 Optional Label Changes

................................ ................................ ................................ ........ 26 7 Guidance for Commenters

................................ ................................ ................................ .... 26 7.1 Preliminary Work Plan

................................ ................................ ................................ ... 26 7.1.1 Trade Irritants

................................ ................................ ................................ .......... 26 7.1.2 Water Quality

................................ ................................ ................................ .......... 27 7.1.3 Environmental Justice

................................ ................................ ............................. 27 7.1.4 Additional Information

................................ ................................ ........................... 27 8 Next Steps

................................ ................................ ................................ ............................. 28Docket Number EPA

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Page 6 of 63 9 References

................................ ................................ ................................ ............................. 29

Appendix A T oxicology Profile

................................ ................................ ............................... 31 Appendix B Environmental Fate

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

................................ ................................ .......................... 54 Appendix D Screening Level Down

- the

- Drain Analysis

................................ ........................ 59 Appendix E Product Chemistry

................................ ................................ ............................... 60

List of Tables Table 1

– Anticipated Risk Assessments for Registration Review

................................ .................. 8 Tabl e 2

– Anticipated Registration Review Schedule

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

– Chemical Identification of BBIT

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

– Physical

- Chemical and Environmental Fate Properties for BBIT and BIT

.................. 10 Table 5

– BBIT Registered Uses

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

– Studies Anticipated as Needed for the Registration Review of BBIT

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

– Toxicological Endpoints for BBIT

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

– Occupational Handler Exposure Scenarios for BBIT

................................ ................... 19 Table 9

– Residential Handler Exposure Scenarios for BBIT

................................ ...................... 19 Table 10

– Residential Post

- Application Exposure Scenarios for BBIT

................................ ...... 19 Table 11

– Environmental Fate and Transport Properties of BBIT and BIT

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

– Avail able Ecological Effects Endpoints

................................ ................................ ..... 24Docket Number EPA

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Page 7 of 63 

## 1 Introduction

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

- Benzisothiazol

- 3(2H)

- one, 2

- butyl , herein referred to as BBIT. The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about BBIT , 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 BBIT’s review.
The registration review process was designed to include a public participation component to solicit input from interested stakeholders. The Agency intends, by sharing this information in the docket, to inform the public of what it knows about BBIT and what types of new data or other information would be helpful for the Agency to receive as it mo ves toward a decision on BBIT

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

- making process for this chemical.



## 1.1 Statutory and Regulatory Authority
The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distributed or sold in the United States generally must be registered by the USEPA based on scientific data showing that they will not cause unreasonable risks to human health or the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides contin ue to meet the statutory standard of no unreasonable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the Agency periodically r eevaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at http://www2.epa.gov/pesticide

- reevaluation

.
The Agency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for 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 f or each case. The docket is the Agency ’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. After reviewing and responding to comme nts and 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) for the BBIT

case

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Page 8 of 63 

## 1.2 Case Overview

The docket for BBIT ( case 5017 ) has been established at http://www.regulations.gov in docket number EPA

- HQ

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- 2015

- 0736

. Documents associated with this registration review can be viewed in this docket. Tables 1 and 2 b elow summar ize the issues relevant to this registration review case and the anticipated registration review schedule

.
Table 1

–Anticipated Risk Assessments for Registration Review

Risk Assessment Assessment Necessary to Support Registration Review Date of Most

Recent Assessment Type of

Assessment Required (New/Updated) Data Anticipated as Needed (See Table 6 for detail s)

Dietary (food) No N/A None N/A

Dietary (drinking water) Yes N/A New WWTP biodegradation simulation studies, Aerobic aquatic metabolism

Occupational Handler Yes 6/8/2009 Updated Indoor Exposure

– Inhalation Indoor Exposure

– Dermal

Residential Handler Yes 6/8/2009 Updated Indoor Exposure

– Inhalation Indoor Exposure

– Dermal
Resident i al Post Application

- Incidental Oral and Dermal Yes 6/8/2009 Updated Indoor Surface Residues

Aggregate Yes None New None
Cumulative Yes None None None
Tolerance Review No N/A None N/A

Ecological Yes 6/10/2009 (eco) 6/2/2009 (fate) New WWTP biodegradation simulation studies, Aerobic aquatic metabolism Aquatic plants and animals N/A = Not applicable

BBIT is used primarily as an antimicrobial, microbi o cide/microbi o stat, a nd fungicide/fungistat in metal working fluids, plastics, polymers, and construction materials. The BBIT case has one pesticidal active ingredient identified under PC code 098951 . The Agency has created the following estimated timeline in Table 2 for the completion of BBIT registration review.

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 2016

- 03 2016

- 03 Close Public Comment Period 2016

- 05 Phase 2: Case Development

Issue Final Work Plan 2016

- 09Docket Number EPA

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Page 9 of 63 Issue Data Call

- In (DCI) 2017

- 09

Receive Data to be Considered in Risk Assessment 2019

- 09

Open 30

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

- 03

Close Public Comment Period 2021

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

- Day Public Comment Period for Pro posed Decision 2021

- 09

Close Public Comment Period 2021

- 11

Issue Final Decision 2022

- 03

Begin Post

- Decision Follow

- up 2022 Total (years) 6

* 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).


## 1.3 Chemical Identification and Properties

Table 3 contains the chemical identification of BBIT (PC Code 098951) which belongs to the isothiazolinone chemical family

. There are several pesticidal active ingredients in this chemical family which have similar pesticidal, toxicological and environment al behavi or characteristics in

common. In the absence of existing data, EPA is choosing to bridge data between compou nds in this class. Table 4 co mpares some of the chemical and physical properties of BBIT and the active ingredient, 1,2

- Benzisothiazol

- 3(2H )

- one (BIT, PC Code 098901)

. Additional c hemical and physical properties of the BIT transformation products may be seen in Appendix E

.
Table 3

– Chemical Identification of BBIT

Chemical Name N

- butyl

- 1,2

- benzisothiazolin

- 3

- one (BBIT) Chemical Classification Isothiazolinone
PC Code 098951
CAS Number 4299

- 07

- 4 Smiles code CCCCN1C(=O)C2=CC=CC=C2S1 Molecular Formula C 11 H 13 NOS Molecular Weight (grams/mole) 207.29

Molecular StructureDocket Number EPA

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Page 10 of 63 The physical and chemi cal property information from BBIT is presented in Table 4. Some of these data are based on EPI

- Suite 4.11 and some are based on the studies for the active ingredient BIT, which has the same ring structure without the four

- carbon chain.

Table 4

– Physical

- Chemical and Environmental Fate Properties for BBIT and BIT

Guideline No./ Study Type BBIT BIT

Structure

Water Solubility(mg/L) 418 at 25 o C 1,380 mg/L at 24 o C

830.7050 UV visible sorption Absorption from 290

- 350 nm (BIT) Absorption from 290

- 350 nm (BIT)

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

- 8 moles/L (PAI) pKa 7.04 at 25 o C (BIT) Acid dissociation constant 9.12 x 10

- 8 moles/L (PAI) pKa 7.04 at 25 o C (BIT) 830.7550 Partition coefficient (log Kow) 2.32 1.4

830.7950 Vapor pressure (mm Hg) 9.9 x 10

- 6 1.14 x 10

- 6

Henry’s Law Constant (calculated ) Atm m 3 mol

- 1 6.5 x 10

- 9 1.64 x 10

- 10

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 five EPA

- registered active products that contain BBIT as an active ingredient (a.i.). One of these products is a technical product (EPA Reg. No. 1258

- 1267) and the other four products are end

- use products
, 1 of which one is a ready

- to

- use and three are soluble concentrates

. The percent a.i. for BBIT ranges from 4.75 to 99.2 percent.



### 1.4.2 Summary of Registered Uses

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

. BBIT can only be applied to metalworking fluids in closed metalworking and delivery systems. In cross linked polyurethane, BBIT products are added to the polyol at a concentration that will yield the desired use level in the final product after reaction with the isocyanate component; however, BBIT products may also be incorporated at an injection port of a reaction injection moldi ng machine. In addition to melt processed polymers (PVC,

1 EPA Reg. Nos. 1258

- 1249, 1258

- 1251, 1258

- 1285, an d 1258

- 1286.Docket Number EPA

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Page 11 of 63 thermoplastic polyurethane, synthetic elastomers and thermoplastic acrylics, etc

. ), BBIT products may be metered into the melt to yield the desired end use concentration. For thermoplastic polyuretha ne , concentrated granules may be produced by absorbing BBIT products through shear mixing. BBIT products may be added to silicone oil for silicone sealants before processing, or to the manufacturing vessel before packing off into containers for supply chai n distribution.

Table 5

– BBIT Registered Uses

Use Application Method Application

Rate

Material Preservative
Construction Materials (latex emulsions, mineral or pigment slurries) Construction Materials ( paints, coatings, adhesives, caulks, spackle) Metalworking Fluids (initial dose) Metalworking Fluids (maintenance dose) Paper (insulation and wall board facing) Paper (stationary and non

- food contact packaging) Plastics (PVC, polyurethane foam and latex rubber) A, B Plastics (silicones, polyesters, polyolefins, elastomers) A
, B Open Pour Open Pour Closed System Closed System Open Pour Open Pour Open Pour Open Pour 500 ppm

1,150 ppm 200 ppm 30 ppm 1,150 ppm 1,150 ppm 5,000 ppm 10,000 ppm

A

. Plastic items i nclude coated fabrics, pet toys, shower curtains, foam seat cushions and mattress padding, floor coverings, tarps, synthetic leather for sneakers, swimming pool liners and marine hose and sleeving.

B . Labels state: “Do not use to treat food/feed or drinkin g water contact items or children ’ s toys.”


### 1.4.3 Usage Information

Production volume data in th e Agency’s Section Seven Tracking System (SSTS) for the years 2003 through 2013 indicate that no more than 250,000 kilograms of BBIT are sold per year in the United States. Data for the years 2014 and 2015 were not used in this estimate since data collection is stil l in progress.



## 1.5 Regulatory Histor y
The first product containing BBIT chemical as an active ingredient was registered in the United States in April of 200 3. This registration was supported by a human health risk assessment (US EPA, 2003) that evaluated occup ational and residential exposures involved in treating plastic materials. Additional assessments were done to evaluate proposed uses in metal working fluids (US EPA, 2004), and construction materials and coatings including wood coati ngs and stains (US EPA, 2009). The most recent human health risk assessment for BBIT ( US EPA, 2015) evaluate d a propose d label amendment for the metal working fluid use to eliminate the requirement for the use only in enclosed machines with loc al exhaust ventilation. Due to inhala tion risk concerns, the closed metalworking system requirement remains in place. The Agency has not conducted an environmental fate or ecological effects assessment for the currently

- registered uses.Docket Number EPA

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Page 12 of 63 A Reregistration Eligibility Decision (RED) was not comp leted for BBIT because it was reg istered after November 1, 1984.



### 1.5.1 Tolerance Information

EPA has not established any tolerance or exemptions from the requirement of tolerances in raw agricultural commodities or processed food and feed products for BBIT under the Federal Food, Drug and Cosmetic Act (FFDCA) Section 408. BBIT has not been cleared as a food additive by the US Food and Drug Administration (US FDA) under FFDCA Section 409.



## 1.6 Incidents

1.6.1 Human Health

There are no incidents re ported for BBIT in the OPP Incident Database System based on a search conducted on February 4, 2016.



### 1.6.2 Ecological No ecological incidents in the I ncident D ata S ystem as of November 24, 2015

. 

## 2 A nticipated Data Needs

Table 6 presents a summary of the data anticipated as being needed to support this registration review.Docket Number EPA

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Page 13 of 63 Table 6

– Studies Anticipated as Needed for the Registration Review of BBIT

GLN Study Name Test Substance Time

Frame 1 Risk Assessment(s)

Data Will Support Use Site(s) Triggering

Anticipated Data Requirement Applicable

Exposure Scenario

835. 3110, 835.3220, 835.3240, 835.3280 2
, 3 WWTP

biodegradation studies TGAI ( B BIT

or BIT) 12 Aquatic exposure Metalworking fluids
, paper production Ecological Drinking Water

835.4300 3 Aerobic aquatic

metabolism TGAI (BBIT

or BIT ) 24 Aquatic exposure Metalworking fluids Ecological Drinking Water 850.4500 4 Algal toxicity TGAI 12 Aquatic plants All Ecological 850.4550 4 Cyanobacteria TGAI 12 Aquatic plants All Ecological

850.1400 Fish, Early Life

-

Stage Degradates 5 24 Aquatic animals Metalworking fluids, paper production Ecological

850.1300 Aquatic

Invertebrate Life Cycle Degradates 5 24 Aquatic animals Metalworking fluids, paper production Ecological

875. 12 00 Dermal Exposure

-

Indoor TEP 24 Human Health Paints and Coatings Open Pour Liquids, Airless Spray and Brush/Roller Paint Application

875. 14 00 Inhalation

Exposure

- Indoor TEP 24 Human Health Paints and Coatings Open Pour Liquids Airless Spray and Brush/Roller Paint Application

875.2300 6 Indoor Surface

Residues TEP 24 Human Health Plastics (Vinyl Flooring) Pet Toys Foam Based Mattress Pads Dermal and Hand to Mouth Exposure

1 The timeframe is measured in months from DCI Receipt

. 2 A n ASRI for BIT provided a value of 30 mg/L (>20 mg/L). Therefore, the registrant must conduct either: (i) Ready Biodegradability or (ii) a) Biodegradation in Activated Sludge or b) Simulation Test

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

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

3 Biodegradation or Aerobic aquatic metabolism data may be generated for either BIT or BBIT; bridging from BIT is appropriate based on the similarity in chemical structure

. 4 Green algae ( Selenastrum capricornutum ) d ata are required for this use pattern. If the EC 50 of BBIT is less than 1.0 mg/L, studies are also required on three additional species ( Anabaena flos

- aquae , Navicula pelliculosa , and Skeletonema costatum ). The Public Draft OPPTS 850.5400 Algal Toxicity gu ideline was split into two separate guidelines and renumbered with the cyanobacteria species separated into OCSPP 850.4550 and the other three species under OCSPP 850.4500.

5 Based on identification of any significant degradates from the Aerobic aquatic m etabolism study (835.4300) . If major degradates persist for more than one week in water
, chronic testing for freshwater fish and invertebrates is needed.

6 It is recommended that a protocol be submitted for review prior to conducting the study.Docket Number EPA

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Page 14 of 63 

## 3 Human Healt h Risk Assessment

The Agency ant icipates the need to conduct a human health risk assessment for BBIT. The Agency expects to require additional data for use in conducting the registration review.
For the purpose of risk assessment of isot hiazolone chemicals group, the A gency determined that chemical

- specific data will be used when available. If there are no chemical

- specific data, the most conservative stud(ies) of the group should be used for deriving the endpoint(s). Some toxicity studies are not available for BBIT; therefore, data were bridged from other isothiazolone chemicals for establishing the appropriate endpoints. Although no additional toxicity studies are required for BBIT presently, the Agency recomm ends that the registrant submit any relevant chemical

- specific information, including valid literature studies, to refine the risk assessment for BBIT, particularly for chronic dietary, dermal, and inhalation endpoints.
Additionally, the Agency anticipates to require additional exposure studies, b as ed on the currently registered uses , for the registration review of BBIT. A detailed description of the available toxicity studies is provided in Appendix A.



## 3.1 Toxicological Endpoints

The A gency recently revised the existing toxicological endpoints for the e ntire isothiazolone chemicals group, to which BBIT belongs. All available information
, including existing toxicology studies for the isothiazolone chemicals as well as valid scientific literature, were considered in establishing the current toxicology endp oints

. As a result, the A gency does not anticipate the need to revise the current toxicology endpoints for BBIT, as part of th e registration review. The current toxicological endpoints for BBIT are shown in Table 7 below.
When revising the existing toxicol ogical endpoints for the isothiazolone chemicals group, t he A gency concluded, when appropriate, that the default 10x uncertainty factors (UF) be reduced to 3x , i.e., remove the toxicokinetic component of the UF (3 x for inter

- species extrapolation and 3x for intra

- species variation) for short

- term ( ST ) and intermedium

- term ( IT ) risk assessments for all routes of exposure , based upon (1) observed effects being portal of entry, local irritation

- like effects irrespective of route of exposure, (2) the lack of systemic toxicities, and (3) no metabolic activation or degradation to a toxic moiety. The A gency also recommended that a dditional uncertainty factors may be used to account for (1) database uncertainty, (2) adjustment of exposure duration s, and/or (3) use of a lowest

- observed

- adverse

- effect

- level ( LOAEL ) for the point of departure (POD)

. This decision appl ies to all of the isothiazolone chemical s.

N o chronic/cancer studies are available for BBIT ; therefore, the CMIT/MIT chronic/cancer study with a no

- observed

- adverse

- effect

- level ( NOAEL ) of 2.0 mg/kg/day was selected for c hronic d ietary exposure

. The UF is 10x (UF A = 3 x for interspecies extrapolation and UF H = 3 x for intraspecies variations)

.

T here i s no d ermal study for BBIT

. F or dermal exposure scenarios (all durations), the CMIT /MIT 90

- day dermal study with a LOAEL of 0.75 mg/kg/day wa s selected as it is a route

specific study wi th the most conservative endpoint. The UF for ST and IT dermal exposureDocket Number EPA

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Page 15 of 63 scenarios is 30x (UF A = 3 x for interspecies ex trapolation, UF H = 3 x for intraspecies variations, and UF LOAEL→NOAEL = 3 x for LOAEL to NOAEL extrapolation) . The UF for long

- term (LT) dermal exposure scenarios is 100x (UF A = 3 x for interspecies extrapolation, UF H = 3x for intraspecies variations, UF LOAEL→NOAEL = 3 x for LOAEL to NOAEL extrapolation, and UF DB = 3 x for using a 90

- day study for long

- term exposure scenario)

.

There is no inhalation study for BBIT. For inhalation exposure scenarios (all durations) , the DCOIT 90

- day inhalation study with a no

- observed

- adverse

- effect

- concentration ( NOAEC ) of 0.02 mg/m 3 was selected as it is a route

- specific study with the most conservative endpoint. The UF for ST and IT inhalation exposure scenarios is 10x (UF A = 3 x for interspecies extrapolation and UF H = 3 x for intraspecies variations) . The UF for long

- term (LT) inhalation exposure scenarios is 3 0x (UF A = 3 x for interspecies extrapolation, UF H = 3x for intraspecies variations, and UF DB = 3 x for using a 90

- day study for long

- term exposure scenario)

.

Table 7

– Toxicological Endpoints for BBIT

Exposure Scenario Dose or

Concentration Used in Risk Assessment Target Margin of Exposure

(MOE), Uncertainty Factor

(UF) Study and Toxicological Effects

Acute Dietary (females 13

- 49) No appropriate endpoint identified from the BBIT database.

Acute D ietary (general population including infants and children) NOAEL = 2000

mg/kg/day UF =100x

(UF A = 3 x for interspecies extrapolation , UF H = 3 x for intraspecies variations, and UF LOAEL→NOAEL = 10x for LOAEL to NOAEL extrapolation ) BBIT Acute Oral Study (MRID 44364915 )

LOAEL = 2000 mg/kg/day, based on clinical signs of toxicity observed on Day 1 (piloerection, sides pinched in, upward curvature of spine, labored breathing, gasping, signs of salivation, breathing irregular, ↑ breathing depth & rate, prostrate, and tip toe ga it) death of one female rat on D ay 2.

Chronic Dietary (G eneral Population) NOAEL = 2.0

mg/kg/day UF =10x

(UF A = 3 x for interspecies extrapolation and UF H = 3 x for intraspecies variations ) CMIT/MIT Chronic/ Cancer (Drinking W ater) Study

– Rat 1 (MRID 43140701)

LO A EL = 6.6/9.8 mg/kg/day
, based on increased incidence of hyperplasia/ hyperkeratosis of the squamous mucosa of the forestomach in female rats (17/80 rats vs 5/80 and 5/80 in water and salt controls
, respectively), necrosis of the granular mucosa in female rats (11/80 rats vs 3/80 in water control), and increased incidence o f edema/inflammation of the submucosa of the glandular stomach in females (9/80 vs 1/80 and 3/80 in water and salt controls
, respectively).Docket Number EPA

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Page 16 of 63 Exposure Scenario Dose or

Concentration Used in Risk Assessment Target Margin of Exposure

(MOE), Uncertainty Factor

(UF) Study and Toxicological Effects

Incidental Oral (short

- [1

- 30 days]/ intermediate

term [1

- 6 months]) NOAEL offspring systemic = 49 mg/kg/day (600 ppm) UF =100x

(UF A = 10x for interspecies extrapolation and UF H = 10x for intraspecies variations ) BBIT Two

- gen eration Reproduction (Dietary)

– R at (MRID 48261201)

LOAEL parental systemic =1700 ppm (141/157 mkd ♂/♀) , based on ↓ body weights (pre

- mating slightly but sig. in ♂ [↓4% WK1 and ↓5% WK 3]); pre

- mating body wt gains ( ♂/♀ : ↓18%/29% during WK 0

- 1; overall pre

- mating [WK 0

- 10] wt gains ↓10% in ♀ but not sig. in ♂) and food consumption (♂: absolute ↓4

- 11% during WK 0

- 1, 2

- 3, & 3

- 4; relative ↓9%) and food efficiency (↓10%. ♀: absolute ↓5% each during WK 0

- 1 & WK 1

- 2 and relative ↓7% during WK 0

- 1).

NOAEL offs pring systemic = 600 ppm (49/56 mkd ♂/♀) LOAEL offspring systemic = 1700 ppm (141/157 mkd ♂/♀) , based on ↓ body weights ( ♂/♀ : pre

mating ↓6

- 17%/7

- 17% [WK 18

- 28]), body weight gains (♂: ↓8% WK 18

- 19), and spleen weight (absolute/relative [to body] ↓9

- 19% on PND 21 in F2 pups ♂ & ♀ ] only).

NOAEL repro = 1700 ppm (141/157 mkd ♂/♀)
Dermal (all durations) L OAEL =

0. 75 mg/kg/day ( skin loading dose 2

= 1.2 μg/cm 2 ) Short

- and intermedium

- term:

UF =30x (UF A = 3x for interspecies extrapolation , UF H = 3 x for intraspecies variations, and UF LOAEL→NOAEL = 3x for LOAEL to NOAEL extrapolation )

Long

- term: UF =100x (UF A = 3x for interspecies extrapolation , UF H = 3 x for intraspecies variations, UF LOAEL→NOAEL = 3x for LOAEL to NOAEL extrapolation, and UF DB = 3x for using a 90

- day study for long

- term exposure scenario ) CMIT/MIT 90

- Day Dermal

– Rat 3 (MRID 43462005)

LOAEL derma l = 0. 75 m g /k g /d ay , based on (i) mild erythema in females at 0. 75 m g /k g /d ay and greater beginning on Day 22 of the study; 0.75 mkd (3/10), 3.75 mkd (6/10), 18.75 (10/10) and desquamation and eschar formation and (ii) similar skin effects in males noted in mid

- and high

- dose groups; 0.75 mkd (0/10), 3.75 mkd (2/10), and 18.75 mkd (10/10).Docket Number EPA

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Page 17 of 63 Exposure Scenario Dose or

Concentration Used in Risk Assessment Target Margin of Exposure

(MOE), Uncertainty Factor

(UF) Study and Toxicological Effects

Inhalation (all durations) NOAEC =

0.02 mg/m 3 (HEC 8

- hour = 0.0045 mg/m 3 ) 4 Short

- and intermedium

- term:

UF =10x (UF A = 3x for interspecies extrapolation and UF H = 3 x for intraspecies variations )

Long

- term: UF =30x (UF A = 3x for interspecies extrapolation , UF H = 3 x for intraspecies variations, and UF DB = 3x for using a 90

- day study for long

- term exposure scenario ) DCOIT 90

- day Inhalation T oxicity Study

– Rat 5 (MRID 43487501)

LOAEC = 0.63 mg/m 3

, based on hyperplasia of the larynx (13/16 animals vs. 1/15 in control), chronic inflammation of the larynx (5/16 vs. 0/15 in control), squamous metaplasia of the larynx (14/16 vs. 0/15 in control), and transitional respiratory epithelium hyperplasia (nose level 1: 4/16 vs 0/15 in control) for male
rats. In females, chronic inflammation of the larynx (9 /16 vs 0/15 in control) and squamous metaplasia (16/16 vs. 0/15 in control) were also observed, as well as goblet cell hyperplasia (7/16 vs. 0/15 in control) and transitional respiratory epithelium hyperplasia (3/16 vs 0/16 in control). I ncreased incidence of histopathological alterations of the nose, larynx, and lung NOAEL /C = no observed adverse effect level /concentration, LOAEL /C = lowest observed adverse effect level /concentration

1 No chronic/cancer studies are available for BBIT; therefore, data were bridged from a c hronic/ c ancer study in d rinking w ater for CMIT/MIT

. 2 Skin Loading (μg/cm 2 ) = (LOAEL 0.75 mg of 13.9% CMIT/MIT/kg/day x 1000 μg/mg unit conversion x 13.9%/100 ai adjustment x 0.4 kg BW rat) /35 cm 2 applied dose = 1.2 μg/cm 2

3 No 90

- day dermal toxicity studies are available for BBIT; therefore, data were bridged from a 90

- day dermal study for CMIT/MIT

. 4 8

- hour Human Equivalent Concentration ( HEC 8 hour ) = NOAEC x ( 6 hours animal tox study/8 hours human exposure ) x RDDR , where t he RDDR is 0.30 for extrathoracic ( ET ) effects ( MMAD = 1.4 μm , GSD = 4.6 and BW rat = 420 grams )

. Rat BW is the average for the 0.63 mg/m 3 treatment group at W eek 13.
5 No 90

- day inhalation toxicity studies are available for BBIT; therefore, data were bridged from a 90

- day inhalation study for DCOIT.


## 3.2 Dietary Exposure

A dietary (food) exposure assessment is not required for BBIT at this time. The Agency will examine the need for a drinking water assessment during the risk assessment stage of this Registration Review.



### 3.2.1 Food

BBIT uses are not expected to result in direct or indirect dietary (food) exposure since a ll FIFRA

- registered BBIT labels specify the product is not intended for use in/on surfaces that may contact food. Therefore, the registered uses of BBIT are not expected to result in direct or indirect dietary (food) exposure and a dietary (food) exposure assessment is not anticipated to be needed

.Docket Number EPA

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Page 18 of 63 

### 3.2.2 Drinking Water A drinking water assessment has not been conducted for B BIT in the past. However, for the metalworking fluid and paper production uses, the A gency cannot rule out the potential for B BIT to enter surface water and to subsequently be present in drinking wat er. Since drinking water risk is a function of many unknown factors including (1) the residues of concern in drinking water, (2) the magnitude of these potential residues of concern, (3) the persistence of B BIT in water, and (4) if residues of B BIT are lik ely to pass through a wastewater treatment plant (WWTP), the A gency anticipates needing environmental fate data listed in Section 4 of this P WP. These data from either BIT or BBIT will be use d to determine whether, and to what extent, residues of BB IT will pass through a WWTP and persist in surface water . Upon recei pt and review, these data and other available sources of information will be used during the risk assessment stage of this Registration Review to determine the potential for discharged or leached residues of B BIT to result in human dietary exposure via drinking water, which may trigger a drinking water assessment.



## 3.3 Occupational and Residential Exposures
The occupational and residential exposures that were evaluated in the previous risk assessments (US EPA, 2003, US EPA, 2004, US EPA, 2009 ) will need to be reevaluated to account for the toxicology PODs that were revised in 2015 and new exposure and surface residue studies that are anticipated to be needed

. The occupational exposures for mach inists us ing BBIT treated metal working fluids was evaluated in 2015 (US EPA, 2015) using the revised PODs and does not need to be reevaluated.



### 3.3.1 Occupational Handler Exposure The occupational handler dermal and inhalation exposures were previous ly assessed using a POD of 30 mg/kg/day that was based on an oral toxicity study. Dermal exposure s will need to be reassessed using the revised POD of 1.2 ug/cm 2 that is based on a dermal toxicity study
, and inhalation exposures will need to be reassessed us ing the revised POD of 0.0045 mg/m 3 that is based on an inhalation toxicity study

. In addition, S eries 875 dermal and inhalation exposure studies will be needed to replace the data from the Pesticide Handlers Exposure Database (PHED) and the Chemical Man ufacturer Association (CMA) study that were used in the previous assessments because these data do not have adequate quality control information (such as field and laboratory recovery samples, method validation samples) and number of replicates (i.e., numb er of times a worker is monitored for a specific activity)

. EPA presented the need for additional handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed t hat additional data are warranted.Docket Number EPA

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Page 19 of 63 The occupational handler exposure scenarios that will need to be evaluated are listed in Table 8.

Table 8

– Occupational Handler Exposure Scenarios for BBIT
Exposure Scenario Exposure Route(s) Duration
Open Pour Liquids During Material Preservation Dermal Inhalation Short, Intermediate, and Long

Term Airless Sprayer and Brush/Roller Application of Preserved Paints Dermal Inhalation Short and Intermediate Term



### 3.3.2 Residential Handler Exposures

The residential handler dermal and inhalation exposures were also previously assessed using the POD of 30 mg/kg/day and will need to be reassessed using the revised PODs of 1.2 ug/cm 2 for dermal exposure and 0.004 5 mg /m 3 for inhalation ex posure. In addition, dermal and inhalation exposure data will be needed to replace the data that were used in the previous assessments as discussed a bove for occupational handlers. The residential handler exposure scenarios that will need to be evaluated are liste d in Table 9.

Table 9

– Residential Handler Exposure Scenarios for BBIT
Exposure Scenario Exposure Route(s) Duration
Airless Sprayer and Brush/Roller Application of Preserved Paints Dermal Inhalation Short and Intermediate Term



### 3.3.3 Residential Post

- Application Exposures

The residential post application dermal and incidental oral exposures were previously assessed using the POD of 30 mg/kg/day and will need to be reassessed using the revised PODs of 1.2 ug/cm 2 for dermal exposure and 49 mg/kg/day for incidental oral exposure. In addition , 875.2300 surface residue studies are needed to replace those studies used in the previous assessment because the previous ly used studies were experimental in nature and did not include the quality control data that is normally included in guideline studies. The residential post application exposure scenarios that will need to be evaluated are listed in Table 10.

Table 10

– Residential Post

- Applicat ion Exposure Scenarios for BBIT

Exposure Scenario Exposed Population Exposure

Route(s) Duration

Playing on Treated Vinyl Flooring Children Dermal Incidental Oral Short and

Intermediate Term
Playing with Treated Pet Toys Children Dermal Incidental Oral Short and

Intermediate Term
Sleeping on Foam Based Mattress Pads Adults and Children Dermal Short and Intermediate TermDocket Number EPA

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Page 20 of 63 

## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

EPA plans to conduct an aggregate assessment for BBIT because this assessment was not conducted previously

. This assessment will include dietary ( drinking water ) exposures and residential incidental oral exposures

. It is anticipated that dermal and inhalat ion exposures will not be aggregated with the dietary and incidental oral exposures because the effects of dermal and inhalation exposures observed in the dermal and inhalation toxicology studies are irritation effects which are not similar to the systemic effects seen in the oral studies.



### 3.4.2 Cumulative Exposures
In 2015, EPA’s Office of Pesticide Programs released a guidance document entitled, Pesticide Cumulative Risk Assessment: Fr amework for Screening Analysis. This document provides guidance on how to sc reen groups of pesticides for cumulative evaluation using a two

- step approach beginning with the evaluation of available toxicological information and if necessary, followed by a risk

- based screening approach. This framework supplements the existing guidan ce documents for establishing common mechanism groups 2 and conducting cumulative risk
assessments

. 3 The agency has utilized this framework for BB IT and determined that although BBI T shares some chemical and/or toxicological characteristics (e.g., chemical structure or apical endpoint) with other pesticides, the toxicological database does not support a testable hypothesis for a common mechanis m of action. No further data are required to determine that no common mechanism of toxicity exists for BB IT and othe r pesticides and no cumulative evaluation is necessary for BB IT.


## 4 Environmental Risk Assessment

The Agency has not previously conducted and anticipates the need to conduct an ecological risk assessment for BBIT. The Agency expects to require additional data for use in conducting the registration review.
The ecological risk assessment planned during registration review will allow the Agency to determine potential acute and chronic risks to aquatic organisms exposed to BBIT that are transported from treatment sites into the aquatic environment. The risk assessment also will allow the Agency to determine whether each use of the BBIT has ‘ no effec t ’ or ‘ may affect ’ federally listed threatened or endangered species (listed species) or their designated critical habitats. When an assessment concludes that a pesticide’s use ‘ may affect ’ a listed species or its designated critical habitat, the Agency wi ll consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services), as appropriate.

2 Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999)
3 Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity (USEPA, 2002)Docket Number EPA

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Page 21 of 63 

## 4.1 Environmental Fate Assessment

Hyd r olysis data are available for BBIT . For all other fate parameters , since BBIT consists of BIT with the addition of a 4

- carbon alip hatic chain and based on the similarity of structures and physical

- chemical properties between BIT and BBIT, environmental fate properties of BBIT are expected to be similar to BIT. Consequently, t h e environmental fate assessment for BBIT is based primarily on data from BIT

. Even though the Agency is not requiring BBIT specific data, registrants may opt to submit BBIT specific data in order to refine the environmental fate
assessment. A summary of the environmental fate data for BIT and BBIT is presented in Table 11.
There were five significant transformation products identified for BIT and each product had an intact benzene ring

. These include:

 Hydroxy

- 1,2

- benzisothiazol

- 3

- one (hydroxylated BIT),

 Sa ccharin (BIT sulfone), and

 B IT

- S

- Oxide (BIT sulfoxide)

 2

- sulfobenzamide ( Ortho

- sulfobenzamide )

 1,2

- benzthiazolin

- 2

- one

Chemical structures of these five products are presented in Appendix B

. Of these five transformation products, three had both intact benzene and isothiazolone rings
, includ ing :

 Hydroxy

- 1,2

- benzisothiazol

- 3

- one (hydroxylated BIT),

 Saccharin (BIT sulfone), and

 B IT

- S

- Oxide (BIT sulfoxide).

BBIT is water soluble and is not likely to volatilize from water

. BBIT and BIT are both stabl e to hydrolysis (MRIDS 44364926 and 47329401 )

.
BIT transforms rapidly by photodegradation in water with half

- lives of 9 hours at pH 5 and 0.7 hours at pH 7 and 9. The photodegradation half

- life was about 1 day for the total of BIT and the
two transformation products with intact benzene ring and isothiazolone rings
, hydroxy BIT and saccharin (MRID 47329402 ).

In the aerobic soil metabolism study, the half

- life of BIT was reported to be l ess than one day (MRID 41199102) , but there is uncertainty about the persi stence and occurrence of the transformation product s , 2

- sulfobenzamide, BIT sulfoxide, and BIT sulfone ( MRID 41199103 )

. BIT was moderately mobile based on Kads values of 1.3

- 12.2 L/kg and Koc values of 254

- 728 L/kg. Sorption was related to clay and organic content ( MRID 41687102 ).Docket Number EPA

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Page 22 of 63 Table 11

– Environmental Fate and Transport Properties of BBIT and BIT
Property (Guideline number) Value Reference (MRID unles s
s pecifi ed)

Comments

Hydrolysis (161

- 1, 835.2120) Stable at 5, 7, and 9 44364926 (BBIT) 47329401 (BIT) Photodegradation in water

(161

- 2, 835.2210) Stable in dark controls

9 hours (pH 5) , 0.7 hours (pH 7 and 9) 47329402 (BIT) Data for BBIT not required Major transformation products Ortho

- sulfobenzamide 1,2

- benzthiazolin

- 2

- one hydroxy

- 1,2

- benzisothiazolin

- 3

- one (hydroxy BIT) Saccharin Aerobic soil metabolism

(162

- 1, 835.4100) Half

- life of <1 day for BIT (observed) 90 % dissipation of BIT by 7

- 28 days and 98

- 99 % dissipation by 60

- 180 days 41199102 and 41199103 (BIT) Data for BBIT not required Ortho

- sul fo benzamide and BIT

S

- oxide were significant transformation products

Leaching

- Adsorption

- Desorption (163

- 1, 835.1230) Kads (Kocs) in L/Kg 2.5 (486) 1.3 (254) 12.2 (728) 2.5 (389) 41687102 (BIT) BIT data is bridgeable to BBIT

Loamy sand Loam Silty clay loam Silt loam Anaerobic aquatic metabolism (162

- 4, 835.4400 Not required (BIT and BBIT) Waived for BIT because of lack of sorption Also waived for BBIT because of structural similarity between BIT and BBIT Aerobic aquatic metabolism (162

- 3, 835.4300) Required (BIT or BBIT) Data on aerobic aquatic metabolism were required in December 2014 Final Work Plan for BIT BIT data is bridgeable to BBIT Activated Sludge Sorption Isotherm (ASSI) Not required (BIT and BBIT) Not required because measured log Kow values for BIT (1.4) and BBIT (2.32) are less than 3 (Table E3) Activated Sludge Respiration Inhibition ( ASRI, 850.6800, OECD 209) For BIT EC 50 = 30 mg/L EC 20 = 11.5 mg/L EC 80 = 79 mg/L. NOEC = 1 (one) mg/L. 47759819 (BIT) BIT data is bridgeable to BBIT

Biodegradation in wastewater treatment plants (835.3110, 835.3220, 835.3240, 835.3280) Required (BIT or BBIT) BIT data is bridgeable to BBITDocket Number EPA

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Page 23 of 63 

### 4.1.1 Water and Sediment

BBIT is water soluble and is not li kely to volatilize from water. BBIT and BIT are both stable to hydrolysis with extrapolated half

- lives of >1 year (MRID s 44364926 and 47329401), but BIT degrades rapidly by photodegradation in water with half

- lives of 9 hours at pH 5 and 0.7 hours at pH 7 and 9. The photodegradation half

- life in water of the sum of BIT and two transformation pr oducts with intact benzene and isothioazol one rings (hydroxy BIT and saccharin) was about 1 day (MRID 47329402).



### 4.1.2 Soil

In the aerobic soil metabolism study, the half

- life of BIT was reported to be less than one day (MRID 41199102). However, there is uncertainty about the persistence and occurrence of the transformation products since the percent formation of 2

- sulfobenzamide, BIT sulfoxide, and BIT sulfone, was only quantified at day 7 and day 28 of a 180

- day study (MRID 41199103 ).
BIT was moderately mobile based on Kads values of 1.3

- 12.2 L/kg an d Koc values of 254

- 728 L/kg. Sorption was related to clay and organic content (MRID 41687102 ).



### 4.1.1 Air

Based on the vapor pressure and Henry’s Law constants for BBIT and BIT in Table 4 and for the BIT transformation p roducts in Table 5, movement from soil or water to air is not expected to be

a significant t ransport process

. 

## 4.2 Water Quality
BBIT is not identified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act. 4 In addition, no Total Maximum Daily Loads (TMDL) have been developed for BBIT. 5 More information on impaired water bodies and TMDLs can be found at the Agency’s website. 6 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 Stan dard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 7 in order to ensure they can be used quantitatively or qualitatively in pesticide risk assessments.



## 4.3 Conceptual Model s for Environmental Exposure Pathways
Based on the summary of registered uses of BBIT presented in Table 5
, physical/chemical properti es of BBIT and BIT in in Table 4
, and environmental fate data presented in Table 11, t he

4 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885
5 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_ group_name=PESTICIDES
6 http://iaspub.epa.gov/waters10/attains_nation_cy.control?p_report_type=T
7 http://www2.epa.gov/pesticide

- reevaluation/opp

- guidance

- submission

- state

- and

- tribal

- water

- quality

- monitoring

dataDocket Number EPA

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Page 24 of 63 Agency has created conceptual models for potential routes of environmental exposure which are included in “Conceptual Models for Environmental Exposure Pathways of Antimicrobial Pesticides” (EPA

- HQ

- OPP

- 2014

- 0638

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

HQ

- OPP

- 2014

- 0638. For metalworking fluids , refer to slide 18

. For paper production, refer to slide 26

. All relevant routes of environmental exposure will be considered in the risk
assessment

. 

## 4.4 Ecological Effects Assessment

4.4.1 Measures of Effect Ecological effects data are used as measures of direct and indirect effects to aquatic and terrestrial organisms. Acute and chronic toxicity data from registrant

- submitted studies conducted in accordance with the 850 O CSPP 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.

4.4.1.1 Data Submitted for BIT
No data have been submitted for BBIT. Data f or BIT are being brid ged to BBIT (see section 4.1). All data requirements and available ecotoxicity endpoints from studies submitted by registrant s are tabulated in Appendix C. Even though the Agency is not requiring BBIT specific data, registrants may opt to submit BBIT specific data in order to refine the ecological
assessment. OPP uses the most sensitive of these endpoints for assessing risk to each terrestrial and aquatic receptor group. The available endpoints selected for the risk assessment are provi ded in Table 13. A data gap exists for algae and cyanobacteria.

Table 12

– 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 1 NOAEC = 0.28 mg ai/L 477598

- 15

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

- 01

Chronic 1 NOAEC = 0.91 mg ai/L 477598

- 14

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

- 01

Chronic Not required --

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

- 01

Chronic Not required

-- Aquatic plants

- A lgae and cyanobacteria TGAI EC 50 NOAEC Data gap --Docket Number EPA

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Page 25 of 63

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

- 01

1 The Agency has adequate chronic fish and invertebrate data for the parent compound; however, if the aerobic aquatic metabolism study shows degradates that persist, chronic fish and invertebrate data are needed for the degradates.

4.4.1.2 Other Data
The ECOTOX databas e will be searched during the risk assessment phase and the data will be reviewed following the A gency’s policy for reviewing public literature for use in assessing risks from pesticides

. Tho se ecotoxicity values found in the public literature to be more s ensitive than those currently in the data and or 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 Environ mental Effects Research Laboratory's Mid

- Continent Ecology Division.



## 4.5 Exposure Analysis Plan

4.5.1 Screening Level Down

- the

- Drain Analysis The Agency will use the General Population and Ecological Exposure from Industrial Releases module of E

- FAST (Exposure and Fate Assessment Screening Tool) to estimate the potential for exposure to aquatic organisms located downstream of industrial wastewater treatment plants

. These aquatic organisms in streams may receive discharges from in

- service use s of products containing BBIT

. The results of th is module of E

- FAST are expressed as number of days of exceedance of concentrations of concern (COC) for aquatic organisms.


## 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicit y. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratio s in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision for BBIT, E PA review ed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA s ection 408(p), BBIT is subject to the endocrine screening part of the Endocrine Disruptor Scree ning Program (EDSP).
EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to i nteract 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 toDocket Number EPA

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Page 26 of 63 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 a nd the E, A, or T effect.
Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingr edients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 8 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.
For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screeni ng battery, please visit our website. 9


## 6 Optional Label Changes

T he Agency invites comment on any label amendments that could be considered to eliminate the anticipated need for EPA to require certain data, reduce the possibility that EPA’s planned risk

asse ssments overestimate risk due to reliance on conservative assumptions, and/or improve label clarity.


## 7 Guidance for Commenters

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



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

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

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of chemicals.
9 http://www2.epa.gov/endocrine

- disruptionDocket Number EPA

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Page 27 of 63 

### 7.1.2 Water Quality

The Agency invites submission of water quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 10 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 justi ce, 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 environm ental 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 BBIT 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 information for non

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

- target plant damage and avian, fish, reptilian, amphibian and mammalian mortalities) not already reported to the Agency 8. Monitoring data

10 http://www2.epa.gov/pesticide

- reevaluation/opp

- guidance

- submission

- state

- and

- tribal

- water

- quality

- monitoring

dataDocket Number EPA

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## 8 Next Steps

After the 60

- day comment period closes in May of 2016 , the Agency will review and respond to any comments received in a timely manner, and then issue a Final Work Plan for the BBIT case

.Docket Number EPA

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## 9 References

MRID 41199102

. Roberts, G. (1989) 1,2, Benzisothiazolin

- 3

- one: Aerobic Degradation in Soil: Study ID: R048/D. Unpublished study prepared by Imperial Chemical Industries PLC. 35 p.

MRID 41199103

. Powell, B. (1989) 1,2

- Benzisothiazolin

- 3

- one (BIT): Identification of Metabolites Formed by Aerobic Degradation in Soil, Report No. D97198B. Unpublished study prepared by Imperial Chemical Indus

- tries Ltd. 48 p.

MRID 41687102. Wilkes, L. (1989) Adsorption/Desorption Study for 1,2

- Benzisothia

- zolin

- 3

- One: Lab Project Number: ADC/PROJECT/#1129. Unpublished study prepared by Analytical Development Corp. 127 p.

MRID 43584001

. Polson, G. (1994) Physical and Chemical Properties of 1,2

- Benzoisothiazol

3(2H)

- One (sic) (BIT): Lab Project Number: 9

- 94B02BIT. Unpublished study prepared by Olin Central Analytical Labs. 94 p.

MRID 44364926. Burt, M. (1997) S123386: Review of Abiotic Degradation

-- Hydro lysis as a Function of pH: Lab Project Number: WILM/MEB/10697: 504624: RD012328B. Unpublished study prepared by Zeneca Biocides. 8 p.
MRID 47329401. Graham, R.; Troth, K. (2007) Hydrolytic Stability: Preventol BIT 85: Final Report. Project Number: 0616/06 4. Unpublished study prepared by Covance Laboratories, Inc. 85 p.
MRID 47329402. Graham, R.; Troth, K. (2007) Photodegradation in Sterile, Aqueous Solution: Preventol BIT 85: Final Report. Project Number: 0616/065, TR/07/019. Unpublished study prepared by Covance Laboratories, Ltd. 119 p.

MRID 47759819. Schaefer, E.; Matthews, M. (2006) 1,2

- Benzisothiazolin

- 3

- One: An Activated Sludge, Respiration Inhibition Test. Project Number: 129E/120, 06RC/088, 129/041806/ASRT/SUB129. Unpublished study prepared by Wildlife International, Ltd. 37p.

MRID 47759821. Stenzel, J.; Schaefer, E. (2007) 1,2

- Benzisothiazolin

- 3

- One: Soil Microorganisms: Nitrogen Transformation Test. Project Number: 129E/119, 06RC/096. Unpublished study prepared by Wildlife International, Ltd. 49 p.

MRID 47759822. Stenzel, J.; Schaefer, E. (2007) 1,2

- Benzisothiazoline

- 3

- One: Soil Microorganisms: Carbon Transformation Test. Project Number: 129E/118, 06RC/097. Unpublished study prepared by Wildlife International, Ltd. 43 p.

MRID 48191702. Roe, B. (2010) Physical and Chemical Characteristics of BIT Technical: Oxidation/Reduction and UV/Visible Absorption. Project Number: 650/140, TC2225. Unpublished study prepared by Case Consulting Laboratories, Inc. 17 p.Docket Number EPA

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Page 30 of 63 US EPA, 1999. Guidance for Identifyin g Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity

. http://www.epa.gov/sites/production/files/2015

- 07/documents/gu ide

- 2

- identify

- pest

- chem_0.pdf

US EPA, 2002. Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Hav e a Common Mechanism of Toxicit y. http://www.epa.gov/sites/production/files/2015

- 07/documents/guidance_on_common_mechanism.pdf

US EPA, 2003. Revised Non

- dietary Exposure/Risk Assessm ent for Dolphin Antimicrobial (N

Butyl

- 1,2

- Benzisothiazolin

- 3 (2H)

– o ne, new a ctive ingredient) during manufacturing and residential consumer use of impregnated plastic products. D286782, D270042, D272198, D272211, D272213, D272215, D272216, D272220, April 14, 2003

US EPA, 200 4

. Occupational Exposure Considerations Regarding DENSIL DG 45 Fungicide Industrial End

- Use Product Registration: Proposed New Use for the active ingredient 1,2

- Benzisothiazolin

- 3

– o ne, 2

- butyl . D2 98317 , April 29 , 200 4

US EPA, 200 9

. Occupational and Residential Exposure and Risk Assessments for the New Uses of 1,2

- Benzisothiazolin

- 3

– o ne, 2

- butyl . D2 98317
, D358428, D358434, June 8 , 200 9.

US EPA, 2015 . 2

- Butyl

- 1, 2

- Benzisothiazolin

- 3 (2H)

- One (BBIT): Dermal and Inhalation MOEs for Machinists Using BBIT Treated Metal Working Fluids in Open Systems. D421679, September 10, 2015.Docket Number EPA

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# Appendix A T oxicology Profile

Acute Toxicity for Product Labelin g
BBIT is Toxicity Category III for both acute oral and acute dermal toxicity. It is Toxicity Category II for inhalation toxicity and Toxicity Category I (Corrosive) for both eye irritation and dermal irritation. BBIT is a dermal sensitizer in female guinea pigs, but not in male guinea pigs.

Table A1

– Acute Toxicity Studies for BBIT

Guideline No. Study Type MRID # Results Toxicity Category 870.1100 purity a.i. (% w/w): 95.5 Acute Oral

– Rat 44364915 LD 50 = 4267 mg/kg (M); 4732 mg/kg (F) III

870.1200 purity a.i. (% w/w): 93.4 Acute Dermal

– Rat 44364916 LD 50 > 2000 mg/kg III

870.1300 purity a.i. (% w/w): 45.2 Acute Inhalation

–

Rat 45083004 LC 50 >0.733 mg/l (M); 0.197

– 0.733 mg/l (F) II

870.2400 Primary Eye

Irritation Waived Corrosive I

870.2500 purity a.i. (% w/w): 93.4 Primary Skin

Irritation

– Rabbit 44364917 Corrosive I

870.2600 purity a.i. (% w/w): 95.5 Dermal Sensitization

Guinea Pig 44364918 Moderate Dermal Sensitizer Not applicable



## Subchronic Toxicity

Adequacy of Database for Subchronic Toxicity: There are two subchronic toxicity studies in the A gency’s hazard database to address subchronic oral toxicity , including a subchronic oral toxicity study in rats ( MRID 44403001 ) and a subchronic oral toxicity study in dogs ( MRID 48262204 )

. A brief summary of the reviewed studies is provided below.

There are no route

- specific subchronic inhalation and dermal toxicity stud ies for BBIT ; these data were bridged from other isothiazolone chemicals whe n the toxicology endpoints were revised recently. T hese studies are not anticipated to be required
, at present, for BBIT registration review risk assessment, based on the currently registered uses . However, s hould new use(s) be added and/or current label s be amended, these studies may be required.Docket Number EPA

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Page 32 of 63 870.3100 90

- Day (13

- Week) Oral Toxicity

– Rat In a subchronic oral toxicity study (MRID 44403001 ) , 1,2

- be nziso

- thiazolin

- 3

- one, 2

- butyl (corrected for 95.5% a.i. purity) was administered to 20 Wistar

- derived Sprague Dawley (Alpk:APfSD) rats/sex/dose each in the feed at concentrations of 0, 40, 200, and 2000 ppm for males and females for 90 days. The mean estimated compound intake in males was 0, 3.1, 15.3, or 149.2 mg/kg/day, respectively, and in females was 0, 3.4, 16.6, or 162.4 mg/kg/day, respectively.

Three males died prior to scheduled termination, one control and two 200 ppm males, but the deaths were not considered treatment

- related. No clinical signs were observed. There were no
treatment

- related neu rotoxic effects or effects on motor activity. There were no treatment

related effects of toxicological significance on body weight, food consumption, or food efficiency. Transient depression of body weight and food consumption in the 2000 ppm males and f emales were attributed to decreased feed palatability and produced an overall body weight gain decrease 12%] at 2000 ppm. There were no treatment

- related effects on ophthalmologic or hematologic endpoints nor were there gross pathologic or organ weight ch anges.
Histopathologic changes indicative of irritative effects on the non

- glandular stomach were ob

serv ed in 20% each of the 2000 ppm male and female animals. These consisted of minimal to slight submucosal inflammation with or without epithelial hyperplasia or erosion; one male had a slight ulcer. No animals in either of the lower dose groups or the control groups showed such changes. These changes were consi dered treatment

- related and adverse.

Under the conditions of this study, the subchronic toxicity LOAEL is 2000 ppm (males: 149.2 mg/kg/day; females: 162.4 mg/kg/day) based on submucosal inflammation of the stomach. The NOAEL for male and female rats is 2 00 ppm (males: 15.3 mg/kg/day; females: 16.6 mg/kg/day).

This subchronic oral toxicity study in rats is classified as Acceptable/Guideline and satisfies the [OPPTS: 870.3100 (§82

- 1)] Subdivision F guideline requirements.

870.31 5 0 90

- Day (13

- Week) Oral T oxicity

– Dog
In a subchronic oral toxicity study (MRID 48262204 ), N

- butyl

- 1,2

- benzisothiazolin

- 3

- one (9 9. 4% a.i.; Lot No. 6180 ) in the vehicle, corn oil, was administered by gelatin capsule , once daily, to four beagle dogs/sex/dose group at doses of 0, 25, 75 or 250 mg/kg/day for at least 90 days. The high dose was reduced to 200 mg/kg/day beginning on Day 1 0 due to one female who was sacrificed in extremis at 2 5 0 mg/kg/day.

No adverse, treatment

- related effects were observed on ophthalmoscopic examinat ions, urinalysis, organ weights or gross or microscopic pathology.
Mortality was observed at high

- dose level. One female was sacrificed in extremis due to abnormal excreta, dermal atonia, emesis, excessive salivation, hypoactivity and thinness. Treatment

- related clinical observations consisted of emesis, diarrhea, soft feces and some mucoid feces in the mid

- and high

- dose males and females. Treatment

- related effects on body weights were observed at high

- dose level in both sexes. Males at this dose actua lly lost weightDocket Number EPA

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Page 33 of 63 (p<0.05) during Weeks 0

- 1 and 0

- 2. Cumulative body weight gains in the males at this dose remained decreased compared to controls throughout the study, and attained statistical significance (p<0.05). Overall (Weeks 0

- 13) body weight gain in high

- dose males was decreased compared to controls. As a result of these decreases, body weights were decreased (non

- significant) in these males throughout the study. Treatment

- related effects in the high

- dose females were limited to decreases (non

- si gnificant) in body weight during Weeks 1 and 2. All other statistically significant differences from controls in body weight or body weight gain were minor, transient, and/or unrelated to dose. Red blood cell parameters (red cell count, hemoglobin, and h ematocrit) were decreased in males and females at both testing intervals ( non

significant ). This change was not dose

- dependent, but the high

- dose groups consistently showed the greatest decrease, while higher platelet counts were found in this dose group. A dose

response decrease in serum albumin and total protein concentrations was observed in the high

dose males and females (p≤0.01). Serum albumin concentration was decreased in the low

- dose males and total protein concentration was decreased (p≤0.05) i n the low

- dose females. Serum calcium, which is predominantly bound to albumin, was also decreased (p<0.01 or NS) in the high

- dose males and females, but the effect in females was only observed during week 7

. Triglycerides were increased or decreased in all treated males, but this effect was not dose

dependent.

The LOAEL is 75 mg/kg/day, based on treatment

- related clinical findings in both sexes and dose

- response decreases in albumin (males) and total protein concentrations (females) . The NOAEL is 2 5 m g/kg/day.
This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3150; OECD 409) for a subchronic oral toxicity study in dogs. 

## Developmental Toxicity

Adequacy of D atabase for Prenatal Developmental Toxicity : The database for prenatal developmental toxicity is considered incomplete. There is one developmental toxicity study in the rat ( MRID 44364920) in the A gency’s hazard database , and a brief summary of the reviewed study is provided below.

N o developmental toxicity study in the rabb it is available for BBIT. The A gency does not believe that a developmental toxicity study in the rabbit for BBIT would provide more conservative data com pared to those of other isothiazolone chemicals. Therefore, a developmental toxicity study in the rabbit is not anticipated to be required for the BBIT registration review
, based on the currently registered uses

. Should new use(s) be added and/or
current labels be amended, a developmental toxicity study in the rabbit may be required.

870.3700 Prenatal Developmental Toxicity (Gavage) Study

– Rat
In a developmental toxicity study (MRID 44364920), 24 presumed pregnant Alpk:AP f SD (Wistar derived) rats per gr oup were administered 1,2

- Benzisothiazolin

- 3

- one, 2

- butyl

- (95.5%; Batch No. JM 5420/80) by gavage in corn oil at doses of 0, 30, 100, or 300 mg/kg/day on gestation days (GD) 7

- 16, inclusive. All doses were adjusted for purity. On GD 22, dams wereDocket Number EPA

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Page 34 of 63 sacrifi ced, subjected to gross necropsy, and all fetuses examined externally, viscerally, and skeletally.

No treatment

- related deaths occurred during the study but several intercurrent deaths due to gavage error were observed. All remaining animals survived to scheduled sacrifice. Treatment

related clinical signs of toxicity among surviving animals were limited to abnormal respiratory noise in 4/24 high

- dose dams on GD 8

- 19 compared with none in the controls or other treated groups.
Body weights, body weight gains, and food consumption by the low

- and mid

- dose groups were similar to the controls throughout the study. Adjusted (based on GD 7) body weights of the high

- dose group were significantly (p  0.05 or 0.01; 96

- 99% of controls) less than that of the controls from GD 8 through GD 19. Body weight gain by the high

- dose group was 82% of the control group level during the dosing interval and reflects slightly (n.s.) lower gravid uterine weights for these dams. Food consumption by t he high

- dose group was 83

- 86% (p  0.01) of that of the controls during the treatment interval.
At the scheduled gross necropsy, ulcerated areas of the stomach were observed in 0, 1, 5, and 16 animals in the control, low

- , mid

- , and high

- dose groups, respe ctively. In addition, the mid

- dose animal which died also had ulcerated areas of the stomach. These lesions were considered to be indicative of local irritation from the test compound. No other treatment

- related lesions were observed in any animal.

The refore, the maternal toxicity LOAEL for the test compound in rats is 100 mg/kg/day based on ulcerated areas of the stomach. The maternal toxicity NOAEL is 30 mg/kg/day.

No treatment

- related differences were observed between the treated and control groups for number of corpora lutea, numbers of implantation and resorption sites, pre

- or post

- implantation losses, gravid uterine weights, fetal body weights, number of fetuses/litter, or fetal sex ratios. No surviving dam had complete litter resorption.

The to tal number of fetuses (litters) examined for external, visceral, and skeletal malformations/ variations was 346(24), 272(22), 273(22), and 298(23) in the 0, 30, 100, and 300 mg/kg/day groups, respectively. No treatment

- related external, visceral, or skele tal malformations/ variations were observed in any group.
Therefore, the developmental toxicity NOAEL for the test compound in rats is  300 mg/kg/day (HDT) and the developmental toxicity LOAEL is not identified.
This study is classified as Acceptable/Guide line and satisfies the requirements for a developmental toxicity study [870.3700 (§83

- 3)] in rats.Docket Number EPA

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Page 35 of 63 

## Reproductive Toxicity

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

- generation reproductive toxicity study f or B BIT (MRID 48261201) in the A gency’s hazard database ; a brief summary of the reviewed study is provided below.

870.3 8 00 Reproduction and Fertility Effects

– Rat

In a two

- generation reproduction toxicit y study (MRID 48261201 ), N

- butyl benzisothiazolin

- 3

- one ( 99.4±1%; Batch # 6180 ) was administered continuously in the diet to 30 Sprague

- Dawley
rats /sex/dose group at dietary levels of 0, 300
, 600 , or 1700 ppm (equivalent to 0/0, 25/27, 49/56, and 141/157 mg/kg /day in males/females, respectively) for two consecutive generations . The P and F 1 generation animals were exposed to the test diets for a minimum of 70 days prior to mating . F 1 offspring selected to be parents of the F 2 generation ( 30 /sex/dose grou p) were fed the same test diet concentrations as their parents beginning on PND 21 . The F2 offspring were terminated after weaning.
All P generation parents survived to scheduled sacrifice. Three F1 adults were found dead or sacrificed during the study; however, none of these mortalities were related to treatment. All other F1 adults survived to scheduled sacrifice.
In the P generation at high

- dose level
, o verall pre

- mating (Weeks 0

- 10) body weight gain was decreased significantly (p<0.05) in the females , but was not significantly different from controls in the males

. Mean P generation maternal body weights, body weight gains, absolute (g/animal/day) and relative (g/kg/day) food consumption, and food efficiency (%) were unaffected by treatment during ges tation.
In the F1 generation at high

- dose level , body weights were decreased significantly throughout the pre

- mating period (Weeks 18

- 28) in the males (p<0.05) and in the females (p<0.01 ). Overall pre

- mating body weight gains were similar to controls at all doses in both sexes. A bsolute food consumption was decreased (p<0.05) during Weeks 18

- 19 (p<0.01 ) through 22

- 23 and 25

- 26 for males and females, respectively. R elative food consumption w as similar to controls for both males and females. F ood effici ency was similar to controls for males throughout the pre

- mating period but increased (p<0.05) during Week 18

- 19 for females

. Mean F1 generation maternal body weights were decreased at high

- dose level during gestation. However, these decreases did not a ttain statistical significance and there were no significant decreases in body weight gains during gestation. These decreases in body weight were considered to be a continuation of the lower mean body weights noted for these females during pre

- mating. Ov erall body weight gains during gestation were similar to controls at all doses. Mean F1 m aternal absolute and relative food consumption and food efficiency were unaffected by treatment during gestation. Overall body weight gains , m ean F1 maternal absolut e and relative food consumption, and food efficiency were unaffected by treatment during lac tation.

No adverse effects of treatment were noted at low

- or mid

- dose level in either generation.Docket Number EPA

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Page 36 of 63 The LOAEL for parental toxicity is 1700 ppm (equivalent to 141/15 7 mg/kg/day in males/females, respectively) based on decreased body weights and food consumption. The NOAEL is 600 ppm (equivalent to 49/56 mg /kg/day in males/females, respectively).
No adverse clinical signs were observed in the F1 or F2 generation pups from birth to PND 21 at any dose. No treatment

- related differences in litter parameters were noted at any dose in either generation. Sexual maturation was unaffected by treatment. There were no treatment

- related effects on gross pathology or histopathol ogy.

At high

- dose level
, b ody weights were decreased (p<0.05) in the F1 generation and the F2 generation on PND 21

. O verall (PND 1

- 21) pup body weight gains were decreased in both males and females of both generations.
In the F2 generation pups, treatment

- related decreases (p<0.05) in absolute and relative (to body) spleen weights were observed in both sexes on PND 21

.
The LOAEL for offspring toxicity is 1700 ppm (equivalent to 141/157 mg/kg/day in males/females, respect ively) based on decreased body weights, body weight gains, and spleen weight (F2 pups only). The NOAEL is 600 ppm (equivalent to 49/56 mg/kg/day in males/females, respectively).

No treatment

- related effects on the mating, fertility, conception/copulation, or gestation indices were observed in either generation. There were no effects of treatment on pre

- coital interval or gestation duration in either generation. No signs of dystocia were noted at any dose. Mean

e strous cycle length s were unaffected by treatment in both generations. No treatment

- related effects were observed on P or F1 generation spermatogenesis endpoints (mean testicular and epididymal sperm numbers, sperm production rate, m otility, progressive motility, and morphol ogy )

.
The LOAEL for reproductive toxicity was not observed . The NOAEL is 1700 ppm (equivalent to 141/157 mg/kg/day in males/females, respectively).
This study is classified as A cceptable/Guideline and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a two

- generation reproduction study in the rat. 

## Chronic Toxicity

Adequacy of D atabase for Chronic Toxicity : There are no c hronic toxicity studies in the A gency’s hazard database for BBIT ; the data were bridged from other isothiazolone chemi cals when the toxicology endpoints were revised recently. T he studies are not anticipated to be required
, at present, for BBIT registration review risk assessment, based on the currently registered uses . However, s hould new use(s) be added and/or current labels be amended, these studies may be required.Docket Number EPA

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Page 37 of 63 

## Carcinogenicity

Adequacy of D atabase for Carcinogenicity : There are no carcinogenicity studies in the A gency’s hazard database for BBIT ; the data were bridged from other isothiazolone chemicals when the toxicology endpoints were revised recently. T he studies are not anticipated to be required
, at present, for BBIT registration review risk assessment, based on the currently registered uses

. However, s hould new use(s) be added and/or current labels be amended, these studies may be required. 

## Mutagenicity

Adequacy of D atabase for M utagenicity : The database for mutagenicity is considered adequate. Several mutagenicity studies have been submitted and found to be acceptable by the A gency. The summaries o f these studies are provided below.

Gene Mutation

870.5300 In Vitro Mammalian Cell Gene Mutation Test
In a mammalian cell gene mutation assay at the TK locus (MRID 44364923), mouse lymphoma L5178Y TK ± cells cultured in vitro were exposed to 1,2

- Benzisothi azolin

- 3

- one, 2

- butyl (BBIT; 95.5% a.i. w/w ; Batch No. Blend JM5420/80) in DMSO in three independent assays. In the first assay cells were exposed at concentrations of 0.2, 0.4, 0.8, 1.6, 3.1 μg/mL in the absence of metabolic activation (S9

- mix) and to co ncentrations of 1.6, 3.1, 6.3, 12.5, 25.0 μg/mL in the presence of S9

- mix. In the second assay cells were exposed to concentrations of 0.1, 0.2, 0.4, 0.8, 1.6 μg/mL without S9

- mix and to concentrations of 3.1, 6.3, 12.5, 25, 50 μg/mL with S9

- mix. In the third assay cells were exposed to concentrations of 0.4, 0.5, 0.6, 0.8, 1.1, 1.5, 2.0 μg/mL without S9

- mix only. The S9

- fraction was obtained from phenobarbital and β

naphthoflavone induced male Sprague

- Dawley rat liver.

BBIT was tested up to cytotoxic co ncentrations. In the first assay in the absence of S9

- mix, the mean mutant frequencies ranged from 2.7 x 10

- 4 to 3.7 x 10

- 4 at concentrations ranging from 0.2 to 1.6 μg/mL compared to the solvent control value of 3.5 x 10

- 4 . In the presence of S9

- mix, th e mean mutant frequencies ranged from 1.1 x 10

- 4 to1.7 x 10

- 4 from the lowest to the highest concentration tested compared to the solvent control value of 1.2 x 10

- 4 . Results from the second and third assays were comparable to those of the first. The mutant frequency of treated cells was not considered significantly increased over the respective solvent control value at any point in this study and no statistical ana lysis was done. The solvent and positive controls induced the appropriate responses. There was no evidence of induced mutant colonies over background.
This study is classified as Acceptable/Guideline . It satisfies the requir ement for FIFRA Test Guidelin e ( OPPTS 870.5300 [ §84

- 2] ) for in vitro mutagenicity (mammalian forward gene mutation) data.Docket Number EPA

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Page 38 of 63 870.5375 In Vitro Mammalian Chromosome Aberration Test

In an i n v itro mammalian cell cytogenetic ( chromosomal aberration ) assay (MRID 44364922), human lymphocyte cultures were cultured for 48 hours, exposed to 1,2

- Benzisothiazolin

- 3

- one, 2

- butyl (BBIT; 95.5% a.i. w/w; Batch No. Blend JM5420/80) in DMSO for three hours and then incubated for an additional 17 or 41 hours. Exposures were as follows: Cell donor 1 (fe male): (68 hour sampling time) nonactivated and activated conditions (S9

- mix): 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25 μg/mL; Cell donor 2 (male): (68 hour sampling time) without S9

- mix: 1, 2, 5, 7.5, 10, 12.5 μg/mL; with S9

- mix: 2, 5, 7.5, 10, 12.5, 15, 17. 5 μg/mL; Cell donor 2: (92 hour sampling time) without S9

- mix: 5, 7.5, 10, 12.5 μg/mL; with S9

- mix: 10, 12.5, 15, 17.5 μg/mL. The S9

- fraction was obtained from phenobarbital/β

- naphthoflavone induced male Sprague

Dawley rat liver.
BBIT was tested up to cy totoxic concentrations. Based on mitotic index determinations, cells from donors 1 and 2 treated at test material concentrations of 2.0, 5.0 and 10.0 without S9

- mix and 2.0, 7.5 and 15.0 μg/mL with S9

- mix were evaluated for chromosomal aberrations at the 68 hour sampling time. Cells from donor 2 treated at 10.0 μg/mL without S9

- mix and at 15.0 μg/mL with S9

- mix were evaluated for chromosomal aberrations at the 92 hour sampling time.
Statistically significant increases in mean percentage of cells with aber rations (primarily breaks and fragments) were observed at 92 hours both in the presence and absence of S9

- mix. BBIT was clastogenic to human lymphocytes in vitro as tested in this study.
This study is classified as Acceptable/Guideline . It satisfies the requirement for FIFRA Test Guideline [OPPTS 870.5375 (§84

- 2) for in vitro cytogenetic mutagenicity data.
Cytogenetics

870.5395 In Vi v o Mammalian Erythrocyte Micronucleus Test

In an in vivo bone marrow micronucleus assay (MRID 443649 24), Charles River CD

- 1 albino mice (10/sex) were treated by oral gavage with N

- Butyl

- 1,2

- benzisothiazolin

- 3

- one ( BBIT; 95.5% a.i. ; Batch No. Blend JM5420/80 ) emulsified in corn oil, at the maximum tolerated doses of 1 250 mg/kg ( males) or 2 000 mg/kg (females)

. Both males and females were sacrificed at both 24 (5/sex) and 48 (5/sex) hours. A cyclophosphamide positive control ( 5 mice/sex) was run concurrently and sacrificed at 24 hours. A vehicle control (corn oil) was also run concurrently with 5 animals/sex sacrificed at both 24 and 48 hours. Bone marrow cells were harvested at 24 and 48 hours post

- treatment from all groups, except the positive control which was harvested only at 24 hours.

The test substance, BBIT , produced no significant increase in the fre quency of bone marrow micronucleated polychromatic erythrocytes at either 24 or 48 hours after treatment. The positive and vehicle controls induced the appropriate response.

B BIT is not considered to be a mutagen under conditions of this study.Docket Number EPA

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Page 39 of 63 This stud y is classified as Acceptable/Guideline and satisfies the requirement for FIFRA Test Guideline § 84

- 2 for in vivo cytogenetic mutagenicity data.
Other Genotoxicity

870.5550 In Vi vo/In Vitro Unscheduled DNA Synthesis (UDS) in Mammalian Cells

In an i n vivo/in vitro unscheduled DNA synthesis (UDS) assay (MRID 44364925) in rat hepatocytes, 1,2

- benzisothiazolin

- 3

- one, 2

- butyl (BBIT; 95.5% a.i. w/w ; Batch No. Blend JM5420/80 ) at doses of 500 and 800 mg/kg, based on the result of a preliminary dose range

fin ding study, was administered to two or three male Alpk:AP SD rats per test group by oral gavage. BBIT was delivered in corn oil at a volume of 10 mL/kg body weight. Hepatocytes were isolated at 2 or 16 hours post

- treatment and cultured for determination of tritiated thymidine incorporation.
No increase in the mean net nuclear grain count or the percentage of cells in repair over the solvent control values was seen at either dose at either harvest time. The solvent and positive control values were approp riate.
The mean net nuclear grain count was below zero for both doses at both treatment times indicating no induction of UDS as tested in this study.
This study was originally classified as an Unacceptable study because no evidence was presented that 800 mg/kg was a limiting upper dose and could be upgraded to acceptable if some evidence of cytotoxicity at 800 mg/kg is available but was not reported or if a higher dose is tested. After revisiting the study report, this study is now classified as Acceptable/Non

guideline . The deficiency cited before was located in section 6.1 Phase I

– Determination of the maximum tolerated dose on page 17 of the study report. Significant histopathological changes to the l ive were observed in the next two higher doses than 800 mg/kg; these two higher doses were considered to be exceeded the maximum tolerated dose (MTD). The animals exposed to 800 mg/kg didn’t show such histopathological changes to the live; therefore, 800 mg/kg was selected as the MTD based on target organ toxicity. 

## Neurotoxicity

870.6200 Neurotoxicity Screening Battery

Adequacy of Database for Neurotoxicity: There are n o neurotoxicity studies in the A gency’s hazard database. In a 90

- day oral (feeding) t oxicity in rats (MRID 44403001), there were no
treatment

- related neurotoxic effects or effects on motor activity observed, in the Functional Observational Battery (FOB) and motor activity conducted. The A gency does not believe that a neurotoxicity screenin g battery study would provide more conservative hazard data compared to the existing database of the entire isothiazolone chemicals group. Therefore, a neurotoxicity screening battery is not anticipated to be required for the BBIT registration review risk
assessment , based on the currently registered use s. Should new use(s) be added and/or current labels be amended, these studies may be required.Docket Number EPA

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Page 40 of 63 

## Immunotoxicity

870.7800 Immunotoxicity Study
Adequacy of Database for Immunotoxicity: There are no immunotoxicity studies in the A gency’s hazard database. The A gency does not believe that an immunotoxicity study would provide more conservative endpoint compared to the existing database of the entire isothiazolone chemicals group. Therefore, the Agency waived the requirement of an immunotoxicity study f or the isothiazolone chemicals group

. 

## Other Toxicological Effects

870.7485 Metabolism and Pharmacokinetics

(1) In a tissue distribution time course study (MRID 48262201 )
, [ 14 C]

- N

- butyl benzisothiazolin

3

- one (radiolabe l l ed at the benzene ring , > 98 % radiochemical purity, batch # SEL/1653) was administered to 30 male Han Wistar rats, by gavage, at a nominal dose level of 5 mg/kg/day for up to 14 days (equivalent nominal radioacti ve dose of 27.03 μCi/kg/ day). Select tissues were measured for radioactive content for up to 60 days after the last admin i s tered dose.
The majority of the administered radioactivity was excreted in the urine and feces. Approximately 87% of the first adm inistered dose and 92% of the 14 th administered daily dose were excreted in the urine within 24 hours of dosing, while approximately 15% of the first and 14 th doses were excreted in the feces within 24 hours post

- dosing.

The tissue distribution of radioa ctivity following oral dosing with [ 14 C]

- N

- butyl benzisothiazolin

- 3

- one was widespread; however, the concentrations in individual tissues were all very low. The highest concentrations of radioactivity were found in the G.I. tract plus contents, skin, blad der, residual carcass, liver and kidneys. High concentrations in the G.I. tract and bladder were attributed to the presence of feces and urine in these organs; and high concentrations in the liver and kidneys can be explained because these organs are the major sites of metabolism and excretion for N

- butyl benzisothiazolin

- 3

- one . High concentrations in the skin and residual carcass (0.440 and 0.201 μg equivalents/g of tissue, respectively) can be explained by lipophilic deposits in these tissues. After te rmination of dosing, the concentrations of radioactivity in the majority of tissues declined rapidly and reached background levels within 7 days. Concentrations of radioactivity in the liver, kidneys, skin, and residual carcass were slower to decline but only those in the skin and residual carcass were measurable by 60 days after last dose. The calculated elimination half

- lives of N

- butyl benzisothiazolin

- 3

- one from the skin and residual carcass were 29.6 and 27.4 days, respectively. There was no evidenc e to suggest persistence of N

- butyl benzisothiazolin

- 3

- one in any of the tissues or organs that were examined.

This tissue distribution time course study in the rat is classified ACCEPTABLE

- GUIDELINE and satisfies the guideline requirement for a Tier 2 m etabolism and pharmacokinetics study [OPPTS 870.7485 ] in the rat.Docket Number EPA

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Page 41 of 63 (2) This summary includes a metabolism study (MRID48349201) and a metabolite identification study (MRID48262203) with N

- butylbenzisothiazolin

- 3

- one.
In a metabolism study (MRID 48349201)
, 14 C

- radiolabelled N

- butyl benzisothiazolin

- 3

- one (>98% a.i., batch # SEL/1653) was administered to male Han Wistar rats (4/dose for pharmacokinetic study, 2/dose for expired air study, 4/dose for excretion balance study, and 20/dose for tissue depletion st udy) via a single oral dose at levels of 5 or 300 mg [ 14 C]

- BBIT/kg. For the metabolite identification study (MRID48262203) , 14 repeated doses of 5 mg [ 14 C]

- BBIT/kg were also given.

Peak concentrations of [ 14 C]

- BBIT were measured in blood of rats 1 hour and 4 hours, respectively, following oral administration of the 5 mg/kg or 300 mg/kg doses. Blood concentrations declined quickly and were below the limits of detection within 48 hours for both doses. The greatest concentrations of radioactivity were see n in the bladder and GI tract within 1 hour and 4 hours post dosing and declined rapidly within 48 hours for both doses. Residual radioactivity 3 days post

- dosing, accounting for 0.3% of the total administered dose, was seen in the lymph nodes, abdominal fat, pancreas, skin, residual carcass, liver, and kidney. The majority of the administered doses were excreted in the urine and feces, negligible amounts were detected in expired air. Overall, tissue distribution and elimination profiles for the 5 mg/kg and 30 mg/kg dose were similar.

Metabolism of [ 14 C]

- BBIT fol lowing oral administration of 5 mg [ 14 C]

- BBIT /kg or 300 mg [ 14 C]

- BBIT /kg in rats is similar and essentially complete with only small amounts of un

metabolized test substance ( <0.5% of administer ed doses) being detected in the urine and feces. Only trace amounts of metabolites were detected in expired air. The predominant urinary metabolites of [ 14 C]

- BBIT were identified as a methyl sulfoxide derivative (Metabolite 5, 26

- 27% of dose), an S

- gluco ronide metabolite (Metabolite 7, 23

- 24% of dose), and a methyl sulfoxide metabolite of BBIT with carbonyl substitution (Metabolite 11, 11

- 18% of dose). These metabolites were also detected in the feces, although at lower and more variable concentrations. Based on the identified metabolites of BBIT, its metabolism is thought to occur via two major routes. Route one involves opening of the isothiazoline ring followed by conjugation of the sulfur atom with glucuronic acid. Route two involves direct oxidation and methylation of the sulfur atom in the isothiazoline rings forming the methyl sulphoxide which then undergoes further oxidation of the N

- alkyl side chain and/or N

- demethylation.

For the 14

- day repeated 5 mg/k g doses study (MRID48262203), urinary metabolite profiles were qualitatively similar between samples collected over 24 hours after the first and final doses and consistent with the single 5 mg/kg dose test results. Same similarity was found for fecal
meta bolite profiles for samples collected over 24 hours after the first and final doses; however, higher amount of parent material and metabolite 6 were observed following repeated dosing.

The metabolism study ( MRID48349201) in the rat is classified as accept able and satisfies the guideline requirement for a metabolism study [OPPTS 870.7485, OECD 417] in rats.
The metabolism study (MRID 48262203) in the rat is classified acceptable and satisfies the guideline requirement for a metabolism study [OPPTS 870.748 5, OECD 417] in rats.Docket Number EPA

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Page 42 of 63 Table A 2

– Toxicity Profile for BBIT

Guideline No./ Study Type MRID No./

Study Classification Dosing and Animal Information Results Subchronic Toxicity 870.3100 90

- day Oral (Rat) MRID 44403001
Acceptable/Guideline Purity 95

. 5 %

2 0 Wistar

- derived Sprague Dawley (Alpk:APfSD) rats/sex/dose
0, 40, 200, and 2000 ppm (♂/♀: 0 /0
, 3.1/3.4, 1 5.3/16.6 , or 149.2/162.4 mg/kg/d ), in feed, for 90 days N OAEL = 200 ppm ( ♂/♀: 15.3/16.6

m /k/d ) LOAEL = 2000 ppm ( ♂/♀: 149.2/162.4 m/k/d ) , based on

su bmucosal inflammation of the stomach

870.3 1 50 90

- day Oral ( Dog ) MRID 48262204

Acceptable/Guideline Purity 9 9.4 %

4 Beagle dogs/ sex/ d o se

0, 25
, 75 , or 250/200 mg /kg/d, gelatin capsule , once daily, for at least 90 days. The high dose was reduced to 200 mg/kg/day beginning on Day 10 due to one female who was sacrificed in extremis at 250 mg/kg/day. NOAEL male = 25 mg/kg/d NOAEL female = 7 5 mg/kg/d , based

on treatment

- related clinical findings in both sexes and dose

- response decreases in albumin (males) and total protein concentrations (females)

Developmental Toxicity 870.3700 Developmental Toxicity (Rat) MRID 44364920

Acceptable/Guideline Purity 95.5 %

2 4 presumed pregnant Alpk:AP f SD (Wistar derived)
rats /dose

0, 3 0, 10 0 , or 300 mg/kg/d, GD 7

– 1 6 NOAEL maternal = 3 0 mg/kg/d LOAEL maternal = 10 0 mg/kg/d
, based on ulcerated areas of the stomach

NOAEL developmental ≥ 30 0 mg/kg/d (highest dose tested [HDT]). LOAEL developmental not established

. Reproduction Toxicity 870.3800 Reproduction MRID 48261201

Acceptable/Guideline Purity 99.4±1%

30 Sprague

- Dawley rats /sex/dose ;
0, 300, 600, or 1700 ppm ( ♂/♀: 0/0, 25/27, 49/56, or 141/157 mg/kg /d), in diet N OAEL parental = 60 0 ppm ( ♂/♀: 49/56 mg/kg/d ) L OAEL parental = 1700 ppm ( ♂/♀: 141/157 mg/kg/d ) , based on decreased body weights and food consumption

NOAEL offspring = 60 0 ppm ( ♂/♀: 49/56 mg/kg/d ) LOAEL parental = 1700 ppm ( ♂/♀: 141/157 mg/kg/d ) , based on decreased body weights, body weight gains, and spleen weight (F2 pups only)

NOAEL reproductive ≥ 1700 ppm ( ♂/♀: 141/157 mg/kg/d ) (HDT); LOAEL reproductive not establishedDocket Number EPA

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Page 43 of 63 Guideline No./ Study Type MRID No./

Study Classification Dosing and Animal Information Results Chronic Toxicity 870.4100 Chronic Toxicity A chronic toxicity study is not available for BBIT

. Carcinogenicity 870.4200 Carcinogenicity A carcinogenicity study is not available for BBIT

. Mutagenicity 870.5300 In vitro Mammalian cell gene mutation test MRID 4 43 6 492 3

Acceptable/Guideline Purity 95.5 %

mouse lymphoma cells (L5178Y TK +/

- )

In the 1 st assay: 0.2 , 0.4, 0.8, 1.6, or 3 .1 μg/mL
,

- S9; 1.6, 3.1, 6.3, 12.5, or 25.0 μg/mL
, + S9;

In the 2 nd assay: 0.1, 0.2 , 0.4, 0.8, or 1.6 μg/mL
,

- S9; 3.1, 6.3, 12.5, 25.0, or 50 μg/mL
, + S9;

In the 3 rd assay: 0.4, 0.5, 0.6, 0.8, 1.1, 1.5, or 2.0 μg/mL
, - S9 Nega tive

870.53 75 In vitro Mammalian cytogenetics ( chromosome aberration ) test MRID 44364922

Acceptable/Guideline Purity 95.5 %

human lymphocyte cultures
Cell donor 1 (♀) (68 hour sampling time): 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25 μg/mL, ±S9;
Cell donor 2 (♂) (68 hour sampling time): 1, 2, 5, 7.5, 10, 12.5 μg/mL,

- S9; 2, 5, 7.5, 10, 12.5, 15, 17.5 μg/mL, +S9;
Cell donor 2 (♂) (92 hour sampling time): 5, 7.5, 10, 12.5 μg/mL,

- S9; 10, 12.5, 15, 17.5 μg/mL, +S9 Posit ive ( ±S9 )

870.539 5 In vivo mammalian Erythrocyte Micronucleus test (mouse) MRID 4436492 4

Acceptable/Guideline Purity 95.5 %

Charles River CD

- 1 albino mice (10/sex)

max. tolerated doses of 125 0 mg/kg (♂) and 20 00 mg/kg (♀) in corn oil, oral gavage; b oth males and females were sacr ificed at NegativeDocket Number EPA

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Page 44 of 63 Guideline No./ Study Type MRID No./

Study Classification Dosing and Animal Information Results

both 24 (5/sex) and 48 (5/sex) hours.

870.5550 ( I n vivo /in vitro ) Unscheduled DNA synthesis MRID 44364925

A cceptable / Nonguideline Purity 9 5.5 %

Rat hepatocyte cells

0, 5 00 , or 80 0 mg/kg in corn oil in a vol. of 10 mL/kg bd wt , 2 (500 mg/kg) or 3 (800 mg/kg) male Alpk:AP SD rats, oral gavage ; h epatocytes were isolated at 2 or 16 hours post

- treatment Negative

Metabolism 870.7485 M etabolism and Pharmacokinetics MRID 48262201

Acceptable/Guideline Purity >98% (radiolabeled)

30 male Han Wistar rats

nominal dose level of 5 mg/kg/day (equivalent nominal radioactive dose of 27.03 μCi/kg/day) , oral gavage, for up to 14 days

. Select tissues were measured for radioactive content for up to 60 days after the last administered dose. A pproximately 87% of the first administered dose and 92% of the 14 th administered daily dose were excreted in the urine within 24 hours of dosing, while approximately 15% of the first and 14 th doses were excreted in the feces within 24 hours post

- dosing.

The highest concentrations of radioactivity were found in the G.I. tract plus contents, skin, bladder, residual carcass, liver and kidneys. After termination of dosing, the concentrations of radioactivity in the majority of tissues declined rapidly and re ached background levels within 7 days. Concentrations of radioactivity in the liver, kidneys, skin, and residual carcass were slower to decline but only those in the skin and residual carcass were measurable by 60 days after last dose. The calculated eli mination half

- lives of BBIT from the skin and residual carcass were 29.6 and 27.4 days, respectively. There was no evidence to suggest persistence of BBIT in any of the tissues or organs that were examined.Docket Number EPA

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Page 45 of 63 Guideline No./ Study Type MRID No./

Study Classification Dosing and Animal Information Results

870.7485 M etabolism and Pharmacokinetics MRID s 48349201 & 48262203

Acceptable/Guideline Purity > 9 8 % (radiolabeled);

Han Wistar male rats ( 4/dose for pharmacokinetic study, 2/dose for expired air study, 4/dose for excretion balance study, and 20/dose for tissue depletion study ) via a single oral dose at levels of 5 or 300 mg [ 14 C]

- BBIT/kg.

For the metabolite identification study (MRID 48262203) , 14 repeated doses of 5 mg [ 14 C]

- BBIT/kg were also given. Peak concentrations of [ 14 C]

- BBIT were measured in blood of rats 1 hour and 4 hours, respectivel y, following oral administration of the 5 mg/kg or 300 mg/kg doses ; then declined quickly and were below the limits of detection within 48 hours for both doses. The greatest concentrations of radioactivity were seen in the bladder and GI tract within 1 ho ur and 4 hours post dosing and declined rapidly within 48 hours for both doses. Residual radioactivity 3 days post

- dosing, accounting for 0.3% of the total administered dose, was seen in the lymph nodes, abdominal fat, pancreas, skin, residual carcass, li ver, and kidney.

The majority of the administered doses were excreted in the urine and feces, negligible amounts were detected in expired air. Overall, tissue distribution and elimination profiles for the 5 mg/kg and 30 mg/kg dose were similar.

The pr edominant urinary metabolites of [ 14 C]

- BBIT were identified as a methyl sulfoxide derivative (Metabolite 5, 26

- 27% of dose), an S

- glucoronide metabolite (Metabolite 7, 23

- 24% of dose), and a methyl sulfoxide metabolite of BBIT with carbonyl substitution (M etabolite 11, 11

- 18% of dose). These metabolites were also detected in the feces, although at lower and more variable concentrations.

U rinary metabolite profiles were qualitatively similar f

or the 14

- day repeated 5 mg/kg doses study (MRID 48262203) . H owever, higher amount of parent material and metabolite 6 were observed following repeated dosing.Docket Number EPA

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Page 46 of 63 Toxicology References for Appendix A

MRID 44364915 Lees, D. (1996) Substance S123386: Acute Oral Toxicity Study in Rats: Lab

Project Number: AR6193: CTL/P/5067. Unpublished study prepared by Central Toxicology Lab. (Zeneca) 91 p.

MRID 44364916 Lees, D. (1996) Substance S123386: Acute Dermal Toxicity Study in the

Rat: Lab Project Number: CTL/P/4992: CR3269. Unpublished study prepared by Central Toxicology Lab. (Zeneca) 41 p.

MRID 44364917 Lees, D. (1996) Substance S123386: Skin Irritation to the Rabbit: Lab

Project Number: CTL/P/4969: EB4412. Unpublished study prepared by Central Toxicology Lab. (Zeneca) 20 p.

MRID 44364918 Lees, D. (1996) Substa nce S123386: Skin Sensitisation to the Guinea Pig:

Lab Project Number: CTL/P/5046: GG6736. Unpublished study prepared by Central Toxicology Lab. (Zeneca) 34 p.

MRID 44364920 Moxon, M.E. (1997) Substance S123386: Developmental Toxicity Study in

the Rat. Ce ntral Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK SK10 4TJ. Report No. CTL/P/5328. Laboratory Study No. RR0714. January 23, 1997. MRID 44364920. Unpublished.

MRID 44364922 Wildgoose, J. (1996) Substance S123386: in vitro cytogenetic assay in

human lymphocytes. Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK, SK10 4TJ. Laboratory Project ID: Report No. CTL/P/5037, Study No. SV0800, July 11, 1996. MRID 44364922. Unpublished

.
MRID 44364923 Clay, P (1996) Substan ce S123386: L5178Y TK± mouse lymphoma

mutation assay. Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK SK10 4TJ. Laboratory Project ID: Report No. CTL/P/5071, Study No. VV0128, July 11, 1996. MRID 44364923. Unpublished.

MRI D 4436492 4 Fox, V., Substanc e S123386: Mouse Bone Marrow Micronucleus Test.

Ce ntral Toxicology Laboratory, Cheshire, UK. Repo rt No. CTL/P/5171. Study No. SM0801. Sept. 19, 1996. MRI D 44364924. Unpublished.

MRID 44364925 Mackay, J.M. (1996) Substance S123386: in viv o rat liver unscheduled

DNA synthesis assay. Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK SK10 4TJ. Laboratory Project ID: Report No. CTL/P/5179, Study No. SR0818, October 11, 1996. MRID 44364925. Unpublished

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Page 47 of 63 MRID 44403001 Rattray , N. J. (1997) Substance S123386: 90 day feeding study in rats

(Dolphin Fungicide). Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK, SK10 UTJ, Report No. CTL/P/5280, February 12, 1997. MRID 44403001. Unpublished.

MRID 45083 004 Rattray, N. (1997) DS 6039: 4

- Hour Acute Inhalation Toxicity Study in

Rats: Lab Project Number: CTL/P/5556: HR2306. Unpublished study prepared by CTL, Inc. 87 p.

MRID 48261201 Stump, D.G. (2007) A dietary two

- generation reproductive toxicity study of

N

- butyl benzisothiazolin

- 3

- one in rats. WIL Research Laboratories, LLC, Ashland, OH . Laboratory Study No. : WIL

- 544004
, April 16, 2007 . MRID 48261201 . Unpublished.

MRID 48262201 Smith, A.D. (2006) N

- butyl benzisothiazolin

- 3

- one: Repeat dose study in

the rat (metabolism and pharmacokinetics)

. Syngenta Limited (CTL), Cheshire, UK

. Laboratory Project ID: Syngenta Number CO04375rl,Report ID: UR0884

- REG
, October 6, 2006

. MRID 48262201 . Unpublished

.
MRID 48262203 Wake, A. (2006). N

- Butyl Benzisothiazolin

- 3

- One : Metabolite

Identification Work. Syngenta Limited (CTL). Laboratory Project ID: CO04375r1, Report ID: UR0869

- REG, November 23, 2006. MRID 48262203. Unpublished.

MRID 48262204 Mertens, J. ( 2007 )

. A 90

- day oral (capsule) toxicity study of N

- Butyl

Benzisothiazolin

- 3

- One in beagle dogs. WIL Research Laboratories , LLC, Ashland , OH. Laboratory Study No.: WIL

- 544002
, 19 February 2007

. MRID 48262204 . Unpublished.

MRID 48349201 Smith, A.D. (2006). N

- Butyl Benzisothiazolin

- 3

- One: Absorption,

Distribu tion, Metabolism and Excretion in the Rat. Syngenta Limited (CTL). Laboratory Project ID: CO04375r1, Report ID: UR0868

- REG, October 6, 2006. MRID 48349201. Unpublished

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Page 48 of 63 

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of Butyl BIT (N

butyl

- 1,2

- Benzisothazolin

- 3

- one ( B BIT) and its Transformation Products

Water and Sediment
Hydrolysis

B utyl BIT (BBIT) is hydrolytically stable for 6 days with an expected half

- life of >1 year under abiotic and buffered conditions at pH 5, 7, and 9 and 50 o C. Based on these results, BBIT is expected to be stable at 25 o C (MRID 44364926). The related compound, BIT, was also stable at 25 o C at pH 5, 7, and 9 (M RID s 41199 1 01, 4418210 1 ).
Aqueous Photolysis
In aqueous ph oto lysis, BIT degraded at pH 5 with a half

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

- life was 0.7 hours. Six photodegradation products were identified , including two transformation products with an intact benzene ring and an intact isothiazolone ring. These two transformation products with two (2) intact rings were h ydroxy

- 1,2

- benzisothiazol

- 3

- one (hydroxylated BIT) and saccharin (BIT sulfone). The half

- lives for the sum of parent BIT and these two transformation products with two intact ring structures were all about 1 day at pH 5, 4.9 days at pH 7, and 9.8 days at pH 9 , but residues were present until the end of the study (30 days)

.
The 2

- sulfobenzamide molecule (ortho sulfobenzamide) , which contains an intact benzene ring but not an intact isothiazolone rin g, reached maximum concentrations of 22.7 % at pH 5, 53 % at pH 7, and 37 % at pH 9 by the end of the study. The transformation product, 1 ,2

- benzthiazolin

2

- one contained an intact benzene ring and a rearranged isothiazolone ring, and reached 50 % of BIT by the end of the study at pH 5. However, 1,2

- benzthiazolin

- 2

- one did not reach significant concentrations at pH 7 and 9 ( MRID 47329402).
Data on photodegra da tion of BBIT in water are not anticipated to be required because the additional 4

- carbon side cha in is not likely to affect the rate of photodegradation.

Octanol

- Water Partition Coefficient and Bioconcentration in Aquatic Organisms

The measured value s of log K ow are 2.32 (unitless) for BBIT and 1.4 (unitless) for BIT (Table 4) and the estimated value s for the transformation products in Table E3 range from

- 3.16

- 1.76. Based on these log Kow values
, which are lower than a log K ow of 3
, indicating low potential for bioconcentration, BBIT, BIT and the transformation products are not likely to beDocket Number EPA

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Page 49 of 63 bioaccumulative in aquatic species , and b ioconcentration data are not anticipated to be required for BIT or BBIT

. Aerobic Aquatic Metabolism
Data were required for BIT in the Final Work Plan (December, 2014) . Ae robic aquatic metabolism data may be generat ed for either compound and bridging is appropriate based on the similarity in chemical structure

.
A na erobic Aquatic Metabolism
For BIT, data on anaerobic aquatic meta bolism were not required because of the r elatively low sorption of BIT to soil and sediment. For BBIT, these data are also not required based on the structural similarity between BIT and BBIT.

Soil
Soil Leaching/Adsorption/Desorption Batch Equilibrium
A leaching

- adsorption

- desorption study for BIT demonstrated K d values of 1. 24

- 9.56 L/kg and K oc values of 235

- 566 L/kg
, and based on the K oc values and FAO classification system 11 , B IT is considered to be moderately mobile i n soil (MRID 41687102). For BBIT, these data are also not required based on the structural simi larity between BIT and BBIT.

Aerobic Soil Metabolism
In the aerobic soil metabolism study, the half

- life of BIT was reported to be less than one day (MRID 41199102). However, there is uncertainty about the persistence and occurrence of the transformati on products since the percent formation of 2

- sulfobenzamide, BIT sulfoxide, and BIT sulfone, was only quantified at day 7 and day 28 of a 180

- day study (MRID 41199103 ). Two major metabolites were identified ; 2

- sulfobenzamide (ortho sulfobenzamide) and BIT

- S

oxide ( also known as BIT sulfoxide)

. Aerobic soil metabolism data are not anticipated to be required for BBIT because of the structural similarity between BIT and BBIT.
Fate and Transport in WWTP
Activated Sludge Sorption Isotherm

The measured value s of log K ow are 2.32 (unitless) for BBIT and 1.4 (unitless) for BIT (Table 4) and the estimated values for the transformation products in Table E3 range from

- 3.16

- 1.76. Based on these log K ow values, which are lower than a log K ow of 3
, indicating low potential for sorption to activated sludge, BBIT, BIT and the transformation products are not expected to be likely to sorb to activated sludge. Therefore, an activated sludge sorption isotherm (ASSI) study for BBIT is not required.

11 http://www.fao.org/docrep/003/x2570e/x2570e06.htmDocket Number EPA

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Page 50 of 63 Activated Sludge Respiration Inhibition
For BIT, the IC 50 was 30 mg/L and the IC 50 for the reference substance, 3,5

- dichlorophenol, was 12 mg/L (MRID 47759819) . ASRI data are not required for BBIT because of the structural similarity between BIT and BBIT.
Activated Sludge Biodegradation

Data on bio degr adation in activated sludge were required for BIT in the December 2014 Final Work Plan . Biodegradation data may be gen erated for either BIT or BBIT, and b ridging from BIT is appropriate based on the similar ity in chemical structure.

A number of transformation products have been identified and characterized for the parent BIT. Similar transformation products would be expected for BBIT.

The transformation products of BIT from photo degradation in water and aerobic soil metabolism studies include :

BIT (1,2

- benzisothiazol

- 3(2H)

- one)

2

- sulfobenzamide (orthosulfobenzamide)

1,2

- benzthiazolin

- 2

- oneDocket Number EPA

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Page 51 of 63 Hydroxy

- 1,2

- benzisothiazol

- 3

- one

Saccharin (1,2

- benzisothiazolin

- 3

- one

- 1,1

- dioxide)

BIT

- S

- Oxide
Table B1 below presents the environmental fate and transport properties of BBIT and BIT.

Table B1 . Environmental Fate and Transport Properties of BBIT and BIT

Property (Guideline number) Value Reference (MRID unles s
s pecified)

Comments

Hydrolysis (161

- 1, 835.2120) Stable at 5, 7, and 9 44364926 (BBIT) 47329401 (BIT) Photodegradation in water

(161

- 2, 835.2210) Stable in dark controls

9 hours (pH 5) , 0.7 hours (pH 7 and 9) 47329402 (BIT) Data for BBIT not required Major transformation products Ortho

- sulfobenzamide 1,2

- benzthiazolin

- 2

- one hydroxy

- 1,2

- benzisothiazolin

- 3

- one (hydroxy BIT) SaccharinDocket Number EPA

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Page 52 of 63 Aerobic soil metabolism

(162

- 1, 835.4100) Half

- life of <1 day for BIT (observed) 90 % dissipation of BIT by 7

- 28 days and 98

- 99 % dissipation by 60

- 180 days 41199102 and 41199103 (BIT) Data for BBIT not required Ortho

- sul fo benzamide and BIT

S

- oxide were significant transformation products

Leaching

- Adsorption

- Desorption (163

- 1, 835.1230)

Kads (Kocs) in L/Kg 2.5 (486) 1.3 (254) 12.2 (728) 2.5 (389) 41687102 (BIT) BIT data is bridgeable to BBIT

Loamy sand Loam Silty clay loam Silt loam

Anaerobic aquatic metabolism (162

- 4, 835.4400 Not required (BIT and BBIT) Waived for BIT because of lack of sorption Also waived for BBIT because of structural similarity between BIT and BBIT Aerobic aquatic metabolism (162

- 3, 835.4300) 12 Required (BIT or BBIT) Data on aerobic aquatic metabolism were required in December 2014 Final Work Plan for BIT BIT data is bridgeable to BBIT Activated Sludge Sorption Isotherm (ASSI) Not required (BIT and BBIT) Not required because measured log Kow values for BIT (1.4) and BBIT (2.32) are less than 3 (Table E3) Activated Sludge Respiration Inhibition ( ASRI, 850.6800, OECD 209) 13 For BIT EC 50 = 30 mg/L EC 20 = 11.5 mg/L EC 80 = 79 mg/L. NOEC = 1 (one) mg/L. 47759819 (BIT) BIT data is bridgeable to BBIT

Biodegradation in wastewater treatment plants (835.3110, 835.3220, 835.3240, 835.3280) 12 Required (BIT or BBIT) BIT data is bridgeable to BBIT

12 Biodegradation or Aerobic aquatic metabolism data may be generated for either compound and bridging is appropriate based on the similarity in chemic al structure.
13 For BIT, based on an ASRI value of 30 mg/L (>20 mg/L), the registrant must conduct either: (i) Ready Biodegradability or (ii) a) Biodegradation in Activated Sludge or b) Simulation Test

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

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

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Page 53 of 63 Environmental Fate References for Appendix B
MRID 41199102. Roberts, G. (1989) 1,2, Benzisothiazolin

- 3

- one: Aerobic Degradation in Soil: Study ID: R048/D. Unpublished study prepared by Imperial Chemical Industries PLC. 35 p.
MRID 41199103. Powell, B. (1989) 1,2

- Benzisothiazolin

- 3

- one (BIT): Identification of Metabolites Formed by Aerobic Degradation in Soil, Report No. D97198B. Unpublished study prepared by Imperial Chemical Indus

- tries Ltd. 48 p.

MRID 41687102. Wilkes, L. (1989) Adsorption/Desorption Study for 1,2

- Benzisothia

- zolin

- 3

- One: Lab Project Number: ADC/PROJECT/#1129. Unpublished study prepared by Analytical Develop ment Corp. 127 p.

MRID 44364926. Burt, M. (1997) S123386: Review of Abiotic Degradation

-- Hydrolysis as a Function of pH: Lab Project Number: WILM/MEB/10697: 504624: RD012328B. Unpublished study prepared by Zeneca Biocides. 8 p.

MRID 47329401. Graham, R.; Troth, K. (2007) Hydrolytic Stability: Preventol BIT 85: Final Report. Project Number: 0616/064. Unpublished study prepared by Covance Laboratories, Inc. 85 p.

MRID 47329402. Graham, R.; Troth, K. (2007) Photodegradation in Sterile, Aqueous Solution: Preventol BIT 85: Final Report. Project Number: 0616/065, TR/07/019. Unpublished study prepared by Covance Laboratories, Ltd. 119 p.

MRID 47759819. Schaefer, E.; Matthews, M. (2006) 1,2

- Benzisothiazolin

- 3

- One: An Activated Sludge, Respiration Inhibition Test. Project Number: 129E/120, 06RC/088, 129/041806/ASRT/SUB129. Unpublished study prepared by Wildlife International, Ltd. 37p.

MRID 47759821. Stenzel, J.; Schaefer, E. (2007) 1,2

- Benzisothiazolin

- 3

- One: Soil Microorganisms: Nitrogen Transformation Te st. Project Number: 129E/119, 06RC/096. Unpublished study prepared by Wildlife International, Ltd. 49 p.

MRID 47759822. Stenzel, J.; Schaefer, E. (2007) 1,2

- Benzisothiazoline

- 3

- One: Soil Microorganisms: Carbon Transformation Test. Project Number: 129E/11 8, 06RC/097. Unpublished study prepared by Wildlife International, Ltd. 43 p.Docket Number EPA

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Page 54 of 63 

# Appendix C Ecotoxicology Profile

As indicated in sections 4.1 and 4.3, data from BIT are being bridged to BBIT and will be used for the risk assessment.


### Toxicity to Terrestrial 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.

Avian Acute

- oral and Dietary Toxicity

Test Species Test Material (% ai) Toxicity Toxicity Category MR 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 acu te toxicity testing is satisfied.Docket Number EPA

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Page 55 of 63 Acute Toxicity to Freshwater Fish

Test Species Test Material

(% ai) Toxicity Endpoint

(mg ai/L) Toxicity

Category MR 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

Three 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 MR 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 on the parent are needed for freshwater organisms (850.1300, 850. 1400)

. However, once degradates have been identified in the Aerobic Aquatic Metabolism study (835.4300), any significant degradates that persist for more than one week may trigger the need for both of these chronic
tests.Docket Number EPA

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Page 56 of 63 Chronic Toxicity to Freshwater Organisms
Species Test material

(% ai) Toxicity

(mg ai/L or kg) Endpoint 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

. Acute Toxicity to Estuarine/Marine Invertebrates

Test Species Test Material (% ai) Toxicity Endpoint

(mg ai/L) Toxicity

Category MR 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 57 of 63 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 ac ute: chronic ratio (ACR) from the freshwater species and the acute data to extrapolate the chronic NOAECs for the estuarine/marine organisms if values are needed for risk assessment.
Aquatic Plants

No data are available. To support the active ingredient
, one green algae ( Selenastrum capricornutum ) study (850.4500) is required for this use pattern. If the EC 50 of BBIT is less than 1.0 mg/L, studies are also required on three additional species ( Anabaena flos

- aquae ( 850.4550 )
, Navicula pelliculosa (850.450 0) , and Skeletonema costatum (850.4500) ).

Benthic Organisms

Based on environmenta l fate properties ( K d <50 L/kg, K oc <1000 , log K ow <3 ), sediment toxicity testing (850.1735, 850.1740) is not needed

. 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

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

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

Tro ut Salmo gairdneri : Lab Project Number: BL/B/1986. Unpublished study prepared by ICI Brixham Laboratory. 22 p.

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

- Static:

Acticide BIT: Lab Project Number: 98702TS: FAR5999 1: FAR5999

- . Unpublished study prepared by Dr U. Noack Laboratorium Fuer Angewandte Biologie. 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: X06 0/B. Unpublished study prepared by Zeneca Ltd.'s Brixham Environmental Lab. 20 p.Docket Number EPA

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Page 58 of 63 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 Biologie. 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, Brixham 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 Environmental Lab. 20 p.

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

Larvae of the Pacific Oyster ( Crassostrea gi gas ): Lab Project Number: BL4917/B. Unpublished study prepared by Brixham Environmental Lab, ZENECA Limited. 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/084. Unpublished study prepared by Wildlife International, Ltd. 60 p.

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. Project 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 with 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. Unpublish ed 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 Wildlife 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 59 of 63 

# Appendix D Screening Level Down

- the

Drain Analysis

No Down

- the

- Drain (DtD) anal ysis was performed for this PWP

.Docket Number EPA

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Page 60 of 63 

# Appendix E Product Chemistry

The chemical and physical property information for BBIT are summarized in Table E1, and for BIT are summarized in Table E 2

. Table E3 contains the chemical and physical properties of the BIT transformation products.

Table E1

– Physical

- Chemical Properties for BBIT

Guideline No./ Study Type Results Reference

Ch emical s tructure None

Smiles code O=C(N(CCCC)Sc1cccc2)c12 None

Molecular formula C 11 H13N1O1S1 N/A
Molecular weight (g/mol) 207.29 None
Water Solubility(mg/L) 418 EPI

- Suite 4.11

830.7050 UV visible sorption Absorption from 290

- 350 nm MRID 48191702 Value f or BIT

830.7370 Dissociation constant Acid dissociation constant 9.12 x 10

- 8 moles/L (PAI) pKa 7.04 at 25 o C MRID 43584001 Value for BIT

830.7550 Partition coefficient 2.32 EPI

- Suite 4.11

830.7950 Vapor pressure (mm Hg) 9.9 7 x 10

- 6 EPI

- Suite 4.11

Henry’s Law Constant (calculated) Atm m 3 mol

- 1 6.5 x 10

- 9 EPI

- Suite 4.11

atm

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

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Page 61 of 63 Table E2

– Physical

- Chemical Properties for BIT

Guideline No./ Study Type Results Reference (MRID)

Chemical structure None

Smiles code O=C(NSc1cccc2)c12 None

Molecular formula C 7 H 5 N 1 O 1 S 1 None
Molecular weight (g/mol) 151.19 None

Water Solubility(mg/L) 1
, 118 ppm at 20 o C 1
, 380 ppm at 24 o C 43584001

830.7050 UV visible sorption Absorption from 290

- 350 nm 48191702

830.7370 Dissociation constant Acid dissociation constant 9.12 x 10

- 8 moles/L (PAI) pKa 7.04 at 25 o C 43584001

830.7550 Partition coefficient (log Kow) 1.4 (PAI) 43584001

830.7950 Vapor pressure (mm Hg) 1.14 x 10

- 6 mm Hg at 25 o C 43584001

Henry’s Law Constant (calculated) Atm m 3 mol

- 1 1.64 x 10

- 10 None (1.14 x 10

- 6 * 151.19)/(760 *1,380)

atm

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

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Page 62 of 63 Table E3

– Physical

- Chemical Properties BIT Transformation Products from EPI

- WEB 4.11

Guideline No./ Study Type Compound

Hydroxy

- 1,2

- benzisothiazol

- 3

- one 1,2

- benzothiazolin

2

- one 2

- sulfobenzamide Saccharin (1,2

- benzisothiazoli

- 3

- one - 1,1

- dioxide) Bit

- S

- Oxide 1,2

- benzisothiazoli

- 3

- one - 1

- oxide)

Chemical
structure

Smiles code O=C(NSc1ccc(O)c2)c

12 1cc(NC(=O)S2)c2cc 1 c1c(C(=O)N)c(S(=O)(=O)(O))c

cc1 O=C(NS(=O)(=O)c1cccc2) c12 O=C(NS(=O)c1cccc2)c 12 Molecular formula C 7 H 5 N 1 O 2 S 1 C 7 H 5 N 1 O 1 S 1 C 7 H 7 N 1 O 4 S 1 C 7 H 5 N 1 O 3 S 1 C 7 H 5 N 1 O 2 S 1

Molecular weight (g/mol) 167.18 151.18 201.20 183.18 167.18

Water Solubility(mg/ L) 1.77 x 10 5 2,354 1 x 10 6 789 27,400

830.7050 UV visible sorption No data but expected

to be similar to parent BIT No data but expected to be similar to parent BIT No data but expected to be

similar to parent BIT No data but expected to be similar to parent BIT No data but expected to be similar to parent BIT 830.7370 Dissociation
constant No data No data No data No data No data

830.7550 Partition coefficient 0.16 1.76

- 3.16 0.91 0.43

830.7950 Vapor pressure (mm Hg) at 25

o C 3.96 x 10

- 7 5.41 x 10

- 6 4.95 x 10

- 10 1.03 x 10

- 7 1.45 x 10

- 6Docket Number EPA

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Page 63 of 63 Guideline No./ Study Type Compound

Hydroxy

- 1,2

- benzisothiazol

- 3

- one 1,2

- benzothiazolin

2

- one 2

- sulfobenzamide Saccharin (1,2

- benzisothiazoli

- 3

- one - 1,1

- dioxide) Bit

- S

- Oxide 1,2

- benzisothiazoli

- 3

- one - 1

- oxide) Henry’s Law Constant (calculated) Atm m 3 mol

- 1 4.92 x 10

- 13 4.57 x 10

- 10 1.31 x 10

- 16 3.15 x 10

- 11 1.16 x 10

- 11

atm

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

References for Appendix E.

U.S. EPA. 2012. EPI

- WEB 4.11. http://www.epa.gov/tsca

- screening

- tools/download

- epi

- suitetm

- estimation

- program

- interface

- v411
MRID 43584001. Polson, G. (1994) Physical and Chemical Properties of 1,2

- Benzoisothiazol

- 3(2H)

- One (sic) (BIT): Lab Project Number: 9

- 94B02BIT. Unpublished study prepared by Olin Central Analytical Labs. 94 p.
MRID 48191702. Roe, B. (2010) Physical and Chemical Characteristics of BIT Technical: Oxidation/Reduction and UV/Visible Absorption. Project Number: 650/140, TC2225. Unpublished study prepared by Case Consulting Laboratories, Inc. 17 p.