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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 Rickard

Risk Management

Rachel Ricciardi

Rose Kyprianou 

Julie Chao

Office of General Counsel

Philip Ross 
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TERMS, ABBREVIATIONS AND SYMBOLS

AD Antimicrobials Division

A.I. or a.i. active ingredient

aPAD acute population adjusted dose 

ASRI activated sludge respiration inhibition

atm-m3/mole atmospheric pressure-cubic meter per mole

BCF bioconcentration factor 

BBIT 1,2-Benzisothiazol-3(2H)-one, 2-butyl

°C degrees Celsius

CAS Chemical Abstracts Service 

CFR Code of Federal Regulations 

CHO Chinese hamster ovary

CMA Chemical Manufacturers Association

CO2 carbon dioxide

COC concentration-of-concern

cPAD chronic population adjusted dose 

DCI data call-in

EC50 median (or 50 percent) effect concentration

EC05 5 percent effect concentration

ECOTOX ECOTOXicology

EDI estimated daily intake

EDSP Endocrine Disruptor Screening Program 

E-FAST Exposure and Fate Assessment Screening Tool

EPI Suite Estimation Program Interface Suite

EPA Environmental Protection Agency

ET Extrathoracic

FDA Food and Drug Administration 

FFDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act 

FWP Final Work Plan

g/mol grams per mole

GLN guideline number

GSD Geometric Standard Deviation

HEC Human Equivalent Concentration

HPV high production volume

IDS Incident Data System 

Koc organic carbon normalized soil-water partition coefficient

Kd soil-water partition coefficient

Kow octanol-water partition coefficient

LC50 median (or 50 percent) lethal concentration

LD50 median (or 50 percent) lethal dose

LOAEC lowest-observed-adverse-effect-concentration 

LOEC lowest-observed-effect-concentration

LOAEL lowest-observed-adverse-effect-level

Log Kow logarithm of the octanol-water partition coefficient

μg microgram

ml/g milliliter per gram

mg/kg milligram per kilogram
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mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury

MMAD Mass Median Aerodynamic Diameter

MOE margin of exposure 

MRID Master Record Identification Number

MRL maximum residue limit 

N/A not applicable 

nm nanometers

NOAEC no-observed-adverse-effect-concentration

NOAEL no-observed-adverse-effect-level

OCSPP Office of Chemical Safety and Pollution Prevention

OECD Organization for Economic Co-operation and Development

OPP Office of Pesticide Programs

PAD population adjusted dose

PAI pure active ingredient

PDM Probabilistic Dilution Model

% percent

PC Code Pesticide Chemical Code

PCF pounds per cubic foot

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

PHED Pesticide Handler’s Exposure Data

PIS primary irritation score

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

dissociation constant of a solution

ppb parts per billion 

ppm parts per million

PWP Preliminary Work Plan

QSAR quantitative structure-activity relationship

RED Reregistration Eligibility Decision

RDDR Regional Dose Deposition Ratio

SAR structure activity relationship

SF safety factor

SSTS Section Seven Tracking System

TEP typical end-use product

TGAI technical grade active ingredient

TMDL total maximum daily loads

UF uncertainty factor

UV/VIS ultraviolet/visible light absorption

% w/w percent weight per weight.

WP wettable powder

WWTPs wastewater treatment plants
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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 Ecological ............................................................................................................... 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 Occupational 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............................................................................................................................. 28
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9 References............................................................................................................................. 29

Appendix A Toxicology 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

Table 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 – Available Ecological Effects Endpoints..................................................................... 24
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1 Introduction

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

Agency”) Preliminary Work Plan (PWP) for 1,2-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 moves 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 continue to meet the statutory standard of no unreasonable 

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

pesticide use practices will occur over time. Through the registration review program, the 

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

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

http://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 CFR 155.40. The Agency

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

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

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

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

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

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

case. 
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1.2 Case Overview

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

number EPA-HQ-OPP-2015-0736. Documents associated with this registration review can be 

viewed in this docket. Tables 1 and 2 below summarize 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 details)

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

Residential 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, microbiocide/microbiostat, and fungicide/fungistat in 

metalworking 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 Preliminary Work Plan 2016-03 2016-03

Close Public Comment Period 2016-05

Phase 2: Case Development 

Issue Final Work Plan 2016-09
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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 Proposed 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 environmental behavior characteristics in 

common. In the absence of existing data, EPA is choosing to bridge data between compounds in 

this class. Table 4 compares some of the chemical and physical properties of BBIT and the active 

ingredient, 1,2-Benzisothiazol-3(2H)-one (BIT, PC Code 098901). Additional chemical 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 C11H13NOS

Molecular Weight (grams/mole) 207.29

Molecular Structure
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The physical and chemical 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 oC 1,380 mg/L at 24 oC

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 oC (BIT)

Acid dissociation constant 9.12 x 10-8

moles/L (PAI)

pKa 7.04 at 25 oC (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 m3 mol-1

6.5 x 10-9

1.64 x 10-10

atm-m3/mol = atmosphere cubic meter per mole; oC = 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 molding machine. In addition to melt processed polymers (PVC, 

 

1 EPA Reg. Nos. 1258-1249, 1258-1251, 1258-1285, and 1258-1286. 
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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 polyurethane, 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 chain 

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 include 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 drinking water contact items or children’s toys.”

1.4.3 Usage Information

Production volume data in the 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 still in progress.

1.5 Regulatory History

The first product containing BBIT chemical as an active ingredient was registered in the United 

States in April of 2003. This registration was supported by a human health risk assessment (US 

EPA, 2003) that evaluated occupational and residential exposures involved in treating plastic 

materials. Additional assessments were done to evaluate proposed uses in metalworking fluids 

(US EPA, 2004), and construction materials and coatings including wood coatings and stains 

(US EPA, 2009). The most recent human health risk assessment for BBIT (US EPA, 2015) 

evaluated a proposed label amendment for the metalworking fluid use to eliminate the 

requirement for the use only in enclosed machines with local exhaust ventilation. Due to

inhalation 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.
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A Reregistration Eligibility Decision (RED) was not completed for BBIT because it was 

registered 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 reported 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 Incident Data System as of November 24, 2015.

2 Anticipated Data Needs

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

review.
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Table 6 – Studies Anticipated as Needed for the Registration Review of BBIT

GLN Study Name Test 

Substance

Time 

Frame1

Risk Assessment(s) 

Data Will Support

Use Site(s) Triggering 

Anticipated Data 

Requirement

Applicable 

Exposure Scenario

835.3110, 

835.3220, 

835.3240, 

835.32802,3 

WWTP 

biodegradation 

studies 

TGAI (BBIT 

or BIT) 12 Aquatic exposure Metalworking fluids, paper production

Ecological

Drinking Water

835.43003 Aerobic aquatic 

metabolism

TGAI (BBIT

or BIT)

24 Aquatic exposure Metalworking fluids Ecological

Drinking Water

850.45004 Algal toxicity TGAI 12 Aquatic plants All Ecological

850.45504 Cyanobacteria TGAI 12 Aquatic plants All Ecological

850.1400 Fish, Early Life -

Stage Degradates5 24 Aquatic animals Metalworking fluids, paper production Ecological

850.1300

Aquatic 

Invertebrate Life 

Cycle

Degradates5 24 Aquatic animals Metalworking fluids, 

paper production Ecological

875.1200 Dermal Exposure -

Indoor TEP 24 Human Health Paints and Coatings

Open Pour Liquids, 

Airless Spray and 

Brush/Roller Paint 

Application

875.1400 Inhalation 

Exposure - Indoor TEP 24 Human Health Paints and Coatings

Open Pour Liquids

Airless Spray and 

Brush/Roller Paint 

Application

875.23006

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 An 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 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) Simulation Test - Aerobic Sewage Treatment: A. Activated Sludge Units, 

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) data are required for this use pattern. If the EC50 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 guideline 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 metabolism 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.
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3 Human Health Risk Assessment

The Agency anticipates 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 isothiazolone chemicals group, the Agency 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 recommends 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, based 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 Agency recently revised the existing toxicological endpoints for the entire 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 endpoints. As a result, the Agency does not 

anticipate the need to revise the current toxicology endpoints for BBIT, as part of the registration 

review. The current toxicological endpoints for BBIT are shown in Table 7 below.

When revising the existing toxicological endpoints for the isothiazolone chemicals group, the 

Agency concluded, when appropriate, that the default 10x uncertainty factors (UF) be reduced to 

3x, i.e., remove the toxicokinetic component of the UF (3x 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 Agency also recommended that additional 

uncertainty factors may be used to account for (1) database uncertainty, (2) adjustment of 

exposure durations, and/or (3) use of a lowest-observed-adverse-effect-level (LOAEL) for the 

point of departure (POD). This decision applies to all of the isothiazolone chemicals.

No 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 chronic 

dietary exposure. The UF is 10x (UFA = 3x for interspecies extrapolation and UFH = 3x for 

intraspecies variations).

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

CMIT/MIT 90-day dermal study with a LOAEL of 0.75 mg/kg/day was selected as it is a routespecific study with the most conservative endpoint. The UF for ST and IT dermal exposure 
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scenarios is 30x (UFA = 3x for interspecies extrapolation, UFH = 3x for intraspecies variations, 

and UFLOAEL→NOAEL = 3x for LOAEL to NOAEL extrapolation). The UF for long-term (LT) 

dermal exposure scenarios is 100x (UFA = 3x for interspecies extrapolation, UFH = 3x for 

intraspecies variations, UFLOAEL→NOAEL = 3x for LOAEL to NOAEL extrapolation, and UFDB = 

3x 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/m3 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 (UFA = 3x for interspecies extrapolation

and UFH = 3x for intraspecies variations). The UF for long-term (LT) inhalation exposure 

scenarios is 30x (UFA = 3x for interspecies extrapolation, UFH = 3x for intraspecies variations, 

and UFDB = 3x 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 Dietary 

(general 

population 

including infants 

and children)

NOAEL = 2000

mg/kg/day

UF =100x 

(UFA = 3x for interspecies 

extrapolation, UFH = 3x for 

intraspecies variations, and 

UFLOAEL→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 

gait) death of one female rat on Day 2.

Chronic Dietary

(General 

Population)

NOAEL = 2.0

mg/kg/day

UF =10x 

(UFA = 3x for interspecies 

extrapolation and UFH = 3x for 

intraspecies variations)

CMIT/MIT Chronic/Cancer (Drinking Water) 

Study – Rat1

(MRID 43140701)

LOAEL = 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 of 

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). 
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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]/

intermediateterm 

[1-6 months])

NOAELoffspring

systemic= 49 

mg/kg/day (600

ppm)

UF =100x 

(UFA = 10x for interspecies 

extrapolation and UFH = 10x for 

intraspecies variations)

BBIT Two-generation Reproduction (Dietary) 

– Rat 

(MRID 48261201)

LOAELparental 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).

 

NOAELoffspring systemic = 600 ppm (49/56 mkd 

♂/♀)

LOAELoffspring systemic = 1700 ppm (141/157 

mkd ♂/♀), based on ↓ body weights (♂/♀: premating ↓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). 

 

NOAELrepro = 1700 ppm (141/157 mkd ♂/♀) 

Dermal 

(all durations)

LOAEL =

0.75 mg/kg/day 

(skin loading dose2

=1.2 μg/cm2)

Short- and intermedium-term:

UF =30x 

(UFA = 3x for interspecies 

extrapolation, UFH = 3x for 

intraspecies variations, and 

UFLOAEL→NOAEL = 3x for LOAEL 

to NOAEL extrapolation)

Long-term:

UF =100x 

(UFA = 3x for interspecies 

extrapolation, UFH = 3x for 

intraspecies variations,

UFLOAEL→NOAEL = 3x for LOAEL 

to NOAEL extrapolation, and 

UFDB = 3x for using a 90-day 

study for long-term exposure 

scenario)

CMIT/MIT 90-Day Dermal – Rat3

(MRID 43462005)

LOAELdermal = 0.75 mg/kg/day, based on (i) 

mild erythema in females at 0.75 mg/kg/day 

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).
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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/m3

(HEC8-hour =

0.0045 mg/m3)

4

Short- and intermedium-term:

UF =10x 

(UFA = 3x for interspecies 

extrapolation and UFH = 3x for 

intraspecies variations)

Long-term:

UF =30x 

(UFA = 3x for interspecies 

extrapolation, UFH = 3x for 

intraspecies variations, and UFDB

= 3x for using a 90-day study for 

long-term exposure scenario)

DCOIT 90-day Inhalation Toxicity Study –

Rat5

(MRID 43487501)

LOAEC = 0.63 mg/m3, 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). Increased 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 chronic/cancer study in drinking water

 for CMIT/MIT.

2 Skin Loading (μg/cm2

) = (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 cm2applied dose = 1.2 μg/cm2

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 (HEC8 hour ) = NOAEC x (6 hours animal tox study/8 hours human exposure) x

RDDR, where the RDDR is 0.30 for extrathoracic (ET) effects (MMAD = 1.4 μm, GSD = 4.6 and BWrat = 420 grams). Rat 

BW is the average for the 0.63 mg/m3treatment group at Week 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 all 

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.
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3.2.2 Drinking Water

A drinking water assessment has not been conducted for BBIT in the past. However, for the 

metalworking fluid and paper production uses, the Agency cannot rule out the potential for

BBIT to enter surface water and to subsequently be present in drinking water. Since drinking

water risk is a function of many unknown factors including (1) the residues of concern in

drinking water, (2) the magnitude of these potential residues of concern, (3) the persistence of

BBIT in water, and (4) if residues of BBIT are likely to pass through a wastewater treatment 

plant (WWTP), the Agency anticipates needing environmental fate data listed in Section 4 of this 

PWP. These data from either BIT or BBIT will be used to determine whether, and to what extent, 

residues of BBIT will pass through a WWTP and persist in surface water. Upon receipt 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 BBIT 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 machinists using BBIT treated 

metalworking 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 previously assessed using a 

POD of 30 mg/kg/day that was based on an oral toxicity study. Dermal exposures will need to be 

reassessed using the revised POD of 1.2 ug/cm2that is based on a dermal toxicity study, and 

inhalation exposures will need to be reassessed using the revised POD of 0.0045 mg/m3that is 

based on an inhalation toxicity study. 

In addition, Series 875 dermal and inhalation exposure studies will be needed to replace the data 

from the Pesticide Handlers Exposure Database (PHED) and the Chemical Manufacturer 

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., number 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 that additional data are warranted. 
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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/cm2for 

dermal exposure and 0.0045 mg/m3for inhalation exposure. In addition, dermal and inhalation 

exposure data will be needed to replace the data that were used in the previous assessments as 

discussed above for occupational handlers. The residential handler exposure scenarios that will 

need to be evaluated are listed 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/cm2for 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 previously 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-Application 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 Term
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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 inhalation 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: Framework for Screening Analysis. This document provides 

guidance on how to screen 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 guidance 

documents for establishing common mechanism groups2and conducting cumulative risk 

assessments.

3 The agency has utilized this framework for BBIT and determined that although 

BBIT 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 mechanism of action. No further data are required to determine that no 

common mechanism of toxicity exists for BBIT and other pesticides and no cumulative 

evaluation is necessary for BBIT.

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 effect’ or ‘may affect’

federally listed threatened or endangered species (listed species) or their designated critical 

habitats. When an assessment concludes that a pesticide’s use ‘may affect’ a listed species or its 

designated critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service 

and/or National Marine Fisheries Services (the Services), as appropriate.

 

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)
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4.1 Environmental Fate Assessment

Hydrolysis data are available for BBIT. For all other fate parameters, since BBIT consists of BIT 

with the addition of a 4-carbon aliphatic 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, the 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), 

 Saccharin (BIT sulfone), and

 BIT-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, including:

 Hydroxy-1,2-benzisothiazol-3-one (hydroxylated BIT), 

 Saccharin (BIT sulfone), and

 BIT-S-Oxide (BIT sulfoxide).

BBIT is water soluble and is not likely to volatilize from water. BBIT and BIT are both stable 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 less than one day

(MRID 41199102), but there is uncertainty about the persistence and occurrence of the 

transformation products, 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). 
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Table 11 – Environmental Fate and Transport Properties of BBIT and BIT

Property (Guideline number) Value Reference (MRID unless

specified)

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-sulfobenzamide and BITS-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

EC50 = 30 mg/L 

EC20 = 11.5 mg/L

EC80 = 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 BBIT
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4.1.1 Water and Sediment

BBIT is water soluble and is not likely to volatilize from water. BBIT and BIT are both stable to 

hydrolysis with extrapolated half-lives of >1 year (MRIDs 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 

products with intact benzene and isothioazolone 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 and 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 products in Table 5, movement from soil or water to air is not expected to be 

a significant transport 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.4In 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 Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water 

Quality Data in OPP’s Registration Review Risk Assessment and Management Process7in order 

to ensure they can be used quantitatively or qualitatively in pesticide risk assessments. 

4.3 Conceptual Models for Environmental Exposure Pathways

Based on the summary of registered uses of BBIT presented in Table 5, physical/chemical 

properties of BBIT and BIT in in Table 4, and environmental fate data presented in Table 11, the 

 

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

5http://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-monitoringdata
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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, EPAHQ-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 OCSPP Harmonized Test Guidelines are used to evaluate 

the potential direct and indirect effects to plants and animals. Relevant data from the open 

literature also may be used if available.

4.4.1.1 Data Submitted for BIT

No data have been submitted for BBIT. Data for BIT are being bridged to BBIT (see section 

4.1). All data requirements and available ecotoxicity endpoints from studies submitted by 

registrants 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 provided 

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

Chronic1 NOAEC = 0.28 mg ai/L 477598-15

Freshwater 

invertebrates TGAI

Acute EC50 = 1.5 mg ai/L 455346-01

Chronic1 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 -

Algae and cyanobacteria

TGAI EC50

NOAEC Data gap --
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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 database will be searched during the risk assessment phase and the data will be 

reviewed following the Agency’s policy for reviewing public literature for use in assessing risks 

from pesticides. Those ecotoxicity values found in the public literature to be more sensitive 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 Environmental 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 uses of products 

containing BBIT. The results of this 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 toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for BBIT, EPA reviewed these 

data and selected the most sensitive endpoints for relevant risk assessment scenarios from the 

existing hazard database. However, as required by FFDCA section 408(p), BBIT is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

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

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

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

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

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

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

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 
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interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

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

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

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

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

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

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

identified for EDSP screening was published on June 14, 20138and includes some pesticides 

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

construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.9

6 Optional Label Changes

The Agency invites comment on any label amendments that could be considered to eliminate the 

anticipated need for EPA to require certain data, reduce the possibility that EPA’s planned risk 

assessments overestimate risk due to reliance on conservative assumptions, and/or improve label 

clarity.

7 Guidance for Commenters

7.1 Preliminary Work Plan

The public is invited to comment on EPA’s 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 intends to solicit information on trade 

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

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

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

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

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

the concern.

 

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-disruption
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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 Process10 in order to ensure they 

can be used quantitatively or qualitatively in pesticide risk assessments.

7.1.3 Environmental Justice 

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

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

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

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

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

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-monitoringdata
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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.
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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-Benzoisothiazol3(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--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 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.
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US EPA, 1999. Guidance for Identifying Pesticide Chemicals and Other Substances that have a 

Common Mechanism of Toxicity. http://www.epa.gov/sites/production/files/2015-

07/documents/guide-2-identify-pest-chem_0.pdf

US EPA, 2002. Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a 

Common Mechanism of Toxicity. http://www.epa.gov/sites/production/files/2015-

07/documents/guidance_on_common_mechanism.pdf

US EPA, 2003. Revised Non-dietary Exposure/Risk Assessment for Dolphin Antimicrobial (NButyl-1,2-Benzisothiazolin-3 (2H) –one, new active ingredient) during manufacturing and 

residential consumer use of impregnated plastic products. D286782, D270042, D272198, 

D272211, D272213, D272215, D272216, D272220, April 14, 2003

US EPA, 2004. Occupational Exposure Considerations Regarding DENSIL DG 45 Fungicide 

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

Benzisothiazolin-3–one, 2 - butyl. D298317, April 29, 2004

US EPA, 2009. Occupational and Residential Exposure and Risk Assessments for the New Uses 

of 1,2-Benzisothiazolin-3–one, 2- butyl. D298317, D358428, D358434, June 8, 2009.

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.
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Appendix A Toxicology Profile

Acute Toxicity for Product Labeling 

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 LD50 = 4267 mg/kg 

(M); 4732 mg/kg (F)

III

870.1200

purity a.i. (% w/w): 

93.4

Acute Dermal – Rat 44364916 LD50 > 2000 mg/kg III

870.1300

purity a.i. (% w/w): 

45.2

Acute Inhalation –

Rat 

45083004 LC50>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 SensitizationGuinea Pig44364918 Moderate Dermal 

Sensitizer

Not applicable

Subchronic Toxicity 

Adequacy of Database for Subchronic Toxicity: There are two subchronic toxicity studies in the 

Agency’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 studies for BBIT; these 

data were bridged from other isothiazolone chemicals when the toxicology endpoints were 

revised recently. These studies are not anticipated to be required, at present, for BBIT 

registration review risk assessment, based on the currently registered uses. However, should new 

use(s) be added and/or current labels be amended, these studies may be required.
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870.3100 90-Day (13-Week) Oral Toxicity – Rat

In a subchronic oral toxicity study (MRID 44403001), 1,2-benziso-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 neurotoxic effects or effects on motor activity. There were no treatmentrelated 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 females 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 changes.

Histopathologic changes indicative of irritative effects on the non-glandular stomach were observed 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 considered 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 200 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.

870.3150 90-Day (13-Week) Oral Toxicity – Dog

In a subchronic oral toxicity study (MRID 48262204), N-butyl-1,2-benzisothiazolin-3-one

(99.4% 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 10 due to one female who 

was sacrificed in extremis at 250 mg/kg/day.

No adverse, treatment-related effects were observed on ophthalmoscopic examinations, 

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 actually lost weight 
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(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-significant) 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 hematocrit) were decreased in males and females at both testing intervals (nonsignificant). 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 doseresponse decrease in serum albumin and total protein concentrations was observed in the highdose 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) in 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 dosedependent. 

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 25 mg/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 Database 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 Agency’s hazard database, and a brief summary of the reviewed 

study is provided below. 

No developmental toxicity study in the rabbit is available for BBIT. The Agency does not 

believe that a developmental toxicity study in the rabbit for BBIT would provide more 

conservative data compared 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:APfSD 

(Wistar derived) rats per group 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 were 
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sacrificed, 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. Treatmentrelated 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 the 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, respectively. 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. 

Therefore, 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 total 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 skeletal 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/Guideline and satisfies the requirements for a 

developmental toxicity study [870.3700 (§83-3)] in rats.
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Reproductive Toxicity

Adequacy of Database for Reproductive Toxicity: The database for reproductive toxicity is 

adequate. There is a two-generation reproductive toxicity study for BBIT (MRID 48261201) in 

the Agency’s hazard database; a brief summary of the reviewed study is provided below.

870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction toxicity 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 F1 generation animals were exposed to the test diets for a minimum of 70 days prior to 

mating. F1 offspring selected to be parents of the F2 generation (30/sex/dose group) 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, overall 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 gestation.

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. Absolute 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. Relative food consumption was similar to controls for both 

males and females. Food efficiency 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 attain 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. Overall body weight gains during gestation were similar to controls at all doses. 

Mean F1 maternal absolute and relative food consumption and food efficiency were unaffected 

by treatment during gestation. Overall body weight gains, mean F1 maternal absolute and 

relative food consumption, and food efficiency were unaffected by treatment during lactation.

No adverse effects of treatment were noted at low- or mid-dose level in either generation.
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The LOAEL for parental toxicity is 1700 ppm (equivalent to 141/157 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 histopathology.

At high-dose level, body weights were decreased (p<0.05) in the F1 generation and the F2 

generation on PND 21. Overall (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, respectively) 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 

estrous cycle lengths 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, motility, progressive motility, and 

morphology).

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 Acceptable/Guideline and satisfies the guideline requirements 

(OPPTS 870.3800; OECD 416) for a two-generation reproduction study in the rat.

Chronic Toxicity 

Adequacy of Database for Chronic Toxicity: There are no chronic toxicity studies in the 

Agency’s hazard database for BBIT; the data were bridged from other isothiazolone chemicals 

when the toxicology endpoints were revised recently. The studies are not anticipated to be 

required, at present, for BBIT registration review risk assessment, based on the currently 

registered uses. However, should new use(s) be added and/or current labels be amended, these 

studies may be required.
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Carcinogenicity 

Adequacy of Database for Carcinogenicity: There are no carcinogenicity studies in the Agency’s 

hazard database for BBIT; the data were bridged from other isothiazolone chemicals when the

toxicology endpoints were revised recently. The studies are not anticipated to be required, at 

present, for BBIT registration review risk assessment, based on the currently registered uses. 

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

required.

Mutagenicity 

Adequacy of Database for Mutagenicity: The database for mutagenicity is considered adequate. 

Several mutagenicity studies have been submitted and found to be acceptable by the Agency. 

The summaries of 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-Benzisothiazolin-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 concentrations 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 βnaphthoflavone induced male Sprague-Dawley rat liver.

BBIT was tested up to cytotoxic concentrations. In the first assay in the absence of S9-mix, the 

mean mutant frequencies ranged from 2.7 x 10-4to 3.7 x 10-4at 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, the 

mean mutant frequencies ranged from 1.1 x 10-4to1.7 x 10-4from 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 analysis 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 requirement for FIFRA Test 

Guideline (OPPTS 870.5300 [§84-2]) for in vitro mutagenicity (mammalian forward gene 

mutation) data.
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870.5375 In Vitro Mammalian Chromosome Aberration Test

In an in vitro 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 (female): 

(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 SpragueDawley rat liver.

BBIT was tested up to cytotoxic 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 aberrations (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 Vivo Mammalian Erythrocyte Micronucleus Test

In an in vivo bone marrow micronucleus assay (MRID 44364924), 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 1250 mg/kg (males) or 2000 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 frequency of bone marrow 

micronucleated polychromatic erythrocytes at either 24 or 48 hours after treatment. The positive 

and vehicle controls induced the appropriate response. 

BBIT is not considered to be a mutagen under conditions of this study.
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This study 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 Vivo/In Vitro Unscheduled DNA Synthesis (UDS) in Mammalian Cells

In an in 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 rangefinding 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 appropriate. 

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/Nonguideline. 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 live 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 no neurotoxicity studies in the Agency’s 

hazard database. In a 90-day oral (feeding) toxicity 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 Agency does not believe that a

neurotoxicity screening 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 uses. Should new use(s) be added and/or current 

labels be amended, these studies may be required.
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Immunotoxicity

870.7800 Immunotoxicity Study

Adequacy of Database for Immunotoxicity: There are no immunotoxicity studies in the 

Agency’s hazard database. The Agency 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 for

the isothiazolone chemicals group.

Other Toxicological Effects 

870.7485 Metabolism and Pharmacokinetics

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

14C]-N-butyl benzisothiazolin3-one (radiolabelled 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 radioactive dose of 27.03 μCi/kg/day). Select tissues were 

measured for radioactive content for up to 60 days after the last administered dose.

The majority of the administered radioactivity was excreted in the urine and feces. 

Approximately 87% of the first administered dose and 92% of the 14th administered daily dose 

were excreted in the urine within 24 hours of dosing, while approximately 15% of the first and 

14th doses were excreted in the feces within 24 hours post-dosing. 

The tissue distribution of radioactivity following oral dosing with [14C]-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, bladder, 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 termination 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 evidence 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 metabolism and pharmacokinetics study 

[OPPTS 870.7485] in the rat. 
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(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), 

14C-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 study) via a single oral dose at levels of 5 or 300 mg [14C]-BBIT/kg. 

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

BBIT/kg were also given.

Peak concentrations of [14C]-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 seen 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 [

14C]-BBIT following oral administration of 5 mg [14C]-BBIT/kg or 300 mg 

[

14C]-BBIT/kg in rats is similar and essentially complete with only small amounts of unmetabolized test substance (<0.5% of administered doses) being detected in the urine and feces. 

Only trace amounts of metabolites were detected in expired air. The predominant urinary 

metabolites of [

14C]-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 (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/kg 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 

metabolite 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 acceptable 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 870.7485, OECD 417] in rats.
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Table A2 – 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%

20 Wistar-derived Sprague 

Dawley (Alpk:APfSD) 

rats/sex/dose

0, 40, 200, and 2000 ppm (♂/♀: 

0/0, 3.1/3.4, 15.3/16.6, or 

149.2/162.4 mg/kg/d), in feed, for 

90 days

NOAEL = 200 ppm (♂/♀: 15.3/16.6

m/k/d)

LOAEL = 2000 ppm (♂/♀:

149.2/162.4 m/k/d), based on 

submucosal inflammation of the 

stomach

870.3150

90-day Oral (Dog)

MRID 48262204

Acceptable/Guideline

Purity 99.4%

4 Beagle dogs/sex/dose

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.

NOAELmale = 25 mg/kg/d

NOAELfemale = 75 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%

24 presumed pregnant 

Alpk:APfSD (Wistar derived) 

rats/dose

0, 30, 100, or 300 mg/kg/d, 

GD 7–16

NOAELmaternal = 30 mg/kg/d

LOAELmaternal = 100 mg/kg/d, 

based on ulcerated areas of the 

stomach

NOAELdevelopmental ≥ 300 mg/kg/d

(highest dose tested [HDT]).

LOAELdevelopmental 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

NOAELparental = 600 ppm (♂/♀:

49/56 mg/kg/d)

LOAELparental = 1700 ppm (♂/♀: 

141/157 mg/kg/d), based on 

decreased body weights and food 

consumption

NOAELoffspring = 600 ppm (♂/♀:

49/56 mg/kg/d)

LOAELparental = 1700 ppm (♂/♀: 

141/157 mg/kg/d), based on 

decreased body weights, body weight 

gains, and spleen weight (F2 pups 

only)

NOAELreproductive ≥ 1700 ppm (♂/♀: 

141/157 mg/kg/d) (HDT);

LOAELreproductive not established
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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 44364923

Acceptable/Guideline

Purity 95.5% 

mouse lymphoma cells (L5178Y 

TK+/-)

In the 1st 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 2nd 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 3rd assay:

0.4, 0.5, 0.6, 0.8, 1.1, 1.5, or 2.0 

μg/mL, -S9

Negative

870.5375

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

Positive (±S9)

870.5395

In vivo mammalian 

Erythrocyte 

Micronucleus test 

(mouse)

MRID 44364924

Acceptable/Guideline

Purity 95.5%

Charles River CD-1 albino mice 

(10/sex)

max. tolerated doses of 1250 

mg/kg (♂) and 2000 mg/kg (♀) in 

corn oil, oral gavage; both males 

and females were sacrificed at 

Negative
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Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

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

hours.

870.5550

(In vivo/in vitro)

Unscheduled DNA 

synthesis 

MRID 44364925

Acceptable/

Nonguideline

Purity 95.5%

Rat hepatocyte cells

0, 500, or 800 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; hepatocytes were isolated 

at 2 or 16 hours post-treatment

Negative

Metabolism

870.7485

Metabolism 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.

Approximately 87% of the first 

administered dose and 92% of the 

14th administered daily dose were 

excreted in the urine within 24 hours 

of dosing, while approximately 15% 

of the first and 14th 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 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 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.
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Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

870.7485

Metabolism and 

Pharmacokinetics

MRIDs 48349201 & 

48262203

Acceptable/Guideline

Purity >98% (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 [14C]-BBIT/kg.

For the metabolite identification 

study (MRID 48262203), 14 

repeated doses of 5 mg [14C]-

BBIT/kg were also given.

Peak concentrations of [14C]-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; 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 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.

The predominant urinary metabolites 

of [

14C]-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 (Metabolite 11, 

11-18% of dose). These metabolites 

were also detected in the feces, 

although at lower and more variable 

concentrations.

Urinary metabolite profiles were 

qualitatively similar for the 14-day 

repeated 5 mg/kg doses study (MRID 

48262203). However, higher amount 

of parent material and metabolite 6 

were observed following repeated 

dosing.
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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) Substance 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. Central 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) Substance 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.

MRID 44364924 Fox, V., Substance S123386: Mouse Bone Marrow Micronucleus Test. 

Central Toxicology Laboratory, Cheshire, UK. Report No. CTL/P/5171. 

Study No. SM0801. Sept. 19, 1996. MRID 44364924. Unpublished.

MRID 44364925 Mackay, J.M. (1996) Substance S123386: in vivo 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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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 45083004 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, 

Distribution, 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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Appendix B Environmental Fate

Environmental Fate and Transport Properties of Butyl BIT (Nbutyl-1,2-Benzisothazolin-3-one (BBIT) and its Transformation 

Products

Water and Sediment

Hydrolysis

Butyl 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 oC. Based on these results, BBIT is 

expected to be stable at 25 oC (MRID 44364926). The related compound, BIT, was also stable at 

25 oC at pH 5, 7, and 9 (MRIDs 41199101, 44182101).

Aqueous Photolysis

In aqueous photolysis, BIT degraded at pH 5 with a half-life of 9 hours, while 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 hydroxy-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 ring, 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-benzthiazolin2-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 photodegradation of BBIT in water are not anticipated to be required because the 

additional 4-carbon side chain is not likely to affect the rate of photodegradation. 

Octanol-Water Partition Coefficient and Bioconcentration in Aquatic Organisms

The measured values of log Kow 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 Kow values, which are lower than a log Kow of 3, indicating low potential for 

bioconcentration, BBIT, BIT and the transformation products are not likely to be 
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bioaccumulative in aquatic species, and bioconcentration 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). Aerobic aquatic 

metabolism data may be generated for either compound and bridging is appropriate based on the 

similarity in chemical structure.

Anaerobic Aquatic Metabolism

For BIT, data on anaerobic aquatic metabolism were not required because of the relatively 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 Kd values of 1.24-9.56 L/kg and 

Koc values of 235-566 L/kg, and based on the Koc values and FAO classification system11, BIT is 

considered to be moderately mobile in soil (MRID 41687102). For BBIT, these data are also not 

required based on the structural similarity 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 

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). 

Two major metabolites were identified; 2-sulfobenzamide (ortho sulfobenzamide) and BIT-Soxide (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 values of log Kow 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 Kow values, which are lower than a log Kow 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.htm
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Activated Sludge Respiration Inhibition

For BIT, the IC50 was 30 mg/L and the IC50 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 biodegradation in activated sludge were required for BIT in the December 2014 Final 

Work Plan. Biodegradation data may be generated for either BIT or BBIT, and bridging from 

BIT is appropriate based on the similarity 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 photodegradation in water and aerobic soil metabolism 

studies include: 

 BIT (1,2-benzisothiazol-3(2H)-one)

 

 2-sulfobenzamide (orthosulfobenzamide)

 1,2-benzthiazolin-2-one
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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 unless

specified)

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 

O

NH S

O
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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-sulfobenzamide and BITS-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

EC50 = 30 mg/L 

EC20 = 11.5 mg/L

EC80 = 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 chemical 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) Simulation Test - Aerobic Sewage Treatment: A. Activated Sludge Units, 

or c) the Porous Pot study is required.
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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 Development 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 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.
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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 ToxicityCategory MRID

Northern bobwhite

(Colinus virginianus)

99 LD50 = 453mg ai/kg bw Moderately toxic 409913-01

Acceptable

72.2 LC50 >5620 ppm Practically nontoxic

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

The available acute toxicity studies categorize technical-grade BIT as being moderately to highly 

toxic to freshwater fish. The guideline (850.1075) for acute toxicity testing is satisfied. 
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Acute Toxicity to Freshwater Fish

Test Species Test Material

(% ai)

Toxicity Endpoint

(mg ai/L)

Toxicity

Category MRID

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 MRID

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. 
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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 477598-15Acceptable

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 MRID

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 LC50 = 1.8 Moderately 

toxic

477598-11

Acceptable

Pacific oyster

(Crassostrea gigas) 76.1 EC50 = 0.047 Very highly toxic

429524-01

Acceptable
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Estuarine/Marine Fish and Invertebrates, chronic

No chronic data are available for estuarine/marine fish (850.1400) or mysids (850.1350). 

Because the acute toxicity to the estuarine/marine fish is less than that of the freshwater fish and 

the mysid is comparable to the daphnid, the agency can use the acute: chronic ratio (ACR) from 

the freshwater species and the acute data to 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 EC50 of BBIT is less than 

1.0 mg/L, studies are also required on three additional species (Anabaena flos-aquae (850.4550),

Navicula pelliculosa (850.4500), and Skeletonema costatum (850.4500)).

Benthic Organisms

Based on environmental fate properties (Kd <50 L/kg, Koc <1000, log Kow <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 

Trout 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: FAR59991: 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: X060/B. Unpublished study prepared by Zeneca 

Ltd.'s Brixham Environmental Lab. 20 p. 
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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 gigas): 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 FlowThrough 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 FlowThough 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. Unpublished study prepared by Wildlife International, Ltd. 

83 p.

47759815 Palmer, S.; Kendall, T.; Kruger, H. (2007) 1,2-Benzisothiazolin-3-One: An Early Life-Stage 

Toxicity Test with the Fathead Minnow (Pimephales promelas): Final Report. Project 

Number: 129A/205, 06RC/090. Unpublished study prepared by 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.
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Appendix D Screening Level Down-theDrain Analysis

No Down-the-Drain (DtD) analysis was performed for this PWP.
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Appendix E Product Chemistry

The chemical and physical property information for BBIT are summarized in Table E1, and for BIT are summarized in Table E2. 

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

Chemical structure

None

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

Molecular formula C11H13N1O1S1 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 for BIT

830.7370

Dissociation constant

Acid dissociation constant 9.12 x 10-8

moles/L (PAI)

pKa 7.04 at 25 oC

MRID 43584001

Value for BIT

830.7550

Partition coefficient 2.32

EPI-Suite 4.11

830.7950

Vapor pressure (mm Hg) 9.97 x 10-6

EPI-Suite 4.11

Henry’s Law Constant

(calculated)

Atm m3 mol-1

6.5 x 10-9

EPI-Suite 4.11

atm-m3/mol = atmosphere cubic meter per mole; oC = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury
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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 C7H5N1O1S1

None

Molecular weight (g/mol) 151.19 None

Water Solubility(mg/L) 1,118 ppm at 20 oC

1,380 ppm at 24 oC

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 oC

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 oC

43584001

Henry’s Law Constant

(calculated)

Atm m3 mol-1

1.64 x 10-10

None

(1.14 x 10-6 * 151.19)/(760 *1,380)

atm-m3/mol = atmosphere cubic meter per mole; oC = degrees Celsius; mg/L = milligrams per liter; mmHg = millimeters of mercury
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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-benzothiazolin2-one2-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 C7H5N1O2S1

C7H5N1O1S1 C7H7N1O4S1 C7H5N1O3S1 C7H5N1O2S1

Molecular 

weight (g/mol) 167.18 151.18 201.20 183.18 167.18

Water 

Solubility(mg/

L)

1.77 x 105 2,354 1 x 106 789 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 

oC

3.96 x 10-7 5.41 x 10-6 4.95 x 10-10 1.03 x 10-7 1.45 x 10-6

O

NH S

O
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Guideline No./

Study Type

Compound

Hydroxy-1,2-

benzisothiazol-3-one

1,2-benzothiazolin2-one2-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 m3 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-m3/mol = atmosphere cubic meter per mole; oC = 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.