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Methylisothiazolinone/Chloromethylisothiazolinone Registration Review Team

Human Health & Environmental Effects

Pat Jennings

Srinivas Gowda

James Breithaupt

David Bays

Jonathan Chen

Tim Dole

Zoë Cavinder

Don Wilbur

Risk Management

SanYvette Williams

James Parker

Eric Miederhoff

Office of General Counsel

Philip Ross 
Docket Number EPA-HQ-OPP-2013-060

www.regulations.gov

Page 3 of 56

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 

°C degrees Celsius

CAS Chemical Abstracts Service 

CCA chromated copper arsenate

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 

CS2 carbon disulfide

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 

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

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

mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury
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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

SAR structure activity relationship

SF safety factor

SSTS Section Seven Tracking System

SO2 sulfur dioxide

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..................................................................................................................9

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

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

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

1.4.2 Summary of Registered Uses..................................................................................11

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

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

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

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

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

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

3 Human Health Risk Assessment ...........................................................................................15

3.1 Existing Toxicological Endpoints ..................................................................................15

3.2 Dietary Exposure ............................................................................................................15

3.2.1 Food.........................................................................................................................16

3.2.2 Drinking Water........................................................................................................16

3.3 Occupational and Residential Exposures .......................................................................16

3.3.1 Occupational Handler Exposure..............................................................................16

3.3.2 Residential Handler Exposures ...............................................................................17

3.3.3 Residential Post-Application Exposures.................................................................18

3.4 Aggregate and Cumulative Exposure .............................................................................18

3.4.1 Aggregate Exposures...............................................................................................18

3.4.2 Cumulative Exposures.............................................................................................18

4 Environmental Risk Assessment...........................................................................................18

4.1 Environmental Fate Assessment.....................................................................................19

4.1.1 Leaching (Wood/Paint/Antifoulant Paint/Plastic/Textiles/e.g., treated article)......19

4.1.2 Water and Sediment ................................................................................................20

4.1.3 Soil ..........................................................................................................................20

4.1.4 Air............................................................................................................................21

4.1.5 Fate and Transport in Wastewater Treatment Plants (WWTPs).............................21

4.1.6 Water Quality ..........................................................................................................21

4.2 Environmental Exposure Pathways................................................................................21

4.3 Ecological Effects Assessment.......................................................................................22

4.3.1 Mode of Action .......................................................................................................22

4.3.2 Measures of Effect (Ecotoxicology Endpoints) ......................................................22

4.4 Exposure Analysis Plan ..................................................................................................24

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates.............................................24

4.4.2 Screening Level Down-the-Drain Analysis ............................................................24

4.5 Effects Analysis Plan......................................................................................................24

5 Endocrine Disruptor Screening Program (EDSP).................................................................24

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

7 Guidance for Commenters ....................................................................................................25

7.1 Preliminary Work Plan ...................................................................................................25

7.1.1 Trade Irritants..........................................................................................................25
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7.1.2 Water Quality ..........................................................................................................26

7.1.3 Environmental Justice .............................................................................................26

7.1.4 Structure Activity Relationships .............................................................................26

7.1.5 Additional Information............................................................................................27

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

9 References.............................................................................................................................28

Appendix A Toxicology Profile ...............................................................................................29

Appendix B Environmental Fate..............................................................................................38

Appendix C Ecotoxicology Profile ..........................................................................................47

Appendix D Screening Level Down-the-Drain Analysis.........................................................53

Appendix E Product Chemistry ...............................................................................................54

List of Tables

Table 1 – Summary of Anticipated Risk Assessments and Data Needs: MIT/CMIT.....................8

Table 2 – Anticipated Registration Review Schedule.....................................................................8

Table 3 – Chemical Identification of MIT/CMIT ...........................................................................9

Table 4 – Physical-Chemical and Environmental Fate Properties for MIT/CMIT.........................9

Table 5 – Summary of MIT/CMIT Registered Uses.....................................................................11

Table 6 – Studies Anticipated as Needed for the Registration Review of MIT/CMIT.................14

Table 7 – Toxicological End-Points for Assessing for MIT/CMIT ORE Exposures ...................15

Table 8 – Toxicological End-Points for Assessing MIT/CMIT Dietary Exposures.....................15

Table 9 – Occupational Handler Exposure Scenarios for MIT/CMIT..........................................17

Table 10 – Residential Handler Exposure Scenarios for MIT/CMIT ...........................................17

Table 11 – Residential Post-Application Exposure Scenarios for MIT/CMIT.............................18

Table 12 – Selected Ecological Effects Endpoints for Risk Assessment of MIT/CMIT..............23
Page 7 of 56

1 Introduction

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

Agency”) Preliminary Work Plan (PWP) for methylisothiazolinone (MIT) and 

chloromethylisothiazolinone (CMIT) or (MIT/CMIT). The PWP document explains what EPA's 

Office of Pesticide Programs (OPP) knows about MIT/CMIT, 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 

MIT/CMIT’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 MIT/CMIT and what types of new data or other 

information would be helpful for the agency to receive as it moves toward a decision on 

MIT/CMIT. 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://www.epa.gov/oppsrrd1/registration_review/.

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

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

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

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

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

review begins when the initial docket is opened for each case. The docket is the agency’s 

opportunity to state what it knows about the pesticide and what additional risk analyses and data 

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

responding to comments and data received in the docket during this initial comment period, the 

agency will develop a Final Work Plan (FWP) and anticipated schedule for the MIT/CMIT Case. 

Documents associated with the MIT/CMIT case can be viewed at http://www.regulations.gov in 

docket EPA-HQ-OPP-2013-0605. Tables 1 and 2 below summarize the issues relevant to this 

registration review case and the anticipated registration review schedule.
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Table 1 – Summary of Anticipated Risk Assessments and Data Needs: MIT/CMIT

Risk Assessment 

Assessment 

Necessary to 

Support 

Registration 

Review

Date of Most 

Recent Assessment

Type of Assessment 

Required 

(New/Updated)

Data Anticipated as Needed

(See Table 6 for details)

Dietary (food) Yes N/A New Immunotoxicity

Dietary (drinking 

water)1 No N/A None None 

Occupational and 

Residential Handler Yes 12/1995 Updated

Immunotoxicity

Dermal Exposure 

Inhalation Exposure

Residental Post 

Application -

Incidental Oral and 

Dermal 

Yes 12/1995 Updated

Immunotoxicity

Indoor Surface Residue 

Dissipation

Residental Post 

Application -

Inhalation 

Yes None New

Immunotoxicity

Inhalation Exposure Chamber 

Study

Aggregate Yes None New Same as above 

Cumulative No N/A None None

Ecological1 Yes 10/98 New

Honeybee acute contact

Toxicity of residues to 

honeybees

1 Drinking water and aquatic ecological assessment are not necessary because CMIT and MIT degrade rapidly in the environment to form straightchain nitrogenous carboxylic acids that eventually mineralize to carbon dioxide and formic acid.

N/A = Not applicable

Table 2 – Anticipated Registration Review Schedule

Anticipated Activity Target Date* Completion Date

Phase 1: Opening the Docket 

Open Docket and 60-Day Comment Period for Preliminary Work Plan 2014-06 2014-06

Close Public Comment Period 2014-08

Phase 2: Case Development 

Issue Final Work Plan 2014-12

Issue Data Call-In (DCI) 2015-12

Receive Data to be Considered in Risk Assessment 2017-12

Open 30-Day Public Comment Period for Preliminary Risk Assessment(s) 2019-06

Close Public Comment Period 2019-07

Phase 3: Registration Review Decision and Implementation 

Open 60-Day Public Comment Period for Proposed Decision 2019-12

Close Public Comment Period 2020-02

Issue Final Decision 2020-06

Begin Post-Decision Follow-up 2020

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).
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1.2 Case Overview

The registration review docket for MIT/CMIT (case 3092) has been established at 

http://www.regulations.gov in docket number EPA-HQ-OPP-2013-0605.

1.3 Chemical Identification and Properties

Table 3 presents the active ingredients to be assessed in case 3092: 5-Chloro-2-methyl-3(2H)-

isothiazolone (PC Code 107103; also referred to as CMIT) and 2-Methyl-3(2H)-isothiazolone (PC 

Code 107104; also referred to as MIT).

Table 3 – Chemical Identification of MIT/CMIT

Chemical Name 5-Chloro-2-methyl-3(2H)-isothiazolone 

(CMIT) 2-Methyl-3(2H)-isothiazolone (MIT)

Chemical Classification Isothiazolinone

Organochlorine Isothiazolinone

PC Code 107103 107104

CAS Number 26172-55-4 2682-20-4

Molecular Formula C4H4ClNOS C4H5NOS

Molecular Weight (grams/mole) 149.60 115.2

Molecular Structure

The Methylisothiazolinone physical chemistry information (Source: MRIDs 43825701, 43825702, 

43825703 (MIT), 42261401, 42261402, 42261403 (CMIT)) relevant to risk assessment is 

summarized in Table 4.

Table 4 – Physical-Chemical and Environmental Fate Properties for MIT/CMIT

Guideline 

No. Parameter

Mixture of 2 AIs (3:1 ratio) SF 886Technical 

(EPA Reg. No. 707-234):

 5-Chloro-2-methyl-3(2H)-isothiazolone:

70.1%

 2-Methyl-3(2H)-isothiazolone: 26%

Total: 96.1% AI

2-Methyl-3(2H)-isothiazolone 96% AI

Kordek 573T (EPA Reg. No. 707-255)

Physical/Chemical Properties

830.7000 pH 2.1 at 25oC (5% solution in water) 2.58 (5% solution in water)

830.7050 UV/Visible 

Absorption Stable to sunlight Stable to sunlight

830.7200 Melting point

NA, this product is semi-solid at room 

temperature.

The melting point is 52-53oC.

48.0-49.5oC
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Guideline 

No. Parameter

Mixture of 2 AIs (3:1 ratio) SF 886Technical 

(EPA Reg. No. 707-234):

 5-Chloro-2-methyl-3(2H)-isothiazolone:

70.1%

 2-Methyl-3(2H)-isothiazolone: 26%

Total: 96.1% AI

2-Methyl-3(2H)-isothiazolone 96% AI

Kordek 573T (EPA Reg. No. 707-255)

830.7220 Boiling point

N/A, this product is a semi solid at room 

temperature.

Not required, product is a semi-solid at 

room temperature with very low vapor 

pressure.

830.7300 Density 11.8 lb/gal or 1.420 g/ml at 25oC 1.35 g/ml at 25oC

830.7370 Dissociation 

constant (pKa)

Not applicable, the active ingredients in this 

product are covalently bonded. They do not 

dissociate into ions when dissolved in water. Not applicable, active ingredient does 

not dissociate into ions.

830.7550

Octanol-water 

partition coefficient 

at 25 oC (Log Kow)

CMIT: 0.401 at 24oC in log P (PAI)

MIT: −0.486 at 24oC in log P (PAI) Log P=−0.486 at 24oC

830.7840 Solubility in water CMIT: ≥65.96 grams at 25oC in 100 ml water

MIT: ≥22.59 grams at 25oC in 100 ml water

≥100 g/100 ml water

830.7860

Solubility in

organic solvents 

(grams/100 ml)

CMIT (grams/100 ml):

Ethyl Acetate ≥57.75

Methanol ≥60.31

Xylene ≥55.01

Hexane-1 ≥ 2.44

Hexane-2 ≥ 2.09

MIT (grams/100 ml):

Ethyl Acetate ≥18.59

Methanol ≥20.52

Xylene ≥16.87

Hexane-1 ≥ 0.17

Hexane-2 ≥ 0.16

MIT (grams/100mL):

Acetonitrile ≥78.6

Methanol ≥79.1

Hexane ≥ 2.371

Xylenol ≥ 15.65

830.7950 Vapor pressure 

(mmHg)

CMIT:1.8x10-2 mm Hg (PAI)

MIT: 6.2x10-2 mm Hg (PAI) 6.2x10-2 mm Hg at 25oC (PAI)

None

Henry's law

constant at 25 oC 

(atm-m3/mol)

CALCULATED

5.37 x 10-9(CMIT)

4.16 x 10-8(MIT) 4.16 x 10-8

(MIT)

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 120 EPA-registered products that contain MIT as an active ingredient (a.i.). There are 

no products that contain CMIT without MIT. 

These two active ingredients (MIT and CMIT) occur together in 101 currently registered products 

in approximately a 3:1 ratio, and are commonly referred to collectively as methylisothiazolinone.

Also, there are 19 registered products found to contain 2-methyl-3(2H)-isothiazolone (MIT) as an
Page 11 of 56

active ingredient without CMIT. All of the products containing MIT and MIT/CMIT are 

formulated as ready to use solutions, flowable concentrates and liquid soluble concentrates. 

1.4.2 Summary of Registered Uses

Table 5 presents a listing of the registered uses of MIT/CMIT including some that have been 

registered since the 2007 RED. All of these uses will be assessed during registration review. 

MIT/CMIT can be applied by the following application methods: open pour addition, pressure 

treatment, spray, dip, mop, wipe, brush/roller or airless sprayer. 

Table 5 – Summary of MIT/CMIT Registered Uses

Use Application Method Application Rate

(ppm a.i.)

Industrial Process and Water Systems

Air conditioner/refrigeration condensate water systems

Air washer water systems

Coal slurry systems

Commercial/industrial water cooling systems

Evaporative condenser water systems

Heat exchanger water systems

Industrial auxiliary water systems

Industrial processing water

Industrial scrubbing system

Industrial waste disposal systems

Laboratory equipment water baths

Oil recovery drilling muds/packer fluids

Pasteurizer/warmer/cannery cooling water systems

Pulp/paper mill water systems

Reverse osmosis water system

Secondary oil recovery injection water

Sewage systems

Wet-end additives/industrial processing chemicals

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

3 to 14

1 to 153

3 to 14

1 to 20

3 to 14

3 to 13

9 to 12

1 to 153

3 to 14

1 to 153

3 to 14

1 to 153

2 to 14

11 to 153

3 to 153

1 to 34

3 to 14

16 to 300

Material Preservative

Adhesives, industrial

Coatings, industrial

Electrical supplies/equipment

Emulsions, resin/latex/polymer

Fuels/oil storage tank bottom water additive

Household cleaning products 

Leather processing liquors

Metalworking cutting fluids

Paints (in-can)

Paints, latex/oil/varnish (applied film)

Paper/paper products

Pesticide formulations

Rubber products

Textiles/textile fibers/cordage

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

1 to 400

1 to 400

19 to 439

1 to 400

1 to 34

1 to 1470

60

1 to 444

1 to 400

7 to 1400

7 to 150

25 to 250

55

7 to 400

Wood Preservative

Wood pressure treatment to forest products

Wood protection treatment to buildings/products outdoor

Pressure Treatment

Spray, Dip, Brush

19 to 6200

15 to 378
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1.5 Regulatory History

MIT and CMIT were registered in the United States as early as 1977 as active ingredients. In 

2007, the agency completed the RED for the MIT/CMIT case. Since then, the agency has 

approved new uses such as air conditioner/refrigeration condensate water systems, industrial water

disposal systems, reverse osmosis water systems, leather processing liquors, rubber products and 

wood protection treatment to buildings/products outdoors.

1.5.1 Tolerance Information

For the active ingredient MIT alone, EPA has no established tolerances or exemptions from 

tolerances in raw agricultural commodities or processed food and feed products under FFDCA 

Section 408. However, MIT is listed as a food contact substance by FDA and four food contact 

notifications (FCNs) have been granted to Thor GmbH and Thor GmbH, Germany. FCN No. 999 

was granted to Thor GmbH for use as an antimicrobial agent for finished coating formulations and 

additives used in the manufacture of paper and paperboard including fillers, binders, pigment 

slurries, and sizing solutions. FCN No. 704 was granted to Thor GmbH, Germany for use as a 

preservative in resinous and polymeric coatings for polyolefin films. FCN No. 675 was granted to 

Thor GmbH, Germany for use as a preservative in aqueous coatings formulated. FNC No. 569 

was granted to Thor GmbH for use as an antimicrobial agent in polymer latex solutions intended 

for use in adhesives. FCN No. 999 was effective November 18, 2010 at a maximum level of 21 

ppm. FCN Nos. 704 and 675 were effective March 22, 2007 and February 8, 2007, respectively,

at a level not to exceed 45 mg/kg (based on isothiazolone active ingredients) in the aqueous 

coating formulation. FCN No. 569 was effective May 21, 2006 with no use rate limitations. 

These FCNs are only effective for the manufacturer or supplier identified in the notification.

One inert tolerance exemption exists for MIT/CMIT under 40 CFR Part 180.920. The use 

limitation is, “not more than 0.0022% (22.5 ppm) in the formulation; 0.00022% (or 2.25 ppm) in 

the final solution applied to growing crops.” “The above materials are exempted from the 

requirements of a tolerance when used in accordance with good agriculture practices as inert (or 

occasionally active) ingredients as pesticide formulations applied to growing crops only.” 

The Agency anticipates reviewing the existing tolerance exemption as well as the potential need 

for additional tolerances/exemptions during the registration review process.

1.6 Incidents

1.6.1 Human Health 

Incidents that are rated as moderate (HC) or higher are reported in individual reports which 

include information regarding the causes of the incident and symptoms experienced. There are 42

individual incident reports listed in the OPP Incident Database System (IDS) for MIT/CMIT for 

the period 1/1/1998 to the present (search conducted on 4/22/14). Thirty seven incidents are rated 

as moderate (HC), one incident is rated as severe (HB) and the remaining four are not rated (H).

The HB incident involved two employees of a paper mill who developed skin rashes in the year 

2000 after a MIT/CMIT product was introduced. One of the employees recovered with treatment 

while the other also experienced respiratory symptoms. Thirty eight of the HC/H incidents 

involved dermal exposure in the workplace and most of these incidents were caused by direct 
Page 13 of 56

contact with the product due to equipment failure, spills or lack of PPE. These exposures resulted 

in skin rashes, blisters and burns, some of which required medical treatment. Three of the HC/H 

incidents involved inhalation exposure with one each occurring in a paper mill, cooling tower and 

formulation plant.

Incidents that are rated as minor (HD) or that cannot be rated (HE) are reported in aggregate 

reports which are listings of the incidents for a manufacturer or distributer over a certain time 

period (often quarterly). Typically these reports only contain basic information such as the date, 

location and product involved and more detailed information such the cause of the incident or 

symptoms experienced are not included. There are 216 aggregate incident reports listed in the IDS 

for MIT/CMIT. Two hundred and eleven of these cases are rated as minor (HD) and the 

remaining five cases are not rated (HE). 

1.6.2 Ecological

No incidents have been reported from January 1998 until May 2014 according to a search of the

OPP Incident Database (IDS).

2 Anticipated Data Needs

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

review.
Page 14 of 56

Table 6 – Studies Anticipated as Needed for the Registration Review of MIT/CMIT

GLN Study Name Test 

Substance

Time Frame 

(Measured in 

months from 

DCI Receipt)

Risk 

Assessment(s) 

Data Will Support

Use Site(s) 

Triggering 

Anticipated Data 

Requirement

Applicable 

Exposure 

Scenario

Studies Anticipated to be Required through the Registration Review DCI

870.7800 Immunotoxicity TGAI 24 Occupational and 

Residential All All potential exposures

875.1100

875.1200

Dermal 

Exposure –

Outdoor and 

Indoor

TGAI or 

surrogate

24 Occupational and 

Residential

All See Tables 9 

and 10

875.1300

875.1400

Inhalation 

Exposure –

Outdoor and 

Indoor

TGAI or 

surrogate

24 Occupational and 

Residential

All See Tables 9 

and 10

875.1700 Product Use 

Information

TGAI 12 All All All

875.2300 Indoor Surface 

Residue 

Dissipation

TGAI 24 Residential Wood

Household Cleaning 

products

See Table 11

875.2500 Inhalation 

Exposure 

Chamber Study

TGAI in 

Paint

24 Occupational and 

Residential

Paint Handler and 

Post 

Application

850.3020 Honeybee acute 

contact

TGAI 12 Ecological Effects Wood preservative Used in hive 

construction

850.3030 Toxicity of 

residue to 

honeybees

TGAI 12 Ecological Effects Wood preservative Used in hive

construction
Docket Number EPA-HQ-OPP-2013-060

www.regulations.gov

Page 15 of 56

3 Human Health Risk Assessment

The agency anticipates the need to conduct a human health risk assessment for MIT/CMIT. The 

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

3.1 Existing Toxicological Endpoints

The agency’s Office of Pesticide Program Health Effects Division Toxicity Endpoint Selection 

Committee established endpoints to be used for assessing occupational and residential exposures 

(ORE) in the 1998 RED. These endpoints are listed in Table 7.

Table 7 – Toxicological End-Points for Assessing for MIT/CMIT ORE Exposures

Exposure

Scenario

Dose Used in Risk 

Assessment

Target MOE for Risk 

Assessment

Study and Toxicological 

Effects

Dermal Dermal Exposure. The primary concern is acute exposure as this chemical is corrosive. There is no 

systemic toxicological endpoint for risk characterization.

Dermal absorption Not available, because methylisothiazolinone is corrosive and a human skin sensitizer.

Inhalation 

Short and 

Intermediate –Term

NOAEL = 

0.34μg/l

Target MOE = 100

(10x inter-species extrapolation, 10x 

intra-species variation)

90-day rat inhalation study 

(MRID 00148418)

NOAEL = 0.34 and LAEL = 

1.15 μg/l, based on microscopic 

lesions in the nasal turbinates 

(rhinitis)

As summarized in Table 8, an acute and chronic RfD value of 0.02 mg/kg/day is used for 

preliminary screening purposes to assess dietary exposures. The final PODs will be determined 

during the registration review risk assessment and will be based on all available studies.

Table 8 – Toxicological End-Points for Assessing MIT/CMIT Dietary Exposures 

Exposure

Scenario

Dose Used in Risk 

Assessment

Target MOE for Risk 

Assessment

Study and Toxicological 

Effects

Acute and chronic 

Dietary

General Population,

including infants 

and children

NOAEL= 2 mg/kg/day UF = 100 (10x inter-species 

extrapolation, 10x intra-species 

variation)

FQPA SF= 1

DB UF = 1

RfD =0.02 mg/kg/day

Rat Chronic/Cancer Study 

(MRID 43140701) based on 

microscopic lesions in the 

stomach at 6 mg/kg/day.

3.2 Dietary Exposure

The agency will need to conduct a dietary exposure (food only) assessment to support 

registration review since no previous dietary assessments have been conducted for CMIT or 

MIT. Uses of CMIT or MIT that may result in dietary exposure (food) include pesticide 
Page 16 of 56

preservatives, adhesives, coatings, emulsions, paper/paper products, and household cleaning 

products. With respect to drinking water exposure, several approved uses as a material 

preservative and in industrial water systems have the potential to result in CMIT/MIT being 

discharged into waste water or leached from preserved materials and subsequently running off 

into surface water. 

3.2.1 Food

EPA anticipates the need to conduct dietary exposure assessments as part of the registration 

review process since they were not conducted for the 1998 RED. Uses that may result in dietary 

exposure include: pesticide preservatives, adhesives, coatings, emulsions, paper/paper products, 

and household cleaning products. Initially, a screening-level analysis will be conducted.

Residue chemistry data are not anticipated to be required at this time. The dietary exposure 

contribution will be considered in the aggregate assessments conducted during registration 

review. It is important to note that if the toxicological point of departure for either the acute or 

chronic scenario changes during the registration review process, additional residue chemistry 

data may be required.

3.2.2 Drinking Water

A drinking water assessment has not been conducted for MIT or CMIT in the past. There are

several approved uses (including wood treatment, industrial processes and water systems) that 

create the potential for MIT and CMIT to enter surface water. However, the environmental fate 

data on degradation indicate that MIT and CMIT are non-persistent and will biodegrade rapidly

to form straight-chain nitrogenous carboxylic acids that eventually mineralize to carbon dioxide 

and formic acid. Therefore, residues of these compounds are not expected to be found in 

drinking water.

3.3 Occupational and Residential Exposures

The agency anticipates the need to revise the occupational and residential (ORE) assessment (US 

EPA, 1995) that was conducted in support of the 1998 RED. The ORE assessment will need to 

be revised to account for the toxicology studies that were submitted after the RED and to utilize 

the exposure data that is anticipated to be needed for registration review. The occupational and 

residential assessment will consider the labelled use as a pesticide preservative.

3.3.1 Occupational Handler Exposure

Occupational handler exposures were assessed in the ORE Assessment for the RED (US EPA, 

1995) for representative industrial processes and water system uses (oil well injection fluid and 

drilling mud, cooling towers, pulp and paper) as well as representative material preservation uses 

(paints and metal working fluids). The inhalation exposures were assessed using the NOAEL of 

0.00034 mg/liter (0.049 mg/kg/day) from a 90 day inhalation toxicity study (MRID 00148418) 

and the resulting MOEs ranged from 190 to 25,000 which were greater than the target MOE of 

100. The dermal exposures were not assessed due to the corrosivity of MIT and gloves were 

specified by the RED instead. 
Page 17 of 56

The occupational handler scenarios as listed in Table 9 will need to be assessed during 

registration review. Scenarios 1 and 2 were assessed in RED and will need to be reassessed to 

account for the toxicology studies that were submitted after the RED and to utilize the exposure 

data that is anticipated to be needed for registration review. Scenarios 3 through 6 were not 

assessed in the RED due to a lack of exposure data and will be assessed utilizing the exposure 

data that is anticipated to be needed for registration review. Dermal exposures do not need to be 

assessed for Scenarios 1 and 6 because these scenario involve the use of end use products and the 

exposures are mitigated the use of chemical resistant gloves as required by the product labels.

Table 9 – Occupational Handler Exposure Scenarios for MIT/CMIT

Scenario Exposure Route(s) Duration

1. Open Pour Addition for Industrial Process/Water Systems 

Treatment and Material Preservation Inhalation Short and Intermediate Term

2. Brush/Roller Application of preserved paints Dermal, Inhalation Short and Intermediate 

Term

3. Airless sprayer application of preserved paints Dermal, Inhalation Short and Intermediate 

Term

4. Machinist Exposure to preserved MWF Dermal, Inhalation Short and Intermediate 

Term

5. Mop, wipe and spray application of preserved cleaning products Dermal, Inhalation Short and Intermediate 

Term

6. Wood Pressure Treatment Inhalation Short and Intermediate 

Term

3.3.2 Residential Handler Exposures

Residential handler inhalation exposures to MIT were assessed in the RED for brush/roller 

application of MIT treated paints. The inhalation MOE for brush/roller application was 25,000 

and was not of concern because it exceeded the target MOE of 30. Inhalation exposures during 

airless sprayer application or mop wipe and spray application of preserved cleaning products 

were not assessed in the RED due to the lack of exposure data and will need to be assessed 

during registration review. 

The residential handler scenarios as listed in Table 10 will need to be reassessed during 

registration review to account for the toxicology studies that were submitted after the RED and 

to utilize the exposure data that are anticipated to be needed for registration review. 

Table 10 – Residential Handler Exposure Scenarios for MIT/CMIT

Scenario Exposure Route(s) Duration

Brush/Roller and Airless Spray application of preserved paints Dermal, Inhalation Short and Intermediate 

Term

Mop, wipe and spray application of preserved cleaning products Dermal, Inhalation Short and Intermediate 

Term
Page 18 of 56

3.3.3 Residential Post-Application Exposures

Residential post application exposures were not assessed in the RED due to the lack of available 

data. The residential post application scenarios as listed in Table 11 will need to be reassessed 

during registration review to account for the toxicology studies that were submitted after the 

RED and to utilize the exposure data that are anticipated to be needed for registration review. 

Table 11 – Residential Post-Application Exposure Scenarios for MIT/CMIT

Scenario Exposure Route(s) Duration

Post application exposure to floors and carpets cleaned with 

preserved household cleaning solutions. 

Dermal 

Incidental Oral 

Short and Intermediate 

Term 

Post application exposure to treated wood Dermal 

Incidental Oral 

Short and Intermediate 

Term 

Post application exposure to MIT vapors in rooms painted with 

preserved paints Inhalation Short and Intermediate Term 

3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures 

EPA anticipates the need to revise the aggregate assessment conducted in support of the 1995

RED. Upon a reevaluation and selection of toxicological endpoints, combined with the human 

health exposure assessments expected as a part of this registration review case, aggregate 

exposures will need to be assessed. This assessment will include dietary (food) exposures and 

residential exposures. 

3.4.2 Cumulative Exposures 

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a 

cumulative risk approach based on a common mechanism of toxicity, EPA has not made a 

common mechanism of toxicity finding as to MIT and CMIT and any other substances and MIT 

and CMIT do not appear to produce a toxic metabolite produced by other substances. For the 

purposes of this registration review, therefore, EPA has not assumed that MIT and CMIT have a 

common mechanism of toxicity with other substances. For information regarding EPA’s efforts 

to determine which chemicals have a common mechanism of toxicity and to evaluate the 

cumulative effects of such chemicals, see http://www.epa.gov/pesticides/cumulative/.

4 Environmental Risk Assessment

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

species determination for 5-chloro-2-methyl-3(H)-isothiazolone. Although based on numerous 

uses of CMIT, potential pathways of exposure to aquatic organisms include transport from inservice use to surface water by way of wastewater treatment plants (WWTPs), leaching from 

treated films on terrestrial structures and subsequent runoff to surface water, and leaching from 

pressure-treated wood in terrestrial environments and subsequent runoff to surface water. Even 

though there are potential pathways by which CMIT and MIT can reach the aquatic environment, 

these chemicals degrade very rapidly via biotic processes. CMIT and MIT by in-service use to 

wastewater treatment plants would not be expected to be persistent enough to enter surface water 
Page 19 of 56

downstream of WWTPs. Any CMIT and MIT that leach out of products and are subsequently 

transported to surface water via runoff would not be expected to persist in the terrestrial and 

aquatic environments based on their rapid potential to degrade by biotic processes (MRIDs 

42086901, 43753203, -04 and -05). 

Although the oilfield uses are limited to the terrestrial environment, releases from these uses 

have the potential to reach ground water if wells are not properly cased and to reach surface 

water if storage ponds overflow. Due to the lack of persistence of CMIT and MIT, however, the 

agency is not planning to conduct an ecological risk assessment.

4.1 Environmental Fate Assessment

Even though there are potential pathways by which CMIT and MIT can reach the aquatic 

environment, these chemicals degrade very rapidly via biotic processes. CMIT and MIT by inservice use to wastewater treatment plants would not be expected to be persistent enough to enter 

surface water downstream of WWTPs. Any CMIT and MIT that leach out of products and are 

subsequently transported to surface water via runoff would not be expected to persist in the 

terrestrial and aquatic environments based on their rapid potential to degrade by biotic processes

(MRIDs 42086901, 43753203, -04 and -05). Due to the lack of persistence of CMIT and MIT, 

the agency is not planning to conduct an ecological risk assessment.

Based on the chemical, physical, and environmental fate properties of CMIT and MIT (Table 4 

and Appendix B) in the aquatic environment are expected to be soluble in water and to rapidly 

degrade to straight-chain nitrogenous carboxylic acids that eventually mineralize to carbon 

dioxide and formic acid. The low log Kow of CMIT and MIT indicate that sorption to soil, 

sludge, and sediments and bioconcentration in aquatic organisms are expected to be limited. 

CMIT and MIT present in aqueous media are not likely to partition into air based on the low 

Henry’s Law constants (of 5.4 x 10-9and 4.2 x 10-8atm m3 mol-1), but based on their vapor 

pressures (10-2 mm Hg), these chemicals could volatilize from soil. 

CMIT (parent compound, 5-chloro-2-methyl-4-isothiazolin-3-one) degrades by dechlorination to 

form MIT (dechlorinated CMIT, methyl-3(2H)-isothiazolone), which then loses a sulfur in the 

process of ring cleavage to form the straight-chain degradate, N-methyl malonamic acid 

(NMMA). NMMA is a low-molecular weight nitrogenous carboxylic acid compound that 

undergoes demethylation and loss of CO2 (decarboxylation) by biotic processes to eventually 

form the terminal degradates, formic acid and CO2. However, NMMA is stable to abiotic 

degradation (MRIDs 42086901, 43753203, -04 and -05).

4.1.1 Leaching (Wood/Paint/Antifoulant Paint/Plastic/Textiles/e.g., treated 

article)

CMIT and MIT are expected to leach from treated wood into water, but no leaching studies have 

been submitted to the agency for the paint and textile uses. The registrant conducted a wood 

leaching study using Southern Yellow Pine and five water types, including separate treatments of 

distilled, deionized (DI) water, artificial seawater, and pH 5, 7, and 9 buffer solutions. For all 

treatments, approximately 55 % of CMIT and MIT leached in first 5 days and approximately 75-

80 % leached in 28 days (MRID 43478401). 
Page 20 of 56

Even though leaching studies have been submitted for the paint and textile uses, the agency is 

not planning on requiring them because the leaching from treated wood is expected to create the 

highest exposure. Also, CMIT and MIT degrade rapidly by biotic processes in the environment 

(MRIDs 42086901, 43753203, -04, -05). 

4.1.2 Water and Sediment

CMIT and MIT are both miscible in water (Table 6) and are expected to preferentially partition 

to the water phase of the aqueous environment rather than to sediment, air, and fish. For CMIT, 

the Freundlich Kads values, which predict partitioning to whole soil and sediment, ranged from 

0.08-4.9 L/kg for five soils with a mean of 1.5 L/kg. Data on sorption of MIT to soil was not 

submitted, but MIT is expected to be an unstable degradate and data on CMIT represents both 

parent CMIT and the degradate MIT. The experimentally-determined Koc values, which 

represent the potential for sorption to the organic carbon portion of soil and sediment, ranged 

from 30-310 L/kg in five soils (MRID 42086902, OCSPP 835.1230). Based on these Koc 

values, CMIT is expected to be mobile to moderately mobile based on the FAO classification 

system. 1 CMIT and MIT have Henry’s Law constants of 10-9to 10-8atm m3 mol-1, indicating 

that partitioning to air from aqueous media is not a significant route of dissipation (Table 6). 

CMIT is reportedly not likely to bioconcentrate in fish to a significant degree based on relatively 

low reported BCF values of 41-54X for two concentrations tested (MRID 44113102). This study

has been screened but not reviewed. It will be reviewed during the registration review process.

The degradation rate of CMIT and the extent of degradate formation and decline depends on the 

route of degradation (abiotic or biotic). Abiotic dissipation routes include hydrolysis (OCSPP 

835.2120) and photodegradation in water (OCSPP 835.2240). For parent CMIT, abiotic 

degradation only occurs at pH 9 with half-lives ranging from 13-17 days for hydrolysis in four 

studies (MRIDs 43971801, 44700501, 42681301, and 42578401) and 6.6 days for 

photodegradation in water (MRID 43753201). The half-life for photodegradation in water for 

MIT was 12.3 days (MRID 43753202). For both hydrolysis and photodegradation, apparent 

accumulation of the degradate NMMA occurs and NMMA did not photodegrade. These 

photodegradation in water studies have been screened but not reviewed. They will be reviewed 

during registration review process. Half-lives of CMIT from biotic degradation processes were 

reported to be 5.3 hours based on an anaerobic aquatic metabolism study (OCSPP 835.4400, 

MRID 43753203) and 9.5 hours based on an aerobic aquatic metabolism study (OCSPP 

835.4300, MRID 43753204). In these aquatic metabolism studies, no major degradates (>10 % 

of applied parent compound) were detected. These aquatic metabolism studies have not been 

formally-reviewed and will be reviewed during the registration review process. Based on these 

results, microbial degradation in the aquatic environment is expected to rapidly degrade CMIT 

and MIT. 

4.1.3 Soil

The registrant has submitted data for CMIT for aerobic soil metabolism (OCSPP 835.4100). 

CMIT was reported to degrade with a half-life of 5.4 hours in aerobic soil but did not form any 

 

1 http://www.fao.org/docrep/003/x2570e/x2570e06.htm
Page 21 of 56

significant non-volatile degradates, indicating that mineralization of these degradates was 

occurring. Of the applied parent compound, 90 % degraded within 2 days (MRID 42086901). 

Data on anaerobic soil metabolism (OCSPP 835.4200) have not been submitted to the agency, 

but the registrant has submitted anaerobic aquatic metabolism data (MRID 43753203) which 

have not been reviewed. If the anaerobic aquatic metabolism data are reviewed and found to 

satisfy the 835.4400 data requirement, then anaerobic soil metabolism would not be anticipated 

to be required.

4.1.4 Air

CMIT and MIT are both miscible in water (Table 6). CMIT and MIT have Henry’s Law 

constants of 10-9to 10-8atm m3 mol-1, indicating that partitioning from water into air is not a 

significant route of dissipation (Table 6). Based on the vapor pressures of 10-2 mm Hg, however,

volatilization from soil into air at the soil/air interface could be a significant route of dissipation. 

If CMIT or MIT reach air, they would be expected to persist since they do not photodegrade 

rapidly in the presence of sunlight.

4.1.5 Fate and Transport in Wastewater Treatment Plants (WWTPs)

Data on degradation of CMIT and MIT during wastewater treatment have not been submitted. 

Sorption to sludge is not likely based on the low log Kow values of 0.40 and -0.49 for CMIT and 

MIT, respectively (Table 5). Based on the reported anaerobic and aerobic aquatic metabolism 

half-lives ranging from about 5 to 9 hours, rapid degradation of CMIT and MIT to NMMA is 

indicated (MRIDs 42086901, 43753203, -04, -05). Consequently, any CMIT and/or MIT that 

persists long enough to reach a wastewater treatment plant from its point of discharge would not 

be expected to persist long enough to enter surface water. The straight-chain degradates,

including NMMA, are transient degradates that are rapidly biodegraded and were not reported to 

be formed at significant quantities (>10 % of applied parent) in metabolism studies (MRIDs 

42086902, 43753203, -04, -05). In addition, these are not expected to enter surface water from 

WWTPs. 

4.1.6 Water Quality

CMIT is not identified as a cause of impairment for any water bodies listed as impaired under 

section 303(d) of the Clean Water Act2. In addition, no Total Maximum Daily Loads (TMDL) 

have been developed for CMIT3. More information on impaired water bodies and TMDLs can be 

found at EPA’s website4.

4.2 Environmental Exposure Pathways

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

properties, and environmental fate data presented in Table 4 and Appendix B, the agency has 

determined that products that contain CMIT and its degradate, MIT, can be released to the 

 

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

3http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_

group_name=PESTICIDES

4 http://www.epa.gov/owow/tmdl/
Page 22 of 56

terrestrial and aquatic environment from leaching and runoff from treated materials. CMIT and 

MIT, however, are not expected to be persistent in the terrestrial and aquatic environment 

because of microbial degradation, with reported half-lives of 5-9 hours to nitrogenous, lowmolecular weight carboxylic acid compounds that eventually mineralize to CO2 (MRIDs 

43753203 and 43753204). Data on degradation and sorption in WWTPs have not been 

submitted, but sorption to sewage sludge is expected to be minimal based on the low log Kow of 

0.40 and -0.49 for CMIT and MIT, respectively (Table 5). Even though biotic degradation is a 

significant route of dissipation for CMIT and MIT, abiotic degradation (hydrolysis and 

photodegradation) is not (MRIDs 43971801, 44700501, 42681301, 42578401, 43753201, and 

43753202). Sorption to soil and sediment is not expected to be significant for CMIT and MIT 

based on experimentally-determined low Freundlich adsorption coefficients of 0.08-4.9 L/kg 

(MRID 42086902). 

4.3 Ecological Effects Assessment

MIT is moderately toxic to practically nontoxic to avian species, but highly toxic to freshwater 

fish and invertebrates. MIT is moderately toxic to highly toxic to marine/estuarine species. A 

risk assessment will not be completed on aquatic non-target species based on a lack of exposure 

due to a lack of persistence because of microbial degradation. However, a risk assessment on 

honeybees will need to be completed because of the wood preservative uses of MIT. The 

anticipated studies, honeybee acute contact study (850.3020) and toxicity of residues to honey 

bee study (850.3030), will need to be completed and submitted by the registrant. Once these

data have been submitted to the agency, a risk assessment can be completed on the wood 

preservative uses of MIT. 

4.3.1 Mode of Action

MIT inhibits the tyrosine phosphorylation of a protein, focal adhesion kinase (FAK), by another 

kinase called SrC, preventing the growth of axons and dendrites which are the major components 

of nerve cells (He et.al. 2006). MIT and CMIT are considered toxicologically the same.

4.3.2 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aquatic and terrestrial organisms. 

All available ecotoxicity endpoints in the agency’s files from MIT studies submitted by 

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

tabulated in Appendix C along with the data requirements and data gaps. The most sensitive 

values for each receptor group are used for the risk assessment (Table 12). For aquatic species 

(plants and animals), the agency does not anticipate conducting an aquatic ecological risk 

assessment because CMIT and MIT degrade rapidly, and as a result, environmental exposure is 

expected to be minimal. In addition, CMIT and MIT form straight-chain nitrogenous carboxylic 

acids that eventually mineralize to carbon dioxide and formic acid. Ecotoxicity endpoints will be 

needed for honeybees because of the wood preservative use pattern. 
Page 23 of 56

Table 12 – Selected Ecological Effects Endpoints for Risk Assessment for MIT/CMIT

Receptor 

Group Surrogate Species Risk Scenario Toxicity Endpoint Reference

Freshwater fish

 Rainbow trout Acute 96-h LC50 = 0.07 ppm MRID# 

41963503

Fathead minnow Chronic MATC = 0.035 ppm MRID# 

42012201

Freshwater 

invertebrates Daphnia

Acute 48-hr EC50 = 0.18 ppm MRID# 

41718803

Chronic MATC = 0.13 ppm MRID# 

41963502

Freshwater benthic 

invertebrates

Subchronic/

Chronic Not requiredA

Estuarine/marine fish Sheepshead minnow Acute LC50 = 0.36 ppm MRID# 

00042556

Chronic Not requiredB

Estuarine/marine 

invertebrates

 Eastern oyster Acute EC50 = 0.028 ppm MRID# 

00042558

Shrimp Acute LC50 = 2.3 ppm MRID# 

00042559

Chronic Not requiredB

Estuarine/marine 

benthic invertebrates

Subchronic/

Chronic Not requiredA

Algae Non-listed Not requiredD

Listed Not requiredD

Aquatic vascular 

plants Duckweed

Non-listed Not requiredD

Listed

Seedling Emergence Non-listed Not requiredB

Listed

Vegetative vigor Non-listed Not requiredB

Listed Not requiredB

Birds

Bobwhite quail Acute LD50 = 62.7 mg/kg MRID# 

41719501

Mallard duck Subacute 

dietary

LC50 =717 ppm MRID# 

41719503

Chronic Not requiredB

Mammals Rat

Acute LD50 = 105 mg/kg MRID# 86092

Chronic Not requiredB

Nontarget insects Honey bee Acute RequiredC

A Fate data indicate that the chemical will not accumulate in the soil.

B For the MIT use patterns, exposure to these non-target organisms is not considered to be a pathway of concern.

C For wood preservative use pattern, exposure of terrestrial beneficial insects could be considered to be a pathway of concern.

D For the MIT use patterns, exposure to plants is not expected because of rapid degradation in the environment. In addition, CMIT and MIT form 

low-molecular weight, straight-chain nitrogenous acids that mineralize to form CO2 and formic acid.
Page 24 of 56

4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available OPP models will be used to determine the estimated environmental concentration 

(EECs) in the aquatic environment if an exposure assessment is necessary. However, the agency 

does not anticipate the need to conduct an ecological assessment because CMIT and MIT 

degrade rapidly which will create only minimal exposure. 

4.4.2 Screening Level Down-the-Drain Analysis

Based on negligible potential for exposure due to rapid degradation of CMIT and MIT, a Downthe-Drain Analysis is not expected to be performed.

4.5 Effects Analysis Plan

Additional open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) 

database. The ECOTOX database will be searched during the risk assessment phase of 

MIT/CMIT and the data reviewed following the Agency’s policy for reviewing public literature 

for use in assessing risks from pesticides

5

. Those ecotoxicity values found in the public literature 

to be more sensitive than those currently in Table 12 and or which satisfy an existing data gap(s) 

will be used during the risk assessment phase of MIT/CMIT to update Table 12. ECOTOX was 

created and is maintained by the USEPA, Office of Research and Development, and the National 

Health and Environmental Effects Research Laboratory's Mid-Continent Ecology Division.

5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

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

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

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

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

taxonomic groups. As part of reregistration decision for MIT/CMIT, 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), MIT/CMIT 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 

 

5

http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/endangered_species_reregistration_work

group/esa_evaluation_open_literature.htm
Page 25 of 56

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

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

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

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

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

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

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

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

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

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

which contains 58 pesticide active ingredients and 9 inert ingredients. MIT/CMIT is not among 

the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. 

Accordingly, as part of registration review, EPA will issue future EDSP orders/data call-ins, 

requiring the submission of EDSP screening assays for MIT/CMIT.

For further information on the status of the EDSP, the policies and procedures, the list of 67 

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

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

6 Optional Label Changes

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

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

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

clarity.

7 Guidance for Commenters

7.1 Preliminary Work Plan

The public is invited to comment on EPA’s Preliminary Work Plan and rationale. The Agency 

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

timely manner prior to issuing a final work plan for the MIT/CMIT 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.
Page 26 of 56

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 Process6in 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 MIT/CMIT compared to the general population. Please 

comment if you are aware of any sub-populations that may have atypical, unusually high 

exposure compared to the general population.

7.1.4 Structure Activity Relationships 

EPA must rely upon information of appropriate quality and reliability for each decision made by 

the agency. In the OPP, the evaluation process for a pesticide chemical traditionally begins with 

the applicant’s submission of a set of studies conducted with the specific pesticide chemical of 

interest. The use of the results of such testing (measured data) is a logical, scientifically rigorous 

process that identifies the physical, chemical, and environmental fate properties of the pesticide, 

as well as the dose and endpoints at which an adverse effect can occur in various animal species. 

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

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

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

decision-making process. In the SAR process, a chemical's molecular structure is compared to 

that of other chemicals for which data are available. These structural similarities are then used to 

make predictive judgments about a chemical’s physical, chemical, and biological properties. 

Thus, the chemical’s physical, chemical, and biological properties are a function of (or directly 

related to) the chemical’s molecular structure. Quantitative SAR is referred to as QSAR. To 

develop a QSAR, a selected set of measured data on a single physical, chemical, or biological 

property is used to derive a model (an equation) to predict the value of that property. 

Since SAR assessments and QSAR modeling are another set of tools that are available to agency 

scientists, OPP has begun a process shift that envisions shifting from the current study-by-study 

approach to an approach in which the use of predicted data, generated using validated models, is 

considered along with information from open literature and studies specifically generated under 

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

 

6 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm
Page 27 of 56

At this time, EPA believes that for certain endpoints, especially physical/chemical and fate 

properties, that SAR and QSAR might be effectively utilized to fulfill these data requirements 

for many antimicrobial pesticide chemicals. When considering biological properties, at this time, 

EPA believes that SAR and QSAR can be most effectively utilized in the evaluation of 

chemicals that exhibit lower toxicity for human health and/or ecotoxicity parameters. This is 

appropriate because the risk assessment for lower toxicity chemicals can be stream-lined, i.e., a 

screening-level assessment procedure rather than multiple tiers of assessments with progressively 

more data requirements. 

If stakeholders believe that submission of predicted data can fulfill one of the data needs for the 

MIT/CMIT case, then the agency invites submission of this information. The submitter would be 

expected to supply a rationale describing the utility of the information and provide 

documentation on the scientific validity of the information. The determination that the predicted 

data fulfills the data requirement would be at the sole discretion of the Agency. Pre-submission 

consultation with the Agency is encouraged. 

7.1.5 Additional Information 

Stakeholders are also specifically asked to provide available information and data that will assist 

the agency in refining its risk assessments, including any species-specific ecological effects 

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

1. Confirmation on the following label information: 

A. Sites of application 

B. Formulations 

C. Application methods and equipment 

D. Maximum application rates 

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

applications 

F. Geographic limitations on use 

2. Use or potential use distribution 

3. Use history 

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

5. Typical application interval 

6. State or local use restrictions 

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

mammalian mortalities) not already reported to the agency 

8. Monitoring data 

8 Next Steps

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

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

case.
Page 28 of 56

9 References 

U.S. Environmental Protection Agency (EPA). 2002. ECOTOX User Guide: ECOTOXicology 

Database System. Version 3.0. Available: http://www.epa.gov/ecotox/.

U.S. Environmental Protection Agency. High Production Volume Information System (HPVIS). 

http://www.epa.gov/hpvis/.
Page 29 of 56

Appendix A Toxicology Profile

Acute Toxicity for Product Labeling

As summarized in Table A1, the acute toxicological data indicate that methylisothiazolinone is 

highly to very highly toxic by acute oral, dermal, and inhalation routes of exposure. It is 

corrosive to eyes and cause severe irritation to skin (Toxicity category I). Methylisothiazolinone

is a dermal sensitizer.

Table A1 Methylisothiazolinone Acute Toxicity Data

Guideline No./ Study Type Result Toxicity

Category (MRID #)

870.1100/ 

Acute oral toxicity

Rats: Both Sex = 105 mg/kg II 86091

870.1200/ 

Acute dermal toxicity

Rabbit: Both Sex = 200 mg/kg I 86092

870.1300/ 

Acute inhalation toxicity

Rat: 0.33mg/L II 41963501

42360901

42360902

870.2400/ 

Acute eye irritation - Rabbit

Corrosive I 86092

870.2500/ 

Acute dermal irritation

Severely irritation I 86092

870.2600/ 

Skin sensitization

Sensitizer 144880

Subchronic Toxicity 

There are three acceptable subchronic toxicity studies: one oral (drinking water) rat study, one 

dermal rat study and one inhalation study.

90 Day Oral (Drinking Water)- Rat; 42810101

Under the conditions of the study, exposure to Kathon 886F at dose levels 25, 75 and 225 ppm 

(males- 2.4, 6.3 and 16.3 mg/kg; females - 4.1, 10.8 and 24.7 mg/kg) resulted in decreases in 

body weight, body weight gain, and food consumption (all of which were minimal), and water 

consumption. Although differences in several parameters were observed (decreased cholesterol 

in females, increased SGOT in females, decreased BUN, foci of erosion and focal blunting of the 

superficial epithelium of the glandular mucosa of the stomach in both sexes), there were no 

toxicologically significant effects observed in either sex. The NOEL is 75 ppm (males 6.3 

mg/kg/day; females 10.8 mg/kg/day). The LOEL is 225 ppm (males 16.3 mg/kg/day; 

females 24.7 mg/kg/day), based on microscopic findings (focal blunting) in the stomach in 

both sexes.
Page 30 of 56

90 Day Inhalation- Rat; 148418

In a subchronic inhalation toxicity study, the exposure of 16 Crl:CD(SD)BR rats/sex/group to 

methylisothiazolinone (14% a.i.) at dose levels of 0.34, 1.15, or 2.64 mg/m3via inhalation for 90 

days resulted in decreased body weight in the high-dose males (Ca. 90% of control) and 

decreased body-weight gains in both sexes (males ca. 84%; females Ca. 89%) at the high-dose 

level. There were no treatment-related deaths, and no effects were observed in the hematology, 

clinical chemistry, ophthalmoscopic, and gross pathology parameters monitored that could be 

attributed to treatment. Treatment-related lesions in the nasal turbinate were observed at the midand high-dose levels, which consisted of eosinophilic droplets in the anterior respiratory mucosa 

(2.64 mg/m3) and rhinitis in the lining of the anterior portion of the nasal cavity (1.15 and 2.64 

mg/m3). These are consistent with a normal physiological response to a respiratory irritant. The 

NOAEL is 0.34 μg/l. The LOAEL is 1.15 μg/l, based on microscopic lesions in the nasal 

turbinates (rhinitis). With the exception of decreased body-weight gain, there were no 

toxicologically significant effects observed in either sex, but the corrosive properties of 

methylisothiazolinone imposed limitations on the dose levels tested for any duration. 

90 Day -Dermal - Rat; 43462005

Under the conditions of this subchronic toxicity study (MRID 43462005), dermal administration 

of methylisothiazolinone [13.9% formulation] to Crl:CD(SR)BR rats [10/sex/group] for 13 

weeks at dose levels of 0, 0.75, 3.75 and 18.75 mg/kg/day resulted in skin effects at all dose 

levels in females and at the mid-and high-dose levels in males. There were no adverse effects on 

survival, body weight gain, food consumption, hematology, clinical chemistry, urinalysis, 

ophthalmoscopy, gross and microscopic lesions [except skin] at any dose level in either sex. The 

dermal LOAEL is < 0.75mg/kg/day based on skin effects. The NOAEL for systemic effects 

can be set at 18.75 mg/kg/day, the highest dose tested. This subchronic study is classified 

Acceptable, and it satisfies the guideline requirement [82-3] for a subchronic dermal toxicity 

study in the rat. 

Developmental Toxicity 

There are two acceptable-guideline developmental toxicity studies in rat and rabbit, respectively.

Rat 

Exposure of Sprague-Dawley CR® rats (25 dams/group) to methylisothiazolinone (14% a.i.) via 

gavage (days 6-15 of gestation) at dose levels of 0 (distilled H2O), 10, 30, or 100 mg/kg/day 

resulted in a dose-related decrease in maternal body-weight gains (62% of control at mid-dose 

and 41% of control at high-dose level) during treatment and a dose-related increase in maternal 

death (control 0/25, low 1/25, mid 2/25, high 3/25). There were no effects on pregnancy rate, 

numbers of corpora lutea, implantations, resorptions, and/or live fetuses; pup weights, sex ratios, 

and crown-rump length were comparable among the groups. There were no adverse findings 

from the visceral or skeletal examinations of the fetuses that could be attributed to treatment. 

Methylisothiazolinone was not found to be fetotoxic, embryotoxic, or teratogenic in rats. The 

maternal toxicity NOAEL is 10 mg/kg/day. The maternal LOAEL is 30 mg/kg/day, based on 

decreased body-weight gains, with support from the dose-related increase in deaths. The 
Page 31 of 56

NOAEL for developmental toxicity was 100 mg/kg/day, the highest dose tested (GDLN 83-

3(a); MRID #78831). 

Rabbit 

In a developmental toxicity study, dose levels of 0.5, 2, 8, or 20 mg methylisothiazolinone 

(13.4% a.i.)/kg body weight per day to presumed-pregnant New Zealand white rabbits 

(16/group) during days 7 through 19 of gestation resulted in: (1) death and gross pathological 

lesions of the stomach at the highest dose (all animals either died or were sacrificed moribund by 

day 15 of gestation); (2) scant or no feces and diarrhea at the 8 and 20 mg/kg/day dose levels; 

and (3) decreased overall body-weight gain (70% of control), corrected body weight (92% of 

control), and food consumption at the 8 mg/kg/day dose level. The numbers of implantations, 

live fetuses, resorptions, dead implants, and dead fetuses per doe were comparable among the 

groups, and fetal body weight (combined and per sex) was comparable among the groups. 

Although there were no statistically significant differences in the incidence of any fetal alteration 

(external, visceral or skeletal malformations, variations, or 13 retarded development), there was a 

tendency for these to occur to a greater degree at the 8 mg/kg/day dose level than in the control 

or other treatment groups. The maternal toxicity NOEL is 2 mg/kg/day. The maternal toxicity 

LOEL is 8 mg/kg/day, based on decreased bodyweight gain, corrected body weight, food 

consumption, and scant/no feces and diarrhea. The developmental toxicity NOEL is 2 

mg/kg/day. The developmental toxicity LOEL is 8 mg/kg/day, based on the slight increase in 

fetal alterations (GDLN 83-3(b); MRID #42311701). 

Reproductive Toxicity

There are three acceptable two generation reproductive toxicity studies: two tested with 3:1 

CMIT and MIT mixture solution and one tested with MIT solution only.

Rat – (MRID 44656101) – Testing with methylisothiazolinone (3:1 CMIT and MIT)

Methylisothiazolinone (14.8% a.i.; Lot No. 0517A001) was administered to groups of 26 male 

and 26 female Crl:CD®BR rats at drinking water concentrations of 0 (water control), 0 (salt 

control), 30, 100, or 300 ppm for two generations. Concentrations in the drinking water were 

based on per cent active ingredient of the test article. The salt control group received water 

containing 15.88% magnesium nitrate and 6.19% magnesium chloride, equivalent to the 

concentrations of these salts in the high dose group. One litter was produced in each generation. 

Premating doses were 2.8, 8.5, and 22.7 mg/kg/day, respectively, for F0 males and 4.4, 11.8, and 

28.0 mg/kg/day, respectively, for F0 females. Premating doses were 4.3, 13.4, and 35.7 

mg/kg/day, respectively, for F1 males and 5.5, 16.0, and 39.1 mg/kg/day, respectively, for F1

females. F1 adults were chosen from the F1 pups and administered the same drinking water 

concentration as their parents. Animals were given treated or control water for at least 10 weeks 

before mating within the same dose group. All animals were continuously exposed to test 

material either in the drinking water or during gestation and lactation until sacrifice. 

Several intercurrent deaths of the F0 males were considered incidental to treatment. No 

treatment-related clinical signs of toxicity were observed in males or females of either generation 
Page 32 of 56

at any time during the study. Food consumption was not affected by treatment. Gross necropsy 

of the parental animals was unremarkable.

Body weights and body weight gains of the low- and mid-dose P males and females and of all 

treated F1 males and females were not affected at any time during the study. Body weight gain 

of the P high dose males and females were similar to the controls showing changes of <10%. 

Body weights of the high-dose P males were significantly (95-96% of control; p  0.05) less than 

the water control group, but not different from the salt control group, during weeks 2-4. 

Cumulative weight gains by the high-dose P males were significantly (78-91% of controls; p 

0.05) less than both control groups through week 5 of the premating interval. Absolute body 

weights of the high-dose P females were similar to both control groups throughout the premating 

interval. Body weight gains by the high-dose P females were significantly (80-81% of controls; 

p  0.05) less than both control groups during week 0-1.

In the mid- and high-dose P and F1 males and females, water consumption was significantly (p

0.05) less than one or both control groups throughout the premating interval. As compared to 

one or both control groups, water consumption by the mid- and high-dose groups was 70.5-

91.9% and 65.5-73.8%, respectively, by P males, 63.3-83.3% and 49.4-68.2%, respectively, by P 

females, 74.4-91.7% and 63.5-79.7%, respectively, for F1 males, and 62.7-82.3% and 47.5-

70.2%, respectively, for P females. Water consumption by the low-dose P males and females 

and F1 males was occasionally significantly (p  0.05) less than one or both control groups. 

Low-dose F1 females had significantly (71.6-89.4% of controls; p  0.05) reduced water 

consumption throughout premating as compared to one or both control groups. Similar 

decreases in water consumption were observed for the P and F1 females during gestation and 

lactation and are considered a continuation of the systemic effects.

Histopathological examination of the reproductive organs from the P and F1 adults was 

unremarkable. Treatment-related microscopic findings were observed in the stomachs of the

high-dose parental animals of both generations: focal superficial erosions, edema and 

inflammation in the submucosa of the glandular and non-glandular areas (except F1 females) and 

hyperplasia and hyperkeratosis of the limiting ridge of the non-glandular stomach occurred vs. 

the controls. The mid dose level animals of both generations showed an increase in hyperplasia/ 

hyperkeratosis compared to the controls while the F1 females showed an increase in erosions. 

Other lesions, in both sexes and generations seen at the mid dose levels were comparable to the 

controls. 

Therefore, the LOAEL for parental toxicity is 100 ppm [8.5, 11.8 mg/kg/day, P 

males/females] based on reduced water consumption and histopathological lesions in the 

stomach of P and F1 males and females. The systemic toxicity NOAEL is 30 ppm [2.8/4.4 

mg/kg/day, P males/females] .No treatment-related effects were noted on maternal body 

weights, body weight gains, or food consumption during gestation and lactation. Mating, 

fertility, gestation, and parturition indices, mean precoital interval, and mean gestation length 

were similar between the treated and control groups of both generations. Mean litter size, live 

births, and pup survival were also similar between the treated and control groups for both 

generations. No treatment-related clinical signs of toxicity were observed in the F1 or F2 pups 

during lactation. 
Page 33 of 56

Mean pup body weights during lactation were similar between the treated and control groups for 

both generations. Gross necropsy of the pups was unremarkable. No histological lesions in the 

stomach were observed in the pups.

Therefore, the NOAEL for reproductive toxicity is 300 ppm (HDT) [22.7/ 28.0, P

males/females]; the reproductive toxicity LOAEL was not identified.

This study is classified as Acceptable/guideline and satisfies the requirements for a reproduction 

study (83-4) in rats.

Rat – (MRID 48444412) – Testing with methylisothiazolinone (3:1 CMIT and MIT)

In the 2-generation reproductive toxicity study (MRID 48444412), methylisothiazolinone 

(14.62% a.i., batch # 080310) was administered to 25 Wistar rats/sex/dose in distilled water by 

gavage at dose levels of 0, 5, 20, or 80 mg/kg/day. Vehicle control group animals were

administered distilled water alone. 

The parental animals (P) were given test diets for 10 weeks before they were mated. Treatment 

for the P females continued through mating, pregnancy, and up to weaning of their offspring. 

The F1 parental animals were not mated until 13 weeks after they were selected from the F1

litters. Selection of parents for the F1 generation was made when the pups were 21 days of age. 

F1 offspring were treated from weaning until they were sacrificed after obtaining the F2

offspring. On day 4 postpartum, litters were standardized to a maximum of 8 pups/litter 

(4/sex/litter, as nearly as possible.)

Parental toxicity was observed at the high dose. Signs of toxicity included decreased body 

weights, decreased body weight gains, and decreased food consumption; these changes were 

observed in males from both generations. At the 80 mg/kg/day dose, epithelial hyperplasia of 

the non-glandular stomach and hyperkeratosis in both P and Fl generation males and P 

generation females were observed. These effects were attributed to the local irritation potential of 

the test material. An associated microscopic finding of leukocytic infiltration in the submucosa 

of both the glandular and non-glandular stomach was also observed in these groups. In the P 

generation, increased intraepithelial globule leukocytes were observed in the glandular stomach 

of both male and female rats.

The parental systemic LOAEL is 80 mg/kg/day, based on epithelial hyperplasia of the nonglandular stomach and hyperkeratosis observed in both P and Fl generation males and P 

generation females. The parental systemic NOAEL is 20 mg/kg/day. 

The reproductive toxicity LOAEL is >80 mg/kg/day, based on lack of adverse effects seen 

at the highest dose tested. The reproductive toxicity NOAEL is 80 mg/kg/day. 

Rat – (MRID 46308201) – Testing with MIT Solution

Under the condition of the study, MIT (purity 51.4%), was administered to 30 male and female 

CD rats per dose level in drinking water at concentrations of 0, 50, 200 or 1000 ppm 
Page 34 of 56

(corresponding to dose levels of 4, 15 or 69 mg/kg/day in P males; 7, 22 or 93 mg/kg/day in P 

females; 5, 19 or 86 mg/kg/day in F1 males; and 8, 26 and 115 mg/kg/day in F1 females). 

There were no treatment-related mortalities or clinical signs of toxicity in either the P or F1

parental rats. For the pre-mating period, body weight and body weight gain were significantly

decreased in P (7-9%) and F1 (10-23%) parental rats at the 1000 ppm dose level. During 

gestation and lactation, body weight in P females was decreased significantly for gestation days 

14-17, 17-20, and 0-20 at the 1000 ppm dose level and during lactation days 7-14 at the 1000 

ppm dose level. Food consumption was significantly decreased in P parental rats at the 1000 

ppm dose level by 5-11% and in F1 parental rats by 9-14%. Food efficiency was only 

significantly decreased in P generation female rats for week 0-1 of the study. Spermatogenesis 

endpoints were unaffected by treatment with test article at any dose level, and estrous cycle 

length in P females was unaffected by treatment.

For P and F1 parental animals, reproductive performance (including male and female mating 

indices, male fertility index, and female fertility index) were not affected by treatment with the 

test article at any dose level. No test article-related effects were noted on the number of F1 pups 

born, live litter sizes, percentages of males per litter and postnatal survival at any dose 

concentration. The mean numbers of F1 pups born, live litter sizes and percentages of males per 

litter were similar among all groups and no statistically significant differences from the control 

group were noted. No differences were noted in gestation length or parturition at any dose level.

Organ weight in P and F1 animals was affected at the 1000 ppm dose. In P males, liver weight 

was decreased non-significantly at the high dose. In P females, spleen weight was decreased 

significantly at all dose levels vs. control. Uterine weight was decreased at all dose levels 

compared to control and was identified as statistically significant at the 200 ppm dose. In F1

males, a decrease in liver weight was observed at the 1000 ppm dose level similar to that 

observed in P males but this decrease was statistically significant. Spleen weight was also 

significantly decreased at the 1000 ppm dose in males and was statistically significant. The 

weight of the pituitary was significantly decreased in F1 males at the 50 and 200 ppm dose levels 

compared to control. At 1000 ppm pituitary weight was also decreased but the decrease was not 

significant. In F1 females, brain weight was slightly but significantly decreased at the 1000 ppm 

dose level compared to control. 

Final body weight in F1 males was significantly decreased compared to control at the 1000 ppm

dose level. Relative weight of the brain was significantly increased at 1000 ppm, as was relative

weight of the kidneys, seminal vesicles, prostate, both testes, right epididymis, right and left 

cauda epididymides, and pituitary.

There were no significant effects of treatment on macroscopic or microscopic changes at any 

dose level in P or F1 parental animals.

The parental systemic LOAEL is 1000 ppm (69/93 mg/kg/day in P males/females; 86/115 

mg/kg/day in F1 males/females), based on decreased body weight, weight gain, and organ 

weight changes. The parental systemic NOAEL is 200 ppm (15/22 mg/kg/day in P

males/females; 19/26 mg/kg/day in F1 males/females).
Page 35 of 56

Offspring litter parameters were unaffected by treatment at any dose level. Body weight and 

body weight gain in both F1 and F2 pups was significantly decreased at the 1000 ppm dose level.

In F1 male pups, absolute weight of the thymus and spleen was decreased (not significantly) at 

the1000 ppm dose level. In F1 female pups, absolute thymus and spleen weight were 

significantly decreased at the 1000 ppm dose level. The absolute weight of the spleen and 

thymus was also observed to be significantly decreased in F2 male and female pups at the 1000 

ppm dose level. However, there were no corresponding macroscopic or microscopic changes to 

these organs. 

The LOAEL for offspring toxicity is 1000 ppm (69/93 mg/kg/day in P males/females; 86-

115 mg/kg/day in F1 males/females) based on decreased body weights, body weight gains, 

and changes in organ weights at this dose level (F2 pups only). The NOAEL is 200 ppm (15-

22 mg/kg/day in P males/females; 19-26 mg/kg/day in F1 males/females).

No treatment-related effects on 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. A LOAEL for 

reproductive toxicity was not achieved (> 1000 ppm). The NOAEL is 1000 ppm

(69/93 mg/kg/day in P males/females; 86-115 mg/kg/day in F1 males/females).

Mutagenicity 

Methylisothiazolinone was positive in the reverse gene mutations in Salmonella typhimurium 

TAl 00 in three independent studies (MRIDs #78827, 96692, and 105044). The response has 

been observed both in the absence and the presence of S9 activation; however, concentrations 5 x 

10 X higher are required to induce mutagenicity when S9 activation is incorporated into the 

assay with this bacterial strain. Similarly, forward gene mutations have been seen in two 

independently performed mouse lymphoma L5178Y assays. The first assay was performed at the 

Rohm and Haas Toxicology Department (RH -81RC-153, 1981) and constitutes the soft agar 

approach while the second (MRID 43419617, 1994) was performed independently and used the 

microsuspension methodology. Both assays showed positive results (+/-S9), based on the 

criteria in use at the time they were performed (on or before 1994). As stated by Dr. David 

Brusick (2007) in his critical evaluation of the genotoxicity of the isothiazolone biocides, 

however, changes have been made in the way data from the mouse lymphoma assay are 

interpreted relative to a positive response. These changes include 1) cytotoxicity, as measured by 

percent relative growth, must be >20% to evaluate the response and 2) the adoption of the 

induced mutation frequency, IMF (i.e., test concentration MF-solvent control MF) and the 

Global Evaluation Factor, CEF (i.e., 100 for standard soft agar method and 90 for the 

microsuspension assay). Using these new criteria, in order for test material to be considered 

positive, the IMF must show an increase over the solvent control background frequency + the 

GEF developed for the mouse lymphoma assay by the International Workshop on Genotoxicity 

Testing (IWGT, 2005). When the data were revisited and the new criteria were applied, results 

from RH-81RC-153 (1981) can no longer be considered positive; however the findings of MRID 

43419617 remain positive. CMIT/MIT was also clastogenic in human lymphocytes at S9 
Page 36 of 56

activated concentrations that induced ≤ 50% decrease in the mitotic index. In vivo, three studies 

(either mouse micronucleus or chromosome aberrations) were negative; however, none of these 

studies were conducted up to the maximum tolerated dose and are, therefore, unacceptable. Two 

in vivo unscheduled DNA synthesis assay rat hepatocytes were also submitted; these studies, 

which were negative up to doses causing overt animal toxicity, were also guideline/acceptable. 

Nevertheless, the lack of an acceptable bone marrow cytogenetic assay precludes the ruling out 

of a mutagenicity concern. 

MIT was not mutagenic in the S. typhimurium tester strain battery and also in strain TA102; it was 

negative for forward mutations up to cytotoxic concentrations in CHO cells. Although chromosome 

aberrations were observed in CHO cells, this clastogenic effect was confined to non-activated and 

S9-activated concentrations that were severely cytotoxic. Similarly, MIT neither induced micronuclei 

in mouse bone marrow up to the lethal doses nor UDS in rat hepatocytes up to the highest dose tested 

(308 mg/kg); higher doses were lethal. Accordingly, there was no mutagenicity concern. 

CMIT caused ≥ 2-fold increases in revertant colonies of S. typhimurium TA 100 in the presence of 

S9 activation; no other assays were performed with this biocide. No further testing was submitted. 

Chronic/Carcinogenicity Toxicity 

There is one acceptable drinking water cancer study (MRID 43140701). Under the condition of 

the study, exposure of 90 male and 80 female Crl:CD®BR rats per group to 

methylisothiazolinone (14.2% a.i.) via the drinking water at dose levels of 30 (males 2.0 mg/kg; 

females 3.1 mg/kg), 100 (males 6.6 mg/kg; females 9.8 mg/kg), or 300 ppm (males 17.2 mg/kg; 

females 25.7 mg/kg), or to tap water or 0.5% salt solution [MgCl2 and Mg(NO3)2] vehicles for 24 

months resulted in a dose-related decrease in drinking water consumption at all dose levels in 

both sexes throughout the study. Decreased body weight (95-98% of control) and body weight 

gain (87% of control at week one, from 91-98% thereafter) were observed in the high-dose 

males, although statistical significance was not always attained. Females displayed an equivocal 

decrease in body weight throughout the study, with the mid- (93-96% of control) and high-dose 

(87-96% of control) groups showing comparable decreases that were not always dose-related. 

During the second year, body-weight gains of the high-dose females were significantly decreased 

(83-88% of control). High-dose males displayed a significant decrease (91-98% of control) in 

food consumption compared to the control groups throughout most of the study, and females at 

all dose levels displayed significant decreases in food intake but a dose response was not always 

evident. Hematology and clinical chemistry parameters were comparable among the groups of 

both sexes, as were the organ weights and eyes. During the first six months of the study, the 

specific gravity of the urine was increased in both sexes, which may be attributed to the decrease 

in water consumption. With the exception of the stomach, none of the gross and non-neoplastic 

lesions observed could be attributed to treatment. An increased incidence in hyperplasia and 

hyperkeratosis of the squamous mucosa of the stomach was observed at the mid- and high-dose 

levels in both sexes, which correlated with the finding of prominence of the limiting ridge and/or 

thickened non-glandular mucosa of the forestomach on gross examination. Additionally, there 

was an increased incidence of necrosis of the glandular mucosa in the mid-dose females and in 

both sexes at the high-dose level. There was no treatment-related increase in the incidence of any 

tumor in either sex. The corrosive properties of methylisothiazolinone imposed limitations on the 
Page 37 of 56

dose levels tested. The NOAEL is 30 ppm (males 2.0 mg/kg/day; females 3.1 mg/kg/day). 

The LOEL is 100 ppm (males 6.6 mg/kg/day; females 9.8 mg/kg/day), based on microscopic 

lesions (hyperplasia/hyperkeratosis in both sexes, necrosis of glandular mucosa in females) 

in the stomach.

Immunotoxicity

There is currently no existing immunotoxicity study for methylisothiazolinone. This is a required 

study and has been identified as a data gap and as an anticipated data need.

Metabolism Studies

The toxicokinetics and metabolism of 14C-CMIT and 14C -MIT were investigated in the rat, as well 

as, the bile-duct cannulated rat. Both CMIT and MIT are absorbed, are extensively metabolized and 

are rapidly excreted. Unmetabolized CMIT or MIT do not appear in the urine, bile or feces. 

Excretion occurs predominately within 24 hours. There is no evidence that CMIT or MIT or its 

metabolites bioaccumulate in tissues. CMIT and MIT is initiated through nucleophilic attack on the 

sulfur-nitrogen bond of the isothiazolone ring, an electrophilic center (i.e., ring opening), loss of 

sulfur (and chlorine) and subsequent metabolism primary to malonamic acid derivative (N-methyl 

malonamic acid). N-methyl-Malonamic acid is the major metabolite for both CMIT and MIT. A 

secondary metabolite formed after ring opening and conjugation is the 3-mercapturic conjugate of3-

thio-methyl-N-methylppropionamide. Overall, DCOIT and CMIT (or MIT) are extensively 

metabolized and excreted in the rat. These biocidal actives or their metabolites do not bioaccumulate. The predominant, first step in their metabolism is opening of the isothiazolone ring 

structure, which de-activated the molecule(s) (i.e., loss of reactivity in biological systems). With both 

DCOIT and CMIT (or MIT) a major route of metabolism is formation of a malonamic acid 

derivative(s) (e.g., N-octyl-malonamic acid and N-methyl-malonamic acid). 
Page 38 of 56

Appendix B Environmental Fate

Environmental Fate and Transport Properties of CMIT and MIT

This environmental fate assessment addresses the persistence and mobility of the parent 

compound 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT) and the dechlorinated CMIT 

degradate (MIT), both of which contain an intact isothiazolone ring. It also addresses the 

persistence and mobility of the low-molecular weight degradates formed upon breakage of the 

ring structure. These degradates with a straight chain include N-methyl malonamic acid, Nmethyl acetamide, N-methyl oxamic acid, malonamic acid, malonic acid, acetic acid, formic acid 

and CO2. 

Based on the chemical and physical properties (Table 6) and environmental fate properties 

(Table B1) of CMIT and MIT, both compounds are highly water soluble, stable to chemical 

degradation (hydrolysis and photodegradation), rapidly degraded by metabolism in the 

environment, unlikely to volatize from water into air, and will be present mostly in water in the 

presence of sediment.

The straight-chain degradates are also highly water-soluble include N-methyl malonamic acid, 

N-methyl acetamide, N-methyl oxamic acid, malonamic acid, malonic acid, acetic acid, formic 

acid and CO2 (terminal degradate). These degradates rapidly degrade in a sequential manner 

and did not reach significant (>10 % of applied parent) concentrations in metabolism studies 

(MRIDs 43753203, -04, -05). 

The submitted data for photodegradation in water (MRIDs 43753201 and 43753202), anaerobic 

aquatic metabolism (MRID 43753203), and aerobic aquatic metabolism (MRIDs 43753204 and 

43753205) and bioconcentration in fish (MRID 44113102) have been screened but not reviewed. 

They will be reviewed during the registration review process.

Water and Sediment

Hydrolysis

CMIT (parent compound, 5-chloro-2-methyl-4-isothiazolin-3-one) was stable to hydrolysis at pH

5 and 7 with half-lives of 13-17 days at pH 9. The only major degradate as pH 9 was N-methyl 

malonamic acid which did not degrade in the studies (MRIDs 43971801, 44700501, and 

42681301). In a separate study using the degradate MIT (methyl-3(2H)-isothiazolone, 

dechlorinated parent as a parent compound), was stable to hydrolysis at pH 5, 7, and 9 (MRID 

42578401).

The presence of hydrolysis of MIT as a degradate and the absence of hydrolysis of MIT as a 

parent compound appear to be contradictory. However, CMIT (parent compound in the 

hydrolysis studies) is an alkyl halide with a high concentration of negative charges located near 

the negatively-charged chlorine, and these electrical charges destabilize the ring structure. As a 
Page 39 of 56

result, negatively-charged hydroxyl (1-OH) groups can attack the ring and break it. The 

hydrolysis of MIT in the studies is consistent with Lyman et al. (1990) which states that alkyl 

halides are potentially susceptible to hydrolysis.7 The absence of hydrolysis of MIT as a parent 

compound (starting compound) in the study is consistent with the fact that MIT does not have the 

high concentration of negative charges at one point in the ring, and Lyman et al. (1990) states 

that aromatic amines (e.g. MIT) are generally resistant to hydrolysis8.

Aqueous Photolysis

Parent CMIT degraded with a reported half-life of 6.6 days to form the degradates N-methyl 

malonamic acid (NMNA) acid and 5-chloro-3-methyl-4-thiozolin-2-one (CMT). Both 

degradates increased throughout the study period and were presumed to be stable. NMNA 

increased to 30-31 % and CMT increased to 38 % of applied parent compound (MRID 

43753201). This study has been screened but not reviewed. It will be reviewed during the 

registration review process.

The dechlorinated parent compound MIT degraded with a reported half-life of 12.3 days. The 

other degradates were a mix of NMNA, N-methylacetamide (NMA), and N-methyl oxamic acid 

(NMO) which increased to 38 % of parent compound by the end of the study (MRID 43753202). 

This study has been screened but not reviewed. It will be reviewed during the registration 

review process.

Aerobic Aquatic Metabolism

CMIT degraded with a reported half-life of 9.5 hours in a 7-day study. Significant quantities of 

aqueous, sediment-extractable residues, and non-extractable sediment residues were present 

throughout the study but carbon dioxide was not formed in significant amounts. Therefore, 

complete mineralization to carbon dioxide was not occurring in the 7-day study duration. The 

registrant did not quantify the degradates because they were so substantially similar, but 

provided a degradation pathway (Figure 11, p. 48). Parent CMIT degrades to straight-chain, low 

molecular-weight compounds such as N-methyl malonamic acid which eventually degrade to 

formic acid, formaldehyde, and carbon dioxide (MRID 43753204). This study has been screened 

but not reviewed. It will be reviewed during registration review process.

MIT degraded with a reported half-life of 8.8 hours in a 7-day study. Significant quantities of 

aqueous and non-extractable residues were present in the study and carbon dioxide reached 9 % 

of applied parent (10 % is considered significant). Therefore, complete mineralization to carbon 

dioxide could be expected if the study was conducted for longer than 7 days. Of the non-volatile 

degradates identified, none exceeded 3.5 % of applied parent and were non-significant. Parent 

MIT degrades to straight-chain, low molecular-weight compounds such as N-methyl malonamic 

acid which eventually degrade to formic acid, formaldehyde, and carbon dioxide (MRID 

 

7 Lyman, Reehl, and Rosenblatt, 1990, p. 7-5

8 Lyman, Reehl, and Rosenblatt, 1990, p. 7-4
Page 40 of 56

43753205). This study has been screened but not reviewed. It will be reviewed during 

registration review process.

Anaerobic Aquatic Metabolism

CMIT degraded with a half-life of 5.3 hours, and in the process, formed carbon dioxide and nonextractable residues but did not form significant non-volatile degradates. Based on these results, 

mineralization of parent compound and these degradates was occurring. By 7 days (end of 

study), aqueous and sediment-extractable residues were <10 % of applied parent compound

(MRID 43753203). This study has not screened but not reviewed. It will be reviewed during 

registration review process.

Soil

Soil Leaching/Adsorption/Desorption Batch Equilibrium

CMIT was mobile to moderately mobile with adsorption Kf values of 0.08-4.9 ml/g (mean of 1.5 

ml/g) and Koc values of 30-310 ml/g (mean of 136 ml/g) in five soils. Sorption was mostly 

related to organic carbon content with an r

2

(goodness of fit value) of 0.33 and to soil pH [H+]

with a r2value of 0.24 (MRID 42086902). The mobility classification is based on the FAO 

system which refers to Log Koc values of 1-2 and 2-3 for mobile to moderately mobile, 

respectively.9

Aerobic Soil Metabolism

CMIT degraded with a half-life of 5.4 hours but did not form any significant non-volatile 

degradates, indicating that mineralization of these degradates was occurring. Of the applied 

parent compound, 90 % degraded by 2 days (MRID 42086901). 

Anaerobic Soil Metabolism

Data on anaerobic soil metabolism have not been submitted to the agency. However, the 

registrant has submitted anaerobic aquatic metabolism data (MRID 43753203) which have not 

been reviewed. If the anaerobic aquatic metabolism data are reviewed and found to satisfy the 

835.4400 data requirement, then anaerobic soil metabolism data would not be anticipated to be 

required.

Leaching from Treated Wood

The registrant conducted a wood leaching study using Southern Yellow Pine and five water 

types. Leaching studies included separate treatments of distilled, deionized (DI) water, artificial 

seawater, and pH 5, 7, and 9 buffer solutions. For all treatments, approximately 55 % of CMIT 

and MIT leached in first 5 days and approximately 75-80 % leached in 28 days (MRID 

43478401). 

 

9 http://www.fao.org/docrep/003/x2570e/x2570e06.htm
Page 41 of 56

Bioconcentration in Fish

CMIT is not likely to bioconcentrate in fish to a significant degree based on reported BCF values 

of 41-54X (MRID 44113102). This lack of bioconcentration is consistent with the low log Kow 

(0.401)10, which is less than the level of concern (log Kow of 3 or greater).11 CMIT also has a 

high water solubility of 659,600 mg/l, but compounds that have a tendency to bioconcentrate 

generally have low water solubility values. However, this study has been screened but not

reviewed. It will be reviewed during registration review process. 

Fate and Transport in WWTP

Activated Sludge Sorption Isotherm

Data on activated sludge sorption isotherm (ASSI) were not submitted but are not required 

because the log Kow values of CMIT and MIT are 0.40 and-0.49, which are less than three. 

According to the Final 158W Rule, ASSI data are not required if the log Kow is <3 (Footnote 

19).

Activated Sludge Biodegradation

Data on activated sludge biodegradation (Ready Biodegradability) were not submitted and are 

required based on the registered use patterns. 

Table 1. Status of Methylisothiazolinone Environmental Fate Studies12

Test Guideline

(parent 

compound unless 

stated)

OCSPP 

Guideline 

No. 

Study result Significant 

Degradation 

Products13

Study status Reference (MRID) 

and Comments

Hydrolysis 835.2120 Stable at pH 

5 and 7

DT50 and 

DT90 of 13 

and 45 days 

(pH 9)

Unidentified 

polar degradates 

adding up to 63 

% of applied 

parent14

Acceptable 43971801

25 oC

Shamim, 

January 6, 1998

Hydrolysis 835.2120 DT50 of 16.9 

days (pH 9)

N-methyl 

malonamic acid 

increased to 64.5 

% of parent by 

Acceptable 44700501

42681301

 

10 Table 6.

11 Bioconcentration in fish 850.1730 tests guideline states that log Kow values of >3 indicate high potential for 

bioconcentration.

12 Parent methylisothiazolone is 5-chloro-2-methyl-3(2H)-isothiazolone, CMIT.

12 Parent methylisothiazolone is 5-chloro-2-methyl-3(2H)-isothiazolone, CMIT.

13 Significant degradates formed at >10 % of applied parent compound.

14 No degradates formed at >10 % of applied compound.
Page 42 of 56

42 days (end of 

study)

25 oC

Gowda, September 

1, 2000

Hydrolysis 

Degradate

(methyl--3(2H)-

isothiazolone 

study))

835.2120 Stable at pH 

5, 7, and 9

None15 Acceptable 

(in RED)16

42578401

24.1 oC

Dechlorinated parent 

compound17

Photodegradation 

in water by 

sunlight

835.2210 6.6 days 

(parent)

N-methyl 

malonamic acid 

increased to 30-

31 % of parent 

by 15 days (end 

of study)

5-chloro-3-

methyl-4-

thiozolin-2-one

increased to 37.6 

% by 15 days

Will be

reviewed during 

reregistration 

review

43753201 (parent)

pH 7 for 15 days at 

24.8 oC

12.3 days 

(degradate)

Mix of N-methyl 

malonamic acid, 

Nmethylacetamide, 

and N-methyl 

oxamic acid 

increased to 37.5 

% of parent by 

30 days (end of 

study)

3-methyl-4-

thiazolin-2-one 

increased to 39.6 

% by 30 days

Will be 

reviewed during 

reregistration 

review

43753202 

Degradate MIT, 

dechlorinated parent

 

15 Degradates cannot form if parent compound is stable.

16 RED located at http://www.epa.gov/oppsrrd1/REDs/3092.pdf .

17 Methyl-3(2H)-Isothiazolone, MIT, dechlorinated parent compound.
Page 43 of 56

Aerobic soil 

metabolism

835.4100 5.4 hours No major nonvolatile 

degradates 

formed

Acceptable 

(in RED)

Look in file to 

find review

42086901

25 oC

~90 % degraded by 

2 days

Anaerobic 

aquatic 

metabolism

835.4400 5.3 hours No major nonvolatile 

degradates 

formed

Will be 

reviewed during 

reregistration 

review

43753203

25 oC

Aerobic aquatic 

metabolism

835.4300 9.5 hours 

(parent)

No major nonvolatile 

degradates 

formed

Will be 

reviewed during 

reregistration 

review

43753204

25 oC

8.8 hours 

(degradate)

N-methyl 

malonamic acid

Will be 

reviewed during 

reregistration 

review

43753205

25 oC

LeachingAdsorptionDesorption

(unaged)

835.1230 Adsorption 

Kf values of 

0.08-4.9 ml/g 

(mean of 1.5 

ml/g)

Koc values 

of 30-310 

ml/g (mean 

of 136 ml/g)

No degradates 

measured

Acceptable 

(in RED)

Look in file to 

find review.

42086902

Sorption mostly 

related to organic 

carbon content 

(r2=0.33) and pH 

[H+] (r2=0.24)

Bioconcentration 

in Fish

850.1730 BCF of 41-

54X

50 % 

depuration of 

0.64-1.6 day

None (not 

required)

Will be 

reviewed during 

reregistration 

review

44113102

Leaching from 

treated wood

AWPA E11-

12

84 % leached 

from treated 

Southern 

No degradation 

at pH 5 and 7 but 

significant 

degradation 

occurred in the 

Acceptable in 

RED

43478401

Kathon WT
Page 44 of 56

Yellow Pine 

in 28 days

55 % leached 

in first 5 days

pH 9 solution. 

Degradate(s) not 

identified, but 

most likely Nmethylmalonamic acid 

(NMMA) based 

on hydrolysis 

study (MRIDs 

44700501, 

42681301)
Page 45 of 56

References

Food and Agriculture Organization of the United Nations (FAO). 1987. Soil Quality Considerations in 

the Selection of Sites for Aquaculture. 

http://www.fao.org/docrep/field/003/ac172e/AC172E05.htm (partial document), 

http://www.fao.org/docrep/field/003/AC172E/AC172E00.htm (whole document)

Gowda, Srinivas. September 1, 2000. Review of 5-chloro-2-methyl-4-isothiazolin-3-one (RH 

651) hydrolysis studies. 

Lyman, W.J., W.F. Reehl, and D.H. Rosenblatt. 1990. Handbook of Chemical Property 

Estimation Methods. American Chemical Society. ISBN O-8412-1761-0.

Shamim, Najm. January 6, 1998. Review: Hydrolysis data submitted in support of registration. 

Review of Lucas, 1996. DP Barcode D228642.

42086901. Wang, W. (1991) Aerobic Soil Metabolism of carbon 14|-RH-651: Lab Project 

Number: XBL 90020: XBL RPT0045: RH TECH. 34-91-03. Un- published study prepared by 

XenoBiotic Labs, Inc. 73 p. 

42086902. Wang, W. (1991) Adsorption and Desorption of carbon 14-RH-651 in Four Soils and 

One Sediment: Lab Project Number: XBL 90024: RPT 0046: RH TECH. 34-91-09. Unpublished 

study prepared by XenoBiotics Labs, Inc. 86 p. 

42578401. Marx, M.; Castle, S.; Shepler, K. (1992) Hydrolysis of (carbon 14)-RH-573 at pH 5, 

7 and 9: Lab Project Number: 223W-1: 223W: 34-92-63. Unpublished study prepared by 

Pharmacology and Toxicology Research Laboratory-West. 69 p.

42681301. Jalali-Araghi, K.; Shepler, K. (1993) Hydrolysis of (carbon 14)-RH-651 (the major 

component of RH-886) at pH 5, 7 and 9: Lab Project Number: 225W-1: 225W: 34P-90-06: 34-

93-07. Unpublished study prepared by Pharmacology and Toxicology Research LaboratoryWest. 134 p.

43478401. Doshi, D. (1994) Aqueous Availability of Kathon WT from Treated Southern Yellow 

Pine: Lab Project Number: 3122.00. Unpublished study prepared by Rohm and Haas Co. and 

Hickson Corp. 325 p.

43753201. Concha, M.; Ruzo, L.; Shepler, K. (1994) Sunlight Photodegradation of (Carbon 14)-

RH-651 (the Major Component of RH-886) in a Buffered Aqueous Solution at pH 7: Lab Project 

Number: 226W-1: 226W: 34P-90-07. Unpublished study prepared by PTRL West, Inc. and 

Rohm and Haas Research Lab. 96 p. 

43753202. Shepler, K. (1995) Sunlight Photodegradation of (Carbon 14)-RH-573 (the Minor 

Component of RH-886) in a Buffered Aqueous Solution at pH 7: Lab Project Number: 224W: 

34P-90-09: 34-94-78. Unpublished study prepared by PTRL West, Inc. and Rohm and Haas Co. 

101 p. 
Page 46 of 56

43753203. Liu, P.; Reynolds, J. (1994) Anaerobic Aquatic Metabolism of (Carbon 14)-RH-651: 

Lab Project Number: XBL90022: RPT00169: 34P-90-60. Unpublished study prepared by 

XenoBiotic Labs, Inc. 112 p.

43753204. Reynolds, J. (1994) Aerobic Aquatic Metabolism of (Carbon 14)-RH-651: Lab 

Project Number: XBL90021: RPT00172: 34P-90-59. Unpublished study prepared by XenoBiotic 

Labs, Inc. 122 p.

43753205. Reynolds, J. (1994) Aerobic Aquatic Metabolism of (Carbon 14)-RH-573: Lab 

Project Number: XBL91006: RPT00170: X117. Unpublished study prepared by XenoBiotic 

Labs, Inc. 143 p.

43971801. Lucas, T. (1996) (Carbon-14) ACTICIDE 14: Hydrolytic Stability: Final Report: Lab

Project Number: 1154-043: CHE 1154-043. Unpublished study prepared by Corning Hazleton 

GmbH. 104 p.

44113101. Reynolds, J. (1996) Aged Leaching of (carbon 14)-RH-651 in Four Soils: (Final 

Report): Lab Project Number: XBL90023: RPT00171: 34P-90-27. Unpublished study prepared 

by XenoBiotic Labs., Inc. 114 p.

44113102. Madsen, T.; Stuerman, L. (1996) RH-651 Bioconcentration and Elimination of 

(carbon 14)-Residues by Bluegill Sunfish (In-Life): (Final Report): Lab Project Number: 34P95-03A: 42387: 34-96-40. Unpublished study prepared by ABC Labs., Inc. and Rohm and Haas 

Co., Biocides Research Labs. 117 p.

44700501. Mazza, L. (1998) Identification of Hydrolytic Degradates of (carbon-14)-RH-651 at 

pH 9: Supplemental Report to MRID 42681301: Lab Project Number: TR-98-039: 24P-97-004: 

13-98-045TR. Unpublished study prepared by Rohm and Haas Company. 141 p. 
Page 47 of 56

Appendix C Ecotoxicology Profile

Toxicity to Terrestrial Receptors

Ecological Toxicity Data 

Ecological effects toxicity testing was performed using a formulation intermediate (Kathon®

886F, 14.17%), or end-use formulations (Kathon® WT, Kathon® OM, or Kathon® WT, 1.5%). 

Testing of the formulation intermediate and end-use products is sufficient to fulfill guideline data 

requirements where ecological effects testing of the technical grade is indicated, due to the 

inherent instability of the active ingredients at higher percentages.

Birds, Acute Toxicity

In order to establish the acute toxicity of methylisothiazolinone to birds, the following test is 

required using the technical grade material: one avian single-dose oral (LD50) study on one species 

of waterfowl or upland game bird (preferably mallard duck or bobwhite quail).

In an acute oral toxicity study conducted using bobwhite quail, methylisothiazolinone (14.17% 

a.i.) gave an LD50 of 62.7 mg/kg. This is sufficient information to characterize 

methylisothiazolinone as moderately toxic to avian species on an acute oral basis. The guideline 

requirement is fulfilled. (MRID #41719501)

Birds, Subacute Toxicity

In order to establish the subacute toxicity of methylisothiazolinone to birds, the following test is 

required using the technical grade material: one subacute dietary study (LC50) on one species of 

waterfowl or upland game bird (preferably the mallard duck or bobwhite quail).

TABLE C1 - Avian Subacute Dietary Toxicity Findings

Species % A.I. LC50 ppm MRID No. Toxicity Category

Mallard114.17% 717 41719503 moderately toxic

Bobwhite Quail114.17% 2200 41719502 practically non-toxic

1 Study is considered to be supplemental because the analytical methodology may not have followed GLP procedures.

There is sufficient information to characterize methylisothiazolinone as moderately toxic to 

practically non-toxic to avian species on a subacute dietary basis (Table 4). Both avian subacute 

dietary toxicity studies are considered to be supplemental because GLP compliance was not 

evident. However, the guideline requirement is considered fulfilled. (MRID #41719502 and 

#41719503)
Page 48 of 56

Toxicity to Aquatic Receptors

Freshwater Fish, Acute Toxicity

In order to establish the toxicity of methylisothiazolinone to freshwater fish, the minimum data 

required on the technical grade of the active ingredient is a single 96-hour LC50 fish toxicity study 

using either a warmwater fish (preferably bluegill sunfish) or a coldwater fish (preferably rainbow 

trout).

TABLE C2 - Freshwater Fish Acute Toxicity Findings

Species % A.I. LC50 ppm MRID Toxicity Category

Rainbow trout 14.17% 0.19 41718802 Highly toxic

Rainbow trout114.17% 0.07 41963503 Highly toxic

Bluegill sunfish 14.17% 0.30 41718801 Highly toxic

1 Study is considered to be supplemental because the results were based on a 14-day exposure period.

There is sufficient information to characterize methylisothiazolinone as highly toxic to both 

cold and warmwater fish (Table 5). The guideline requirements for freshwater fish acute toxicity 

are fulfilled. (MRIDs #41718802 and #41718801, respectively)

Freshwater Fish, Chronic Toxicity

In order to establish the chronic toxicity of methylisothiazolinone to freshwater fish, the minimum 

data required on the technical grade of the active ingredient is a single fish early life stage study 

using the technical material.

In a chronic toxicity study conducted using fathead minnows, methylisothiazolinone (14.17% a.i.) 

gave a Maximum Allowable Toxicant Concentration (MATC) of 0.035 ppm. The MATC (the 

geometric mean of the NOEL and LOEL), based on significantly reduced weight at 0.06 mg a.i./L, 

was >0.02 and <0.06 ppm. The guideline requirement for freshwater fish chronic toxicity is 

fulfilled. (MRID #42012201)

Freshwater Invertebrates, Acute Toxicity

The minimum testing required to assess the acute toxicity of methylisothiazolinone to freshwater 

invertebrates is a single 48-hour LC50 test. Two studies were reviewed.
Page 49 of 56

Table C3 - Freshwater Invertebrate Acute Toxicity Findings

Species % A.I. LC50 ppm MRID # Toxicity Category

Daphnid Ceriodaphnia 1.5%10.20 42358701 highly toxic

Daphnid Daphnia 14.17% 0.18 41718803 highly toxic

1Adjusted to 100% a.i.

There is sufficient information to characterize methylisothiazolinone as highly toxic to freshwater 

invertebrates (Table 6). The guideline requirement for freshwater invertebrate acute toxicity is 

fulfilled. (MRIDs #42358701 and #41718803)

Freshwater Invertebrates, Chronic Toxicity

In order to establish the chronic toxicity of methylisothiazolinone to freshwater invertebrates, the 

minimum data required on the technical grade of the active ingredient is an invertebrate life cycle 

study using the technical material.In a freshwater invertebrate chronic toxicity study conducted 

using Daphnia, methylisothiazolinone (14.17% a.i.) gave an MATC of 0.13 ppm. The MATC, 

based on survival, was >0.10 and <0.18 ppm. The guideline requirement for freshwater 

invertebrate chronic toxicity is fulfilled. (MRID #41963502)

Estuarine and Marine Animals, Acute ToxicityThe minimum data required to evaluate acute 

toxicity to estuarine/marine species are a fish 96-hour LC50 test using either a marine or estuarine 

species, a mollusc 96-hour EC50 shell deposition study or 48-hour EC50 on oyster embryo/larvae, 

and a shrimp 96-hour LC50 test using either a marine or estuarine species.

Table C4 - Estuarine/Marine Acute Toxicity Findings

Species % A.I. LC50/EC50

(ppm)

MRID # Toxicity 

Category

Sheepshead Minnow 13.9% 0.36 00042556 highly toxic

Marine copepod Acartia tonsa1unspecified 

purity

0.056 42840301 highly toxic

Pink Shrimp 13.9% 2.3 00042559 moderately toxic

Fiddler Crab Uca pugilator113.9% 59.0 00042557 moderately toxic

Eastern Oyster Embryo-larvae 13.9% 0.028 00042558 highly toxic
Page 50 of 56

1Study is considered to be supplemental because a test organism was used that is not recommended.

There is sufficient information to characterize methylisothiazolinone as moderately toxic to highly

toxic to estuarine/marine species (Table 7). Certain studies are considered to be supplemental 

because test organisms were used that are not recommended, nevertheless, these studies are 

considered to have satisfied the guideline requirements. The guideline requirements for 

estuarine/marine acute toxicity are fulfilled (MRID #00042556, #42840301, #00042559, 

#00042557, and #00042558).

Table C5 - Estuarine/Marine Acute Toxicity Findings

Species % A.I. LC50/EC50

(ppm)

MRID # Toxicity 

Category

Sheepshead Minnow 13.9% 0.36 00042556 highly toxic

Marine copepod Acartia tonsa1unspecified 

purity

0.056 42840301 highly toxic

Pink Shrimp 13.9% 2.3 00042559 moderately toxic

Fiddler Crab Uca pugilator113.9% 59.0 00042557 moderately toxic

Eastern Oyster Embryo-larvae 13.9% 0.028 00042558 highly toxic

1Study is considered to be supplemental because a test organism was used that is not recommended.

There is sufficient information to characterize methylisothiazolinone as moderately toxic to highly 

toxic to estuarine/marine species (Table 7). Certain studies are considered to be supplemental 

because test organisms were used that are not recommended, nevertheless, these studies are 

considered to have satisfied the guideline requirements. The guideline requirements for 

estuarine/marine acute toxicity are fulfilled. (MRID #00042556, #42840301, #00042559, 

#00042557, and #00042558)
Page 51 of 56

References

00042556 Heitmuller, T. (1980) Acute Toxicity of Kathon WT to Sheepshead Minnows, 

Cyprinodon variegatus: Report No. BP-80-3-53. (Unpublished study received Aug 28, 1980 

under 707-128; prepared by EG&G, Bionomics, submitted by Rohm & Haas Co., Philadelphia, 

Pa.; CDL:243239-A).

00042557 Heitmuller, T. (1980) Acute Toxicity of Kathon WT to Fiddler Crabs, Uca pugilator: 

Report No. BP-80-3-52. (Unpublished study received Aug 28, 1980 under 707-128; prepared by 

EG&G, Bionomics, submitted by Rohm & Haas Co., Philadelphia, Pa.; CDL: 243238-A).

00042558 Hollister, T.A. (1980) Acute Toxicity of Kathon WT to Embryo Larvae of Eastern 

Oysters, Crassostrea virginica: Report No. BP-80-5-85. (Unpublished study received Aug 28, 

1980 under 707-128; prepared by EG&G, Bionomics, submitted by Rohm & Haas Co., 

Philadelphia, Pa.; CDL:243237-A.)

00042559 Heitmuller, T. (1980) Acute Toxicity of Kathon WT to Pink Shrimp, Penaeus 

duorarum: Report No. BP-80-3-51. (Unpublished study received Aug 28, 1980 under 707-128; 

prepared by EG&G, Bionomics, submitted by Rohm & Haas Co., Philadelphia, Pa.; 

CDL:243240-A).

00086091 Rohm and Haas Company (1977) Toxicity Data: Kathon 886 All-magnesium 

Formulation: Report No. 77-38. (Unpublished study received on unknown date under 707-129; 

CDL:233075-B).

41718801 Ward, T.; Boeri, R. (1990) Acute Flow-Through Toxicity of Kathon 886 F Biocide to 

the Bluegill Sunfish, Lepomis machcrochirus: Lab Project Number: 9002-RH: 89RC-0342. 

Unpublished study prepared by Resource Analysts Inc., Envirosystems Div. 287 p.

41718802 Ward, T.; Boeri, R. (1990) Acute Flow Through of Kathon 886 Biocide to the 

Rainbow Trout, Oncorhynchus mykiss: Lab Project Number: 9003-RH: 89RC-0343. 

Unpublished study prepared by Resource Analysts Inc., Envirosystems Div. 250 p.

41718803 Ward, T.; Boeri, R. (1990) Acute Flow Through of Kathon 886 Biocide to the

Rainbow Trout, Oncorhynchus mykiss: Lab Project Number: 9001-RH: 89RC-0345. Unpublished 

study prepared by Resource Analysts Inc., Envirosystems Div. 209 p. 41741401 Derbyshire, R. 

(1990) Product Chemistry (of) Kathon 886F Microbiocide: Lab Project Number: 1770.02. 

Unpublished study prepared by Rohm and Haas Co. 518 p.

41719501 Pedersen, C. (1990) Kathon 886 Biocide: 21-Day Acute Oral LD50 Study in Bobwhite 

Quail: Lab Project Number: 90 QD148: 89RC-0339. Unpublished study prepared by Bio-Life 

Associates, Ltd. 45 p.

41719502 Pederson, C. (1990) kathon 886 biocide: 8-Day Acute oral LD50 Study in Bobwhite 

Quail: lab project number: 90 QC148: 89RC-0340. Unpublished study prepared by Bio-life 

Associates, Ltd. 45 p.
Page 52 of 56

41719503 Pedersen, C. (1990) Kathon 886 Biocide: 8-Day Acute Dietary LC50 Study in Mallard 

Ducklings: Lab Project Number: 90 DC 145: 89RC-0341. Unpublished study prepared by BioLife Associates, Ltd. 61. p.

41963502 Ward, T.; Boeri, R. (1991) Chronic Toxicity of Kathon 886 Biocide to the Daphnid, 

Daphnia magna: Lab Project Number: 9005-RH: 89RC-0346. Unpublished study prepared by 

Resource Analysts, Inc. 507 p.

41963503 Ward, T.; Boeri, R. (1991) Acute Flow Through Toxicity of Kathon 886 Biocide to 

the Rainbow Trout, Oncorhynchus mykiss--14 Day Prolonged Test: Lab Project Number: 9006-

RH: 89RC-0348. Unpublished study prepared by Resource Analysts, Inc. 306 p.

42358701 Jop, K. (1992) Kathon WT 1.5 Percent Biocide--Acute Toxicity to Cerlodaphnia dubia 

under Static Conditions: Final Report: Lab Project Number: 92-404209: 91RC-0196: 86.0392-

6152.132. Unpublished study prepared by Springborn Labs, Inc. 36 p.

He. K., J. Huang, C.F. Langenaur, E. Aizenman. (2006). Methylisothialinone, a neurotoxic 

biocide, disrupts the association of SrC family tyrosine kinases with focal adhesion kinase in 

developing cortical neurons. J. Pharmacol. Exp. Therap. 317(3): 1320-1329.
Page 53 of 56

Appendix D Screening Level Down-theDrain Analysis

Based on negligible potential for exposure due to rapid degradation of CMIT and MIT, a Downthe-Drain analysis is not expected to be performed.
Page 54 of 56

Appendix E Product Chemistry

MIT/CMIT product chemistry information is summarized in Table E1 (MRIDs 43825701, 

43825702, 43825703 (MIT), 42261401, 42261402, 42261403 (CMIT)).

Table E1 – Product Chemistry of MIT/CMIT

Guideline 

No.

Physical and Chemical 

Properties

Mixture of 2 AIs (3:1 ratio) SF 

886Technical (EPA Reg. No. 707-234):

 5-Chloro-2-methyl-3(2H)-

isothiazolone: 70.1%

 2-Methyl-3(2H)-isothiazolone: 26%

Total: 96.1% AI

2-Methyl-3(2H)-isothiazolone 96% AI

Kordek 573T (EPA Reg. No. 707-255)

830.1550 Product identity and 

composition Refer to Table 3. Refer to Table 3.

830.1600 Description of 

materials used to 

produce the product

CBI CBI

830.1620 Description of 

production process CBI CBI

830.1650 Description of 

Formulation Process CBI CBI

830.1670 Discussion of 

Formation of 

Impurities

CBI CBI

830.1700 Preliminary analysis CBI CBI

830.1750 Certified limits CBI CBI

830.1800 Enforcement analytical 

method 

Reverse phase HPLC with 254 nm UV 

detection.

HPLC with UV Detection

830.1900 Submittal of samples CBI CBI

830.6302 Color Yellow to yellow orange (amber) Shagbark (dark brown)

830.6303 Physical State Semi-solid 25oC Semi-solid at 25oC

830.6304 Odor Weakly sweet and pungent

Odor was not performed since MSDS 

states that inhalation may cause 

irritation of the nose and throat.

830.6313 

Stability to normal and 

elevated temperature, 

sunlight, metals/metal 

ions 

CMIT:

Room temperature - slightly unstable (2-

week testing)

54C -unstable (2-week testing)

Metal, mild steel -unstable (1-week 

testing)

Metal ions, FeCl3 - unstable (1-week 

testing)

Sunlight -stable to slightly unstable (24, 

48 and 72 hours)

MIT:

Room temperature - stable (2-week 

testing)

54oC -slightly unstable (2-week testing)

Stable with metals mild steel at 50oC, 

metal ions FeCl3 at 50oC, sunlight (72 

hrs) and at normal and elevated 

temperature (54oC).
Page 55 of 56

Guideline 

No.

Physical and Chemical 

Properties

Mixture of 2 AIs (3:1 ratio) SF 

886Technical (EPA Reg. No. 707-234):

 5-Chloro-2-methyl-3(2H)-

isothiazolone: 70.1%

 2-Methyl-3(2H)-isothiazolone: 26%

Total: 96.1% AI

2-Methyl-3(2H)-isothiazolone 96% AI

Kordek 573T (EPA Reg. No. 707-255)

Metal, mild steel -stable (1-week 

testing)

Metal ions, FeCl3 - slightly unstable (1-

week testing)

Sunlight -stable to slightly unstable (24, 

48 and 72 hours)

830.6314 Oxidation/Reduction Not reported Not required; product does not contain 

an oxidizing or reducing agent.

830.6315 Flammability FP: 175oF Not applicable

830.6316 Explodability Not applicable Not applicable

830.6320 Corrosion 

Characteristic

No reported No corrosion was observed on 

packaging material when stored for 28 

days at 38-40oC.

830.7000 pH 2.1 (5% in water) at 25oC 2.58 (5% solution in water)

830.7050 UV/Visible Absorption Stable to sunlight Stable to sunlight

830.7100 Viscosity Not applicable Not applicable

830.7200 Melting point 

Not applicable, this product is a semi 

solid at room temperature.

CMIT: 52.0 - 53.0 oC

MIT: 48.0 - 49.5oC

48.0 - 49.5oC

830.7220 Boiling point 

N/A, this product is a semi solid at room 

temperature

Not required, product is a semi-solid at 

room temperature with very low vapor 

pressure.

830.7300 Density 11.8 lb/gal

1.420 g/ml at 25oC

1.35 g/ml at 25oC

830.7370 Dissociation Constant 

Not applicable, the active ingredient 

does not dissociate into ions when 

dissolved in water.

Not applicable, active ingredient does 

not dissociate into ions.

830.7550 Partition coefficient (noctanol/water) 

CMIT: 0.401 at 24oC in log P (PAI)

MIT: −0.486 at 24oC in log P (PAI) Log P=-0.486 at 24oC

830.7840 Solubility in water

CMIT: ≥65.96 grams at 25oC in 100 ml 

water

MIT: ≥22.59 grams at 25oC in 100 ml 

water

≥100 g/ml water at 25oC

830.7860 Solubility in organic 

solvents

CMIT:

Solubilities at 25oC in g/100 ml solvent:

Ethyl Acetate ≥57.75

At 25oC:

Acetonitile: ≥78.6 g/100 ml

Methanol: ≥79.1 g/100 ml
Page 56 of 56

Guideline 

No.

Physical and Chemical 

Properties

Mixture of 2 AIs (3:1 ratio) SF 

886Technical (EPA Reg. No. 707-234):

 5-Chloro-2-methyl-3(2H)-

isothiazolone: 70.1%

 2-Methyl-3(2H)-isothiazolone: 26%

Total: 96.1% AI

2-Methyl-3(2H)-isothiazolone 96% AI

Kordek 573T (EPA Reg. No. 707-255)

Methanol ≥60.31

Xylenol ≥ 55.01

Hexane-1 ≥ 2.44

Hexane-2 ≥ 2.09

MIT:

Solubilities at 25oC in g/100 ml solvent:

Ethyl Acetate ≥18.59

Methanol ≥20.52

Xylenol ≥ 16.87

Hexane-1 ≥ 0.17

Hexane-2 ≥ 0.16

Hexane: 2,371 ppm

Xylenol: 15.65 g/100 ml

830.7950 Vapor pressure CMIT:1.8x10-2 mm Hg (PAI)

MIT: 6.2x10-2 mm Hg (PAI) 6.2x10-2 mm Hg at 25oC (PAI)