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Page 2 of 60 Methylisothiazolinone /Chloromethylisothiazolinone Registration Review Team

Human Health & Environmental Effects Pat Jennings Srinivas Gowda James Breithaupt David Bays Jonathan Chen Tim Dole Don Wilbur Risk Management T ina Pham Rose Kyprianou Seiichi Murasaki
Office of General Counsel Philip RossDocket Number EPA

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Page 3 of 60 TERMS, ABBREVIATIONS AND SYMBOLS
A.I. or a.i. active ingredient atm

- m 3 /mole a tmospheric pressure

- cubic meter per mole BCF b ioconcentration f actor °C d egrees Celsius CAS Chemical Abstracts Service CFR Code of Federal Regulations CHO Chinese h amster o vary
CMIT c hloromethylisothiazolinone CO 2 c arbon dioxide DCI data call

- in EC 50 m edian (or 50 percent) e ffect c oncentration ECOTOX ECOTOXicology EDSP E ndocrine Disruptor Screening Program EPA Environmental Protection Agency FDA Food and Drug Administration FFDCA Feder al Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FWP Fin al Work Plan g/mol g rams per mole GLN guideline number IDS Incident Data System Koc o rganic carbon normalized soil

- water partition coefficient Kd s oil

- water partition coefficient Kow o ctanol

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

- observed

- adverse

- e ffect

- l evel Log K ow l ogarithm of the octanol

- water partition coefficient μg m icrogram MIT methylisothiazolinone ml/g m illiliter p er g ram mg/kg m illigram p er k ilogram mg/kg/day m illigram p er k ilogram p er d ay mg/L m illigram p er l iter mm Hg m illimeter of mercury MOE m argin of e xposure MRID Master Record Identification Number MRL m aximum r esidue l imit N/A n ot a pplicable
nm n anometers NOAEL n o
- o bserved

- a dverse

- e ffect

- l evel OCSPP Office of Chemical Safety and Pollution Prevention OPP Office of Pesticide Programs PAI p ure active i ngredient PC Code Pesticide Chemical Code pH power of h ydrogen or power of the con centration of the hydrogen ionDocket Number EPA

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Page 4 of 60 pKa p ower of the acid dissociation constant or negative base

- 10 logarithm of the acid

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

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

actor TGAI t echnical grade active i ngredient TMDL total maximum daily l oads UF uncertainty factor UV/VIS ultraviolet/v isible light a bsorption WWTPs w astewater treatment plantsDocket Number EPA

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### Table of Contents 1 Introduction

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

................................ ................................ ................. 7 1.2 Updates to the Workplan

................................ ................................ ................................ .. 8 1.3 Case Overview

................................ ................................ ................................ .................. 9 1.4 Chemical Identification and Properties

................................ ................................ .......... 10 1.5 Use/Usage Description

................................ ................................ ................................ ... 11 1.5.1 Registrations

................................ ................................ ................................ ............ 11 1.5.2 Summary of Registered Uses

................................ ................................ .................. 12 1.6 Regulatory History

................................ ................................ ................................ ......... 13 1.6.1 Tolerance Information

................................ ................................ ............................. 13 1.7 Incidents

................................ ................................ ................................ .......................... 14 1.7.1 Human Health

................................ ................................ ................................ ......... 14 1.7.2 Ecological

................................ ................................ ................................ ................ 15 2 Anticipated Data Needs

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

................................ ................................ ........................... 17 3.1 Existing Toxicologi cal Endpoints

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

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

................................ ................................ ................................ ......................... 18 3.2.2 Drinking Water

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

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

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

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

- Application Exposures

................................ ................................ . 20 3.4 Aggregate and Cumulative Exposure

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

................................ ................................ ............................... 20 3.4.2 Cumulative Ex posures
................................ ................................ ............................. 20 4 Environmental Risk Assessment

................................ ................................ ........................... 21 4.1 Environmental Fate Assessment

................................ ................................ ..................... 21 4.1.1 Leaching (Woo d/Paint/Antifoulant Paint/Plastic/Textiles/e.g., treated article)

...... 22 4.1.2 Water and Sediment

................................ ................................ ................................ 22 4.1.3 Soil

................................ ................................ ................................ .......................... 2 3 4.1.4 Air

................................ ................................ ................................ ............................ 23 4.1.5 Fate and Transport in Wastewater Treatment Plants (WWTPs)

............................. 23 4.1.6 Water Quality

................................ ................................ ................................ .......... 23 4.2 Environmental Exposure Pathways

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

................................ ................................ ....................... 24 4.3.1 Mode of Action

................................ ................................ ................................ ....... 24 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

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

................................ ................................ ................................ .. 26 4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............. 26 4.4.2 Screening Level Down

- the

- Drain Analysis

................................ ............................ 26 4.5 Effects Analysis Plan

................................ ................................ ................................ ...... 26 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 26 6 Optional Label Changes

................................ ................................ ................................ ........ 27 7 Next Steps

................................ ................................ ................................ ............................. 27 8 References

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

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Page 6 of 60 Appendix A T oxicology Profile

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

................................ ................................ .............................. 38 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 46 Appendix D Screening Level Down

- the

- Drain Analysis

................................ ......................... 52 Appendix E Product Chemistry

................................ ................................ ............................... 53 Appendix F Special Studies

................................ ................................ ................................ ..... 56 Appendix G Comments Received Concerning the Preliminary Work Plan

............................ 57
List of Tables Table 1

– Summary of Anticipated Risk Assessments and Data Needs: MIT/CMIT

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

– Anticipated Registration Review Schedule

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

– Chemical Identification of MIT/CMIT

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

– Physical

- Chemical and Environmental Fate Properties for MIT/CMIT

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

– Summary of MIT/CMIT Registered Uses

................................ ................................ ....... 12 Table 6

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

................... 16 Table 7

– Toxicological End

- Points for Assessing for MIT/CMIT ORE Exposures

..................... 17 Table 8

– Toxicological End

- Points for Assessing MIT/CMIT Dietary Exposures

....................... 17 Table 9

– Occupational Handler Exposure Scenarios for MIT/CMIT

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

– Residential Handler Exposure Scenarios for MIT/CMIT

................................ ............. 20 Table 11

– Residential Post

- Application Exposure Scenarios for MIT/CMIT

............................... 20 Table 12

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

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

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## 1 Introduction

This document is the United States Environmental Protection Agency’s ( USEPA, EPA or “the A gency”) Final Work Plan ( FWP ) for m ethylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT) or (MIT/CMIT)

. The FWP 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 wou ld 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 inform ation would be helpful for the Agency to receive as it moves toward a decision on MIT/CMIT

. 

## 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 prac tices will occur over time. Through the re gistration review program, the Agency periodically reevaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at http://www2.epa.gov/pesticide

reevaluation

. The Agency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration. The regulations governing registration review begin at 40 CF R 155.40

. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened fo r 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. The Preliminary Work Plan (PWP) for MIT/CMIT was published on June 25, 2014 and the 60

- day comment period ended on August 25, 2014. Public comments received concerning the PWP and d ocuments associated with the MIT/CMIT case can be viewed at http://www.regulations.gov in docket EPA

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## 1.2 Updates to the Workplan Since the publication of the PWP, the Agency has made the following updates:

 Updated Tables 1 and 6 , Anticipated Data Needs, to remove G uideline 850.3030 ( Toxicity of r esidues to h oneybee s ) and add Textile Leaching Study

.  Updated Table 2, the anticipated registration review schedule table

.  Updated Section 1.5.2, Summary of Registered Uses, to include a summary of uses under FDA jurisdiction

.  Updated Section 1.7.1, Human Health Incident Reports, based on information received during the public comment period.

 Updated Section 3.1, Existing Toxi cological Endpoints, to address dermal sensitization.

 Updated Section 3.3.3, Residential Post

- Application Exposure, to address textile leaching.

 Removed Section 7, Guidance for Commenters

.  Updated Section 8, Next Steps (now Section 7).

 Added Appendix F, Special Studies , for Textile Leaching Study.

 Added Appendix G, Comments Receiv ed Concerning the Preliminary Work Plan

. Since the PWP was published, the Agency has determined that for compounds such as MIT/CMIT, the study guideline 850.3030 regarding toxicity of residues to honeybees will not result in information which is necessary for risk assessment. Therefore, this data has been removed from the anticipated data needs.
The Agency received 41 submissions during the public comment period on the initial docket. See Appendix G for the Agency ’s responses to these comments.
Comments received result ed in a modification to the anticipated data needs or registration review schedule for MIT/CMIT

. A textile leaching study was added to evaluate human exposures to textile s treated with MIT/CMIT. This document makes final the work plan fo r the MIT/CMIT registration review process.Docket Number EPA

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## 1.3 Case Overview Tables 1 and 2 below summarize the issues relevant to this registration review case and the anticipated registration review schedule.
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 detail s)

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 Textile Leaching Study
Residental Post Application

- Inhalation Yes N/A New Immunotoxicity Inhalation Exposure Chamber Study Aggregate Yes N/A New Same as above Cumulative No N/A None None Tolerance Review Yes N/A None None Ecological 1 Yes 10/ 19 98 N ew Honeybee acute contact

1 Drinking water and aquatic ecological assessment are not necessary because CMIT and M I T degrade rapidly in the environment to form straight

chain 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 Preli minary Work Plan 2014

- 06 2014

- 0 6

- 25 Close Public Comment Period 2014

- 08 2014

- 08

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

- 12 2014

- 12 Issue Data Call

- In (DCI) 2015

- 12 Receive Data to be Considered in Risk Assessment 2017

- 12 Open 30

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

- 06 Close Public Comment Period 2019

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

- Day Public Comment Period for Pro posed Decision 2019

- 12 Close Public Comment Period 2020

- 02 Issue Final Decision 2020

- 06 Begin Post

- Decision Follow

- up 2020 Total (years) 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).Docket Number EPA

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## 1.4 Chemical Identification and Properties
Table 3 presents the active ingredient s to be assessed in c ase 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 C 4 H 4 ClNOS C 4 H 5 NOS Molecular Weight (grams/mole) 149.60 115.2

Molecular Structure

The m ethylisothiazol in one p hysical 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 25 o C (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

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 25 o C 1.35 g/ml at 25 o CDocket Number EPA

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Page 11 of 60 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)

830.7370 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 o C (Log K ow ) CMIT: 0.401 at 24 o C in log P (PAI)

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

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

830.786 0 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 25 o C (PAI)

None Henry's law constant at 25 o C (atm

- m 3 /mol) CALCULATED 5.37 x 10

- 9 (CMIT)

4.16 x 10

- 8 (MIT) 4.16 x 10

- 8 (MIT)

atm

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

## 1.5 Use/Usage Description 1.5.1 Registrations There are 1 20 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 cu rrently registered products in approxim ately a 3:1 ratio, and are commonly referred to collectively as methylisothiazolinone. Also , there are 19 registered products found to contain 2

- m ethyl

- 3(2H)

- isothiazolone (MIT) as an 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

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### 1.5.2 Summary of Registered Uses
Table 5 presents a listing of EPA

- 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

. Additionally, there are uses of MIT/CMIT which f all under FDA jurisdiction. Examples of such uses include: materials preservative s in cosmetic products, hand soaps, and shampoo , as well as food

- contact antimicrobial agent for finished coating formulations and additives used in the manufa cture of paper, paperboard , and adhesives (see section 1.6.1).
Table 5

– Summary of MIT / CMIT Registered Uses

Use Application Method Application Rate (ppm a.i.) Industrial Process and Water Systems A ir conditioner/refrigeration condensate water systems A ir washer water systems C oal slurry systems C ommercial/industrial water cooling systems E vaporative condenser water systems H eat exchanger water systems I ndustrial auxiliary water systems I ndustrial processing water I ndustrial scrubbing system I ndustrial waste disposal systems L aboratory equipment water baths O il recovery drilling muds/packer fluids P asteurizer/warmer/cannery cooling water systems P ulp/paper mill water system s R everse osmosis water system S econdary oil recovery injection water S ewage systems W et

- 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 Ope n 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 Pou r, 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 400Docket Number EPA

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Page 13 of 60 Use Application Method Application Rate (ppm a.i.) Wood Preservative
W ood pressure treatment to forest products W ood protection treatment to buildings/products outdoor Pressure Treatment Spray, Dip, Brush 19 to 6200 15 to 378 

## 1.6 Regulatory Histor y MIT and C MIT 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 wate r disposal systems, reverse osmosis water systems, leather processing liquors, rubber products and wood protection treatment to buildings/products outdoors.


### 1.6.1 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 (FC Ns) have been granted to Thor GmbH and Thor GmbH, Germany

. FCN No. 999 was granted to Thor GmbH for use as an an timicrobial agent for finished coating formulations and additives used in the manufacture of paper and paperboard including fillers, binders, pi gment 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 coatin gs 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 Nov ember 18, 2010 at a maximum level of 21 ppm

. FCN No s . 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 ingredient s ) 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 app lied to growing crops only. ” The Agency ant icipates reviewing the existing tolerance exemption as well as the potential need for additional tolerances/exemptions during the registration review process.Docket Number EPA

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## 1.7 Incidents 1.7.1 Human Health Incidents Report ed in the OPP Incident Database System (IDS) Incidents that are rated as moderate (HC) or higher are listed as individual reports in the IDS and these reports include information regarding the causes of the incident and symptoms experienced

. T here are 4 2 individual incident reports listed in the IDS for MIT/CMIT for the period 1/1/1998 to the present (s earch conducted on 4/22/14)

. Thirty seven incidents are rated as moderate (HC), one incident is rate d 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 oth er 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 contact with the product due to equipment failure, spills or lack of personal protectiv e equipment ( 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 an d eleven of these cases are rated as minor (HD) and the remaining five cases are not rated (HE). Incidents Reported in the Literature
There is a growing body of literature concerning contact sensitization to me thylisothiazolinone , particularly in E uro pe (where methyisothiazolinone is referred to as MI) . In a study conducted in Belgium (Aerts et al, 2014) the medical charts of 8680 patients tested between 2010 and 2013 were reviewed , and it was determined that the sensitization rate had increased from 3.6 % to 5.3 % for MCI/MI and from 3.1 % to 7.2 % for MI by 2012. In addition the sensitization rate for MI had increased to 7.2% in 2013. The p atients mainly affected were women using cosmetics

. Similar results were reported in a French study ( Revidal

- Gerda network, 2014) where patients patch tested with a challenge concentration of 200 ppm MI in 2010, 2011 and 2012 sho wed an increasing proportion of MI positive tests (1.5%, 3.3% and 5.6%, respectively)

. In addition, a significant increase in se nsitization was observed in a study conducted in Portugal (Gameiro, 2014)

. The prevalence rose <1% in 2005 to 3.4% in 2008

. After 2012, and with the addition of the MI patch test, the sensitization rates increased to 5.15% in 2012 and 10.9% in the first ha lf of 2013

. Of the thirty five cases observed after 2011, 6 were nurses, 4 we re hairdressers or beauticians, 5 were cleaners and two were factory workers. Based on the increasing rates of contact allergy, the Scientific Committee on Consumer Safety (SCCS) of the European Union issued an op i nion (SCCS , 201 4 ) that : Current clinical data indicateDocket Number EPA

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Page 15 of 60 that 100 ppm MI in cosmetic products is not safe for the consumer , no safe concentrations of MI have been demonstrated for leave

- on cosmetic products or wet wipes and 15 ppm MI is considered safe for rinse off cosmetic prod ucts . This is a revision of the previous opini o n ( SC C NFP , 200 4 ) where is was stated that the proposed use of MI as a preservative at a maximum concentration of 100 ppm in the finished cosmetic produc t does not pose a risk to the health of the consumer. In addition to the reports of contact allergy related to the use of MIT/CMIT in personal care products such as cosmetics, there are some cases related to consumer products such as baby wipes that may have been treated with EPA

- registered products

. In Chang and Nakrani, ( 2014 ) , six cases of children with chronic, perianal / buttock and facial dermatitis who had used wet wipes containing MIT are de s cribed

. These children all tested positive t o patch testing with MIT/CMIT and the symptoms resolved after the use of the wipes was stopped

. A similar case is de s cribed in Admani et al, 2014.
There are also several reports of contact allergy t hat are related to EPA registered use of MIT/CMIT as a preservative in paints. Affected individuals in the occupational setting include paint manufacturing workers ( Hardcastle, 2005 and Thyssen, 2006) and professional painters ( Mose et al, 2012 and Tokunage, 2013)

. Indi viduals have also been affected by paints applied in their place of residence and in some cases these effects were caused by inhalation exposure ( A lwan, 2014 and Lundov, 2014)

. Incidents Reported in the Public Com ments
There were 4 1 public comments and 39 of these comments included descriptions of medical problems that the commenters had experienced due to alleged contact with personal care and consumer products treated with MIT

. The personal care products included hand soaps, shampoos, body washes, sunscreens and prescription skin creams

. T he consumer products included baby wipes, toilet paper, laundry detergents, dish detergents and carpet cleaners The medical problems reported primarily were dermal effects with the exception of one commenter who also reported systemic effects such as heart effects, short term memory loss and muscle spasms

. The dermal effects included rashes, swelling, blistering and in one case, hair loss

. 

### 1.7.2 Ecological

No ecological incidents have been report ed from January 19 98 until May 2014 according to a search of the OPP Incident Database (IDS)

. 

## 2 A nticipated Data Needs

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

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– 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 for wooden structures SS Textile Leaching Study TGAI 24 Residential Textiles See Table 11Docket Number EPA

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## 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. These additional studies include product use information, an immunotoxicity study, a dermal exposure study, an inhalation exposure study , an indoor surface residue dissipati on study, an inhalation exposure chamber study , and a textile leaching study (as noted in Table 6 )

. 

## 3.1 Existing Toxicological Endpoint s The Agency established the endpoints listed in Table 7 to be used for assessing occupational and residential exposures (ORE) in the 1998 RED

. These endpoints will be re evaluated during registration review to account for any toxicology studies that were submitted or published after the RED

. In addition , an end

- point for dermal exposure will need to be selected to evaluate the risk of dermal sensitization.
Table 7

– Toxicological End

- Poin ts for Assessing for M IT/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

. T he final P O Ds will be determined during the registration review risk assessment and will be b ased on all available studies.
Table 8

– Toxic ological End

- P oints 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 D ietary

General P opulation , 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.Docket Number EPA

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## 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 r esult in dietary exposure (food) include pesticide preservatives, adhesives, coatings, emulsions, paper/paper products, and household cleaning products. With respect to drinking water exposure, several approved uses as a mat erial preservative and in industrial water systems have the potential to result in CMIT/MIT being discharg ed 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 die tary exposure assessment s as part of the registration review process since they were not conducted for the 1998 RED

. Uses that may result in dietary exposure include : p esticide preservatives , adhesives, coatings, emulsions, paper/paper products, and househ old cleaning products

. Initially, a screening

- level analysis will be conducted.
R esidue 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 conduc ted 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

. H owever, the environm ental 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 compound s 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 or published after the RED and to utilize the exposure data that is anticipated to be needed for registration review

. The occupational and residential as sessment 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 usesDocket Number EPA

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. The inhalation exposures were assessed using the NOA E L 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 RE D instead

. T he occupational handler scenarios as listed in Table 9 will need to be assessed during registration review

. Scenarios 1 and 2 were assessed during the RED process and will need to be reassessed to account for the toxicology studies that were submitted or published 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 a nd will be assessed utilizing the exposure data that is anticipated to be required for registration review

. Dermal exposures do not need to be assessed for S cenarios 1 and 2 because these scenario involve the use of end use products and the exposures are m itigated by 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. Wood Pressure Treatment Inhalation Short and Intermediate Term
3. Brush/Roller Application of preserved p aints Dermal , Inhalation Short and Intermediate Term 4. Airless sprayer application of preserved paints Dermal , Inhalation Short and Intermediate Term
5. Machinist Exposure to preserved MWF Dermal , Inhalation Short and Intermediate Term
6. Mop, wipe and spray ap plication of preserved cleaning products Dermal , 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 w as 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 as sessed 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 or published after the RED and to u tilize the exposure data that are anticipated to be needed for registration review

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– Residential Handler Exposure Scenarios for MIT/CMIT
Scenario Exposure Route(s) Duration Brush/Roller and Airless Spray a pplication of preserved p aints Dermal , Inhalation Short and Intermediate Term Mop, wipe and spray application of preserved cleaning products Dermal , Inhalation Short and Intermediate Term



### 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 assessed during registration review to account for the toxicology studies that were submitted or published after the RED and to u tilize the immunotoxicity, indoor surface residue dissipation, inhalation chamber , and textile leaching 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 exposures to textiles treated with MIT/CMIT preserved finishing solutions or auxiliaries. 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 conduct an aggregate assessment during registration review . Upon 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 othe r 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/

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## 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 b ased on n umerous uses of CMIT, potential pathways of exposure to aquatic organisms include transport from in

service 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 che micals 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 downstream of WWTPs

. Any CMIT and MIT that leach out of products and are su bsequently 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)

. A lthough the oilfield us es are limited to the terrestrial environment, releases from t hese 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 e nvironmental fate 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 in

service 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 transport ed to surface water via runoff would not be expected to persist in the terrestrial and aquatic environment s based on their rapid potential to degrade by biotic processes (MRIDs 42086901, 43753203,

- 04 and

- 05)

. Due to the lack of pe rsistence of CMIT and MI T, 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 ar e 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

- 9 and 4.2 x 10
- 8 atm m 3 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 c leavage to form the straight

- chain degradate , N

- methyl malonamic acid (NMMA)

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- 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 woo d into water, but no leaching stud ies 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 4 3478401)

. 

### 4.1.2 Water and Sediment CMIT and MIT are both miscible in water (Table 4 ) and are expected to preferentially partition to the water phase of the aqueous environment rather than to sediment , air, and fish

. For CMIT, t he 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 MI T 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 fr om 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

- 9 to 10
- 8 atm m 3 mol
- 1 , indi cating that partitioning to air from aqueous media is not a significant route of dissipation (Table 4 )

. C MIT 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, a biotic degradation only occurs at pH 9 with half

- lives ranging from 13

- 17 days for hydrolys is 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 M I T was 12.3 days (MRID 43753202)

. For both hydrolysis and photodegradation , a pparent accumulation of the degradate NMMA occurs and NMMA did not photo degrade

. These photodegradation in water studies have been screened but not reviewed

. They will be reviewed during registration review process
. H alf

- 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 meta bolism studies, no major degradates ( > 10 % of applied parent compound) were detected

. These aquatic metabolism studies have not been

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- reviewed and will be reviewed during the registration review process
. Based on these results, microbial degradatio n 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 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 have been submitted to the Agency for anaerobic aquatic metabolism (MRID 43753203) which will be reviewed for the registration review risk assessment

. 

### 4.1.4 Air CMIT and MIT a re both miscible in water (Table 4 )

. CMIT and MIT have Henry’s Law constants of 10
- 9 to 10
- 8 atm m 3 mol
- 1 , indicating that partitioning from water into air is not a significant route of dissipation (Table 4 )

. Based on the vapor pressures of 10
- 2 mm Hg, h owever , volatili zation 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 Transp ort in Wastewater Treatment Plants ( WWTP s) Data on degradation of CMIT and MIT during wastewater treatment have not been submitted

. S orption to sludge is not likely based on the low log Kow values of 0.40 and

- 0.49 for CMIT and MIT, respectively (Table 4 ). Based on the reported anaerobic and aerobic aquatic metabolism half

- lives ranging from about 5 to 9 hours , rapid degr a dation 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 bio degraded 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 a re 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 Act

. 2 In addition, no Total Maximum Daily Loads (TMDL) have been developed for CMIT

. 3 More information on impaired water bodies and TMDLs can be found at EPA’s website

. 4

2 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885 3 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutan t_ group_name=PESTICIDES 4 http://www.epa.gov/owow/tmdl/Docket Number EPA

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## 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 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 r eported half

- lives of 5

- 9 hours to nitrogenous, low

molecular weight carboxylic acid comp o unds that eventually mineralize to CO 2 (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 M I T, respectively (Table 4 )

. Even though biotic degradation is a significant route of dissipation for CMIT and MIT , abiotic degradation (hydrolysis and photodegradation) is not (MRIDs 43971801, 4470 0501, 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 Effe cts 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 stud y , honeybee acute cont act study (850.3020) , will need to be completed and submitted by the registrant

. Once these data ha ve been submitted to the Agency , a risk assessment can be completed on the wood preservative uses of MIT

. 

### 4.3.1 M ode 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

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. Ecotoxicity endpoints will be needed for honeybees because of the wood preservative use pattern

. 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 LC 50 = 0.07 ppm MRID# 41963503 Fathead minnow Chronic MATC = 0.035 ppm MRID# 42012201

Freshwater invertebrates Daphnia Acute 48

- h r EC 50 = 0.18 ppm MRID# 41718803 Chronic MATC = 0.13 ppm MRID# 41963502 Freshwater benthic invertebrates Subchronic/ Chronic Not required A

Estuarine/marine fish Sheepshead minnow Acute LC 50 = 0.36 ppm MRID# 00042556 Chronic Not required B

Estuarine/marine invertebrates Eastern oyster Acute EC 50 = 0.028 ppm MRID# 00042558 Shrimp Acute LC 50 = 2.3 ppm MRID# 00042559 Chronic Not required B Estuarine/marine benthic invertebrates Subchronic/ Chronic Not required A
Algae Non

- listed Not r equired D Listed Not required D Aquatic vascular plants Duckweed Non

- listed Not r equired D Listed Seedling Emergence Non

- listed Not required B Listed Vegetative vigor Non

- listed Not required B Listed Not required B

Birds Bobwhite quail Acute LD 50 = 62.7 mg/kg MRID# 41719501 Mallard duck Subacute

dietary LC 50 =717 ppm MRID# 41719503 Chronic Not required B
Mammals Rat Acute LD 50 = 105 mg/kg MRID# 86092 Chronic Not required B Nontarget insects Honey bee Acute R equired C

A Fate dat a 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 o f rapid degradation in the environment

. In addition, CMIT and MIT form low

- molecular weight, straight

- chain nitrogenous acids that mineralize to form CO 2 and formic acid

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## 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 Down

the

- 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 assessm ent phase of MIT /CMIT an d the data reviewed following the Agency ’s policy for reviewing public literature for use in assessing risks from pesticide s
. 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 assessme nts 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 i n 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 est rogen, or other such endocrine effects as the Administrator

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- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemica l 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 be tween 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 pesti cide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 6 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists sh ould be construed as a list of known or likely endocrine disruptors. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit o ur website. 7 

## 6 Optional Label Changes

T o eliminate the anticipated need for EPA to require certain data, reduce the possibility that EPA’s planned risk assessments overes ti mate risk due to reliance on conservative assumptions, and/or improve label clarity , registrants may consider amending product labeling

. 

## 7 Next Steps
A DCI will be developed regarding the data needs listed under the “Risk Assessments and Anticipated Data Needs” section of this document. The Agency expects to issue the DCI by December of 2015.

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

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- 0074 for the final second l ist of chemicals. 7 http://www.epa.gov/endo/Docket Number EPA

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## 8 References
Admani, 2014, Methylisothiazolinone: A Case of Perianal Dermatitis Caused by Wet Wipes and Review of an Emerging Pediatric Allergen, Pediatric Dermatology, Vol

. 31, N o. 3, pp 350

- 352. Aerts et al. 2014 , The Dramatic Increase in the Rate of Methylisothiazolinone Contact Allergy in Belgium: a Multicenter Study, Contact Dermatitis, Vol

. 71 , pp 41

- 48

. Alwan, 2014, Presumed Airborne Contact Allergy to Methylisothiazolinone in Paint Causing Acute Severe Facial Dermatitis and Respiratory Difficulty, British Association of Dermatologists 171 (Supplement 1), pp 131

- 137. Chang and Nakrani, 2014, Six Children with Allergic Contact Dermatitis to Methyl

- isothiazolinone in Wet Wipes (Baby Wipes), Pediatrics, Vol 133, N o. 2, Feb 2014. P ages e434

– e438. Gameiro, 2014, Methylisothiazolinone: Second ‘Epidemic’ of Isothiazolinone Sensitization, Contact Dermatitis, Volume 70, pp 238

- 260, 2014. Hardcastle, 2005 Occupational contact dermatitis to 1,2

- benzisothiazolin

- 3

- one and 5

- chloro

- 2

- methylisothiazolin

- 3

- one/2

- methylisothiazolin

- 3

- one in paint manufacturers , C ontact D ermatitis, Volume 53 , Issue 2 , Pages:115

- 116 , A ugust 2005 Lundov, 2014, Emission of Isothiazolinones from Water Based Paints, Enviro. Science and Technology, Volume 48, pp 6989

- 6994, May 28, 2014. Mose, 2012, Occupational Contact Dermatitis in Painters: an Analysis of Patch Test Data from the Danish C ontact Dermatitis Group, Contact De r matitis, Volume 67, pp 293

- 297.
Revidal

- Gerda Network, 2014, Outbreak of Contact Sensitization to Methylisothiazolinone: an Analysis of French Data from the Revidal

- Gerda Network, Contact Dermatitis, Vol 70, Issue 5, pp 262

- 269, May 2014. SCCNFP, 2004, Evaluation and Opinion on Methylisothiazolinone, Scientific Committee on Cosmetic Products and Non

- Food Products (SCCNFP), April 23, 2004.
SCCS, 2014, Scientific Committee on Consumer Safety, Opinion on Methylisothiazolinone (P94)

– Submission II, 12 December 2013, SCCS/1521/13, revision of 27 March 2014. Thyssen, 2006, Contact Dermatitis from Methyisothiazolinone in a Paint Factory, Contact Dermatitis, Vol

. 54, pp 322

- 324, June 2006. Tokunaga, 2013 Occupational Airborne Contact De r matitis by Isothiazolinones Contained in Wall Paint Products, Allergology International, Vol

. 62, Number 3, pp 395

- 397

. 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/

.Docket Number EPA

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# Appendix A T oxicology Profile

Acut e Toxicity for Product Labeling

As summarized in Table A 1 , 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). Methylisothiazoli none 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), th ere 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.Docket Number EPA

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Page 30 of 60 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/m 3 via inhalation for 90 days resulted in decreased body weight i n the high

- dose males (Ca. 90% of control) and decreased body

- wei ght 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 mid

and high

- dose levels, w hich 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 NO A EL is 0.34 μg/l. The LO A EL is 1.15 μ g/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 methylisothiazo linone [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 effec ts 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 (disti lled H 2 O), 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 NO A EL is 10 mg/kg/day. The maternal LOAEL is 30 mg/k g/day, based onDocket Number EPA

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Page 31 of 60 decreased body

- weight gains, with support from the dose

- related increase in deaths. The 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, dos e 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 a t 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 (9 2% 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 comparab le 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, a nd 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 accepta ble 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 )
M ethylisothiazolinone (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 b ased 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 F 0 males and 4.4, 11.8, and 28.0 mg/kg/day, respectively, for F 0 females

. Premating doses were 4.3, 13.4, and 35.7 mg/kg/day, respectively, for F 1 males and 5.5, 16.0, and 39.1 mg/kg/day, respectively, for F 1 females

. F 1 adults were chosen from the F 1 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 sa me 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 F 0 males were considered incidental to treatment

. No treatment

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Page 32 of 60 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 F 1 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 th e 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 F 1 males and females, water consumption was sig nificantly (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% a nd 49.4

- 68.2%, respectively, by P females, 74.4

- 91.7% and 63.5

- 79.7%, respectively, for F 1 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 F 1 males was occasionally significantly (p  0.05) less than one or both control groups

. Low

dose F 1 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 F 1 females during gestation and lactation and are considered a continuation of the systemic effects. Histopathological examination of the reproductive organs from the P and F 1 adults was unremarkable

. Treatment

- related microscopic fi ndings 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 F 1 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 F 1 females showed an increase in erosions

. Oth er 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 le sions in the stomach of P and F 1 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 la ctation

. 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 F 1 or F 2 pups during lactation.Docket Number EPA

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Page 33 of 60 Mean pup body weights during lactation were similar between the treated and control groups fo r 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 admini stered 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 F 1 parental animals were not mated until 13 weeks after they were selected from the F 1 litters. Selection of parents for the F 1 generation was made when the pups were 21 days of age

. F 1 offspring were treated from weaning until they were sacrificed after obtaining the F 2 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 decreas ed food consumption; these changes were observed in males from both generations

. At the 80 mg/kg/day dose, e pithelial hyperplasia of the
non
- glandular stomach and hyperkeratosis in both P and F l generation males and P generation females were observed. Thes e 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 s tomach was also observed in these groups. In the P gene ration, increased intraepithelial globule leukocytes were observed in the glandular stomach of both male and female rats. The parental systemic LOA EL is 80 mg/kg/day, based on epithelial hyperplasia of the non

glandular stomach and hyperkeratosis observed in both P and F l generation males and P generation females
. The parental systemic NOAEL is 20 mg/kg/day
. T he 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 ppmDocket Number EPA

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Page 34 of 60 (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 F 1 males; and 8, 26 and 115 mg/kg/day in F 1 females).
There were no treatment

- related mortalities or clinical signs of toxicit y 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 F 1 (10

- 23%) parental rats at the 1000 ppm dose level. During gestation and lactation, body weight in P females w as 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% a nd in F 1 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 F 1 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 l evel. No test article

- related effects were noted on the number of F 1 pups born, live litter sizes, percentages of males per litter and postnatal survival at any dose concentration. The mean numbers of F 1 pups born, live litter sizes and percentages of male s 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 F 1 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 i dentified as statistically significant at the 200 ppm dose. In F 1 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 signific antly decreased at the 1000 ppm dose in males and was statistically significant. The weight of the pituitary was significantly decreased in F 1 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 F 1 females, brain weight was slightly but significantly decreased at the 1000 ppm dose level compared to control. Final body weight in F 1 males was significantly decreased compared to control at the 1000 ppm dose leve l. 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 F 1 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 ga in, 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 F 1 males/females).Docket Number EPA

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Page 35 of 60 Offspring litter parameters were unaffected by treatment at any dose level. Body weight and body weight gain in both F 1 and F 2 pups was significantly decreased at the 1000 ppm dose level. In F 1 male pups, absolute weight of the thymus and spleen was decreased (not significantly) at the1000 ppm dose level. In F 1 female pups, absolute thymus and spleen weight were si gnificantly 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 micros copic 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 F 1 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 F 1 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 t yphimurium 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 posi tive; however the findings of MRID 43419617 remain positive. CMIT/MIT was also clastogenic in human lymphocytes at S9 activatedDocket Number EPA

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Page 36 of 60 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 negativ e 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 stra in 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 conce ntrations 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 mutagen icity 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 i s 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 [MgCl 2 and Mg(NO 3 ) 2 ] vehicles for 24 months resulted in a dose

- related decrease in drinking water consump tion 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 attribut ed 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 thicke ned 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 i n the incidence of any tumor in either sex. The corrosive properties of methylisothiazolinone imposed limitations on theDocket Number EPA

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Page 37 of 60 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 immunot oxicity study for m ethylisothiazolinone

. This is a requ ired study and has been identified as a data gap and as an anticipated data need

. 

## Metabolism Studies

The toxicokinetics and metabolism of 14 C

- CMIT and 14 C

- 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 t issues. 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 bio

accumulate. The predomina nt , first step in their metabolism is opening of the isothiazolone ring structure, which de

- activated the molecu l e(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)

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Page 38 of 60 

# Appendix B Environmental Fate

Environme ntal Fate and Transport Properties of CMIT and MIT

T his 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 cont ain 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

- m ethyl malonamic acid, N

methyl acetamide, N

- m ethyl oxamic acid, m alonamic acid, m alonic acid , acetic acid, formic acid and CO 2 . Based on the chemical and physical properties (Table 4 ) 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 a re 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 CO 2 (terminal degradate)

. These degradates rapidly degrade in a sequential manner and did not reach significant ( > 10 % of applied parent) conce ntrations 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 n ot reviewed

. The y 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 m ajor 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 stabl e 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 aDocket Number EPA

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Page 39 of 60 result, negatively

- charged hydroxyl ( 1

- OH) groups can attack the ring and break it

. The hyd rolysis of MIT in the studies is consistent with Lyman et al. (1990) which states that alkyl halides are potentially susceptible to hydrolysis. 9 The absence of hydrolysis of MIT as a parent compound (starting compound) in the study is consistent with th e 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 hydrolysis

. 10 Aqu eous Photoly s is
Parent CMIT degraded with a report ed 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 reviewe d

. It will be reviewed during the registration review process. The dechlorinated parent compound MIT degraded with a reported half

- life of 1 2.3 days

. The other degradates were a mix of NMNA, N

- methylacetamide (NMA) , and N

- methyl oxamic acid (NMO) which increased to 3 8 % of parent compound by the end of the study (MRID 43753202)

. This study has been screened but not reviewed

. It will be reviewed during t he 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 substanti ally 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 4375 320 4 )

. 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)

. Th erefore, complete mineralization to carbon dioxide could be expected if the study was conducted for longer than 7 days

. Of the non

- volatile degr adates 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 dioxi de (MRID 4375320 5 )

. This study has been screened but not reviewed

. It will be reviewed during registration review process
.

9 Lyman, Reehl, and Rosenblatt, 1990, p. 7

- 5 10 Lyman, Reehl, and Rosenblatt, 1990, p. 7

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Page 40 of 60 A n a erobic Aquatic Metabolism
CMIT degraded with a half

- life of 5. 3 hours, and in the process, formed carbon dioxide and non

extractable 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) , aqu eous and sediment

- extractable residues were <10 % of applied parent compound (MRID 4 3753203 )

. This study has not screened but not reviewed

. It wi ll be reviewed during registration review process
. Soil Soil Leaching/Adsorption/Desorption Batch Equilibrium
C MIT was mobile to moderately mobile with a dsorption K f values of 0.08

- 4.9 ml/g (mean of 1.5 ml/g) and K oc values of 30

- 310 ml/g (mean of 136 ml/g) in five soils

. Sorption was mostly related to organic carbon content with a n r 2 (goodness of fit value) of 0.33 and to soil pH [H + ] with a r 2 value of 0.24 (MRID 42086902)

. Th e 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. 11
Aerobic Soil Metabolism
CMIT degraded wit h 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)

. A n a erobic 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)

.

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

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Page 41 of 60 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) 12 , which is less than the level of concern (log Kow of 3 or greater). 13 CMIT also has a high water solubility of 659,600 mg/l , but compounds that have a tendency to bioconcentrate generally ha ve low water solubilit y 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) are not required because the log Kow values of CMIT and MIT are 0.40 and

- 0.4 9 , which are less than three

. According to the Final 158W Rule, ASSI data are not required if the log Kow is <3 (Footnote 19 , Antimicrobial Environmental Fat e Data Requirements Table )

. CMIT and MIT are not expected to sorb to sludge ; they rapid degrad e via biotic processes (MRIDs 42086901, 43753203,

- 04 and

- 05) and aquat ic exposure in wastewater effluent from in

- service use is not expected to be significant. Activated Sludge Biodegradation Data on activated sludge biodegradation are not required even though the registered use patterns require these data in 158W. T hough there are potential pathways by which CMIT and MIT can reach the aquatic environment, these chemicals degrade very rapidly via biotic processes (MRIDs 42086901, 43753203,

- 04 and

- 05). As a result, CMIT and MIT aquatic exposure in wastewater effluent from in

- service use is not expected to be significant.
Table B 1
. Status of Methylisothiazolinone Environmental Fate Studies 14

Test Guideline (parent compound unless stated) OCSPP

Guideline No. Study result Significant Degradation Products 15 Study status Reference (MRID) and Comments

Hydrolysis 835.2120 Stable at pH 5 and 7

DT 50 and DT 90 of 13 and 45 days (pH 9) Unidentified

polar degradates adding up to 63 % of applied parent 16 Acceptable 43971801

25 o C

Shami m, January 6, 1998

12 Table 4

. 13 Bioconcentration in fish 850.1730 tests guideline states that log Kow values of >3 indicate high potential for bioconcentration

. 14 Parent methylisothiazolone is 5

- chloro

- 2

- methyl

- 3(2H)

- isothiazolone, CMIT

. 14 Parent methylisothiazolone is 5

- chloro

- 2

- methyl

- 3(2H)

- isothiazolone, CMIT

. 15 Significant degradates formed at > 10 % of applied parent compound

. 16 No degradates formed at > 10 % of applied compound.Docket Number EPA

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Page 42 of 60 Hydrolysis 835.2120 DT 50 of 16.9 days (pH 9) N

- methyl

malonamic acid increased to 64.5 % of parent by 42 days (end of study) Acceptable 44700501

42681301

25 o C Gowda, September 1, 2000 Hydrolysis Degradate (methyl

- - 3(2H)

- i sothiazolone study)) 835.2120 Stable at pH 5, 7, and 9 None 17 Acceptable (in RED) 18 42578401

24.1 o C Dechlorinated parent compound 19

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 registration review 43753201 (parent)

pH 7 for 15 days at 24.8 o C

12.3 days (degradate) Mix of N

- methyl

malonamic acid, N

methylacetamide, 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 registration review 43753202

Degradate MIT , dechlorinated parent

Aerobic soil metabolism 835.4100 5.4 hours No major non

volatile degradates formed Acceptable

(in RED) 42086901

25 o C

17 Degradates cannot form if parent compound is stable. 18 RED located at http://www.epa.gov/oppsrrd1/REDs/3092.pdf

. 19 Methyl

- 3(2H)

- Isothiazolone, MIT, dechlorinated parent compound.Docket Number EPA

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Page 43 of 60 Look in file to find review ~90 % degraded by

2 days Anaerobic aquatic metabolism 835.4400 5.3 hours No major non

volatile degradates formed Will be

reviewed during registration review 43753203

25 o C

Aerobic aquatic metabolism 835.4300 9.5 hours (parent) No major non

volatile degradates formed Will be

review ed during registration review 43753204

25 o C

8.8 hours (degradate) N

- methyl

malonamic acid Will be

review ed during registration review 43753205

25 o C

Leaching

Adsorption

Desorption (unaged) 835.1230 Adsorption K f 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 (r 2 =0.33) and pH [H + ] (r 2 =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 registration review 44113102

Leaching from treated wood AWPA

E11

- 12 84 % leached

from treated Southern Yellow Pine in 28 days
55 % leached in first 5 days No degradat ion

at pH 5 and 7 but signifi cant degradation occurred in the pH 9 solution

. De gradate(s) not identified, but most likely N

methyl

malonamic acid (NMMA) based on hydrolysis study ( MRIDs 44700501, 42681301) Acceptable in

RED 43478401

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Page 44 of 60 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, 19 98

. 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

- publishe d 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 L abs, 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 Lab oratory

- West. 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. a nd Rohm and Haas Co. 101 p

.Docket Number EPA

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Page 45 of 60 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. (19 94) 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 C orning 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: 34P

- 95

- 03A: 42387: 34

- 96

- 40. Unpublished study prepared by ABC Labs., Inc. and Rohm and Haas Co., Bioc ides 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 an d Haas Company. 141 p

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Page 46 of 60 

# 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 o f 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 (LD 50 ) 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 LD 50 of 62.7 mg/kg

. This is sufficient information to c haracterize 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 (LC 50 ) on one species of waterfowl or upland game bird (preferably the mallard duck or bobwhite quail).

TABLE C1

- Avian Subacute Dietary Toxicity Findings Spec ies % A.I. LC 50 ppm MRID No. Toxicity Category

Mallard 1 14.17% 717 41719503 moderately toxic
Bobwhite Quail 1 14.17% 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 subacu te 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)Docket Number EPA

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Page 47 of 60 

## Toxicity to Aquati c Receptors

F reshwater 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 LC 50 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. LC 50 ppm MRID Toxicity Category

Rainbow trout 14.17% 0.19 41718802 Highly toxic

Rainbow trout 1 14.17% 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 12 )

. 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 LC 50 test

. Two studies were reviewed.Docket Number EPA

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Page 48 of 60 Table C3

- Freshwater Invertebrate Acute Toxicity Findings Species % A.I. LC 50 ppm MRID # Toxicity Category
Daphnid Ceriodaphnia 1.5% 1 0.20 42358701 highly toxic
Daphnid Daphnia 14.17% 0.18 41718803 highly toxic

1 Adjusted to 100% a.i.
There is sufficient information to characterize methylisothiazolinone as highly toxic to freshwater invertebrates (Table 4 )

. 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 th e 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 Toxicity The minimum data required to evaluate acute toxicity to estuarine /marine species are a fish 96

- hour LC 50 test using either a marine or estuarine species, a mollusc 96

- hour EC 50 shell deposition study or 48

- hour EC 50 on oyster embryo/larvae, and a shrimp 96

- hour LC 50 test using either a marine or estuarine species.
Table C4

- Estuarine/Marine Acute Toxicity Findings Species % A.I. LC 50 /EC 50 (ppm) MRID # Toxicity Category
Sheepshead Minnow 13.9% 0.36 00042556 highly toxic
Marine copepod Acartia tonsa 1 unspecified purity 0.056 42840301 highly toxic

Pink Shrimp 13.9% 2.3 00042559 moderately toxic

Fiddler Crab Uca pugilator 1 13.9% 59.0 00042557 moderately toxic
Eastern Oyster Embryo

- larvae 13.9% 0.028 00042558 highly toxic

1 Study is considered to be supplemental because a test organism was used that is not recommended.Docket Number EPA

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Page 49 of 60 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 re commended, nevertheless, these studies are considered to have satisfied the guideline requirements

. The guideline requirements for estuarine/marine acute toxicit y are fulfilled (MRID #00042556, #42840301, #00042559, #00042557, and #00042558)

. Table C5

- Estuarine/Marine Acute Toxicity Findings Species % A.I. LC 50 /EC 50 (ppm) MRID # Toxicity Category
Sheepshead Minnow 13.9% 0.36 00042556 highly toxic
Marine copepod Acartia tonsa 1 unspecified purity 0.056 42840301 highly toxic

Pink Shrimp 13.9% 2.3 00042559 moderately toxic

Fiddler Crab Uca pugilator 1 13.9% 59.0 00042557 moderately toxic
Eastern Oyster Embryo

- larvae 13.9% 0.028 00042558 highly toxic

1 Study 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)Docket Number EPA

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Page 50 of 60 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. 4174 1401 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

. Unpublish ed study prepared by Bio

- life Associates, Ltd. 45 p.Docket Number EPA

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Page 51 of 60 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 Bio

- Life 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 Percen t 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. Aizenma n. (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

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Page 52 of 60 

# Appendix D Screening Level Down

- the

Drain Analysis

Based on negligible potential for exposure due to rapid degradation of CMIT and MIT, a Down

the

- Drain analysis is not expected to be performed.Docket Number EPA

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Page 53 of 60 

# 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 or ange (amber) Shagbark (dark brown) 830.6303 Physical State Semi

- solid 25 o C Semi

- solid at 25 o C

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) 54 o C

- slightly unstable (2

- week testing) Stable with metals mild steel at 50 o C, metal ions FeCl3 at 50 o C, sunlight (72 hrs) and at normal and elevated temperature (54 o C).Docket Number EPA

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Page 54 of 60 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) Sunlig ht

- stable to slightly unstable (24, 48 and 72 hours)

830.6314 Oxidation/Reduction No t reported Not required; product does not contain an oxidizing or reducing agent.

830.6315 Flammability FP: 175 o F 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

- 40 o C. 830.7000 pH 2.1 (5% in water) at 25 o C 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 o C MIT: 48.0

- 49.5 o C 48.0

- 49.5 o C

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 25 o C 1.35 g/ml at 25 o C

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 ( n
octanol/water) CMIT: 0.401 at 24 o C in log P (PAI)

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

- 0.486 at 24 o C

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 25 o C: Acetonitile: ≥78.6 g/100 ml Methanol: ≥79.1 g/100 mlDocket Number EPA

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Page 55 of 60 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 25 o C (PAI)Docket Number EPA

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Page 56 of 60 

# Appendix F Special Studies

Justification for Non

- Codified Study Guideline Number: Special Study Study Title: Textile Leaching Study

Rationale for Requiring the Data

MIT/CMIT is registered for use as a preservative in t extiles , textile fibers , and cordage

. Dermal and incidental oral exposures to MIT/CMIT are expected during use of clothing , towels and blankets made from MIT/CMIT treated textiles. T here are no leaching studies available to assess these exposures. Practical Utility of the Data
How will the data be used? These data are crucial in the refinement or confirmation of post

- application exposure predictions. Data collected from textile leaching studies will be used to establish transfer residue rates for textiles treated with MIT/CMIT and will provide a better u nderstanding of the potential exposure and risk for individuals using textiles treated with MIT/CMIT

. The use of actual empirical data for assessment inputs will address critical limitations of risk modeling (i.e., assumptions based on estimated inputs), r esulting in more accurate risk assessments. How could the data impact the Agency’s future decision

- making? Currently there are no leaching data available to assess the dermal and incidental oral exposure of MIT/CMIT resulting from the use of MIT/CMIT in t extile s and thus the risks from these uses are unknown. Quantifying the potential risk to human health will provide the Agency with the ability to conduct more robust assessments based on precise empirical data. In the absence of these data, the Agency may impose unnecessary mitigation measures, which in turn will impact the results of future risk assessment and decision

- making. For future decisions, these refined data will allow the Agency to conduct human

- health risk assessments using real

world, chemical

- specific inputs and thus, minimize the potential for underestimating or overestimating risk.Docket Number EPA

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Page 57 of 60 

# Appendix G Comments Received Concerning the Preliminary Work Plan

On June 25, 201 4 EPA opened a 60

- day public comment period on the preliminary work plan (PWP) for the registration review of for MIT/CMIT . The comment period ended on August 25, 201 4 . During the public comment period the Agency received 41 submissions

. Two of these submissions contained specific comments on the PWP and 39 o f these submissions were unofficial incident reports

. A. Comments on the Preliminary Workplan
Submitter: C.A Niemi
1. Comment on Section 3 Human Health Risk Assessment : Methylisothiazolinone is a known dermal allergen

. The preservative m ethylisothiazolinone (MI) is the American Contact Dermatitis Society Contact Allergen of the Year for 2013. (Castanedo

- Tardana, M. P.; Z ug, K. A. (2013). “ Methylisothiazolinone

. ” Dermatitis : 24 (1): 26.) The Human Health Risk assessment does not explicitly call out dermal allergy as an endpoint in the risk assessment. EPA needs to be sure to determine effects based on this endpoint in the risk assessment. Exposure scenarios should focus on occupational and residential exposure, in particular exposures based on use of personal care products and cleaning products. Response: EPA acknowledges that there has been an increase in the number of incidents reported in the literature related to the use of MIT/CMIT as preserv atives in personal care and cleaning products

. EPA intends to evaluate dermal allergy as an endpoint in the risk assessment to assess occupational and residential exposures that occur from the use of EPA registered MIT/CMIT prod ucts t o preserve treated articles (i.e. textiles/clothing )

. 2. Comment on Section 3 Human Health Risk Assessment: This section does not appear to explicitly call out endpoints associated with dermal contact for occupational groups classed by the Bureau of Labor Statistics as Hairdressers, hairstylists, and cosmetologists. MIT/CMIT are found in a broad array of products that people commonly use. These include personal care products, cleaning products, etc. In particular, personal care products are a source o f occupational exposure of MIT/CMIT to people working in the field of Hairdressers, hairstylists, and cosmetologists (See Women in the Labor Force: A Databook, 2013 edition; www.bls.gov/cps/wlf

- data book

- 2013.pdf

). Table 11, page 38, indicates that women workers in this category comprise 92.8 % of the total workers in that category. Women in this field may have atypical or disproportionately high and adverse human health impacts from exposure to MIT/CMMIT, compared to the general population. EPA needs to investigate the occupational exposures to MIT/CMIT, in particular for women who are employed in this workforce category.Docket Number EPA

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Page 58 of 60 Response: EPA acknowledges that there has been an increase in the nu mber of incidents reported in the literature , related to the use of MI T /CMIT preserved personal care products that would be used by hairdressers, hairstylists and cosmetologists

. However, b ecause the se products are under the jurisdiction of the Food and Drug Administration , the EPA does not register the preservatives that are used in these products

. The EPA has advise d the FDA that these incidents have been reported.
Submitter: D. Todd
3. Comment: Please reconsider the presumptions of safety regarding
m ethylisothiazolinone, isothiazolinone and variants (methylchloro

- , benzo

- etc).
R esearch paper from Europe which refutes earlier safety studies given the new data: http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_145.pdf
Other references: http://www.thelancet.com/journals/lancet/article/PIIS0140

- 6736(89)91318

- 4/abstract http://rihuc.huc.min

- saude.pt/bitstream/10400.4/1683/1/Methylisothiazolinone.pdf Response : EPA has reviewed the references highlighted above and has included the references , where appropriate, in the incident report section of this FWP

. The research paper from Europe is an opinion issued by the Scientific Committee on Consumer Safety ( SCCS , 201 4 ) where it was co n cluded that: “ Current clinical data indicate that 100 ppm MI in cosmetic products is not safe for the consumer, no safe concent rations of MI have been demonstrated for leave on cosmetic products or wet wipes and 15 ppm MI is considered safe for rinse off cosmetic products. ” This reference is included in the incident report section of the FWP. The reference from the L ancet is a 198 9 article on cosmetic dermati t is resulting from the use of MIT in leave

- on cosmetics such as moisturizing
creams
. This article is included in SCCS, 2014 ; therefore , it is not included in th e incident report section

. The reference from Rihuc is an article (Gameiro, 2014) about MIT sensitization in Portugal. This reference is included in the incident report section.Docket Number EPA

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Page 59 of 60 B. Public Comment s that Included Incident Reports The Agency encourages the public to report all future incidents related to EPA

- registered uses ( i.e. household cleaning products, detergents, and treated wipes ) (see Table 5) to the National Pesticide Information Center (NPIC) . More information on how to report incidents to NPIC can be found at: http://npic.orst.edu

. Table G

- 1 provides a summary of public c omments which consisted of incident reports where the commenters described medical problems alleged to have been caused by contact with MIT. The Agency acknowledges these reports and will take these under consideration when conducting the risk assessment.

Table G

- 1

– S ummary of Public Comments that Included Incident Reports

Comment # Use E ffects Comment 0003 Not Specified Rash on uns pecified
areas. Requested chemical to be

banned

. Suffers severe reaction from even the slightest exposure. 0004 Make

- up remover wipes, liquid

soaps and shampoos Rash on f ace and hands Used same products for

years and r eactions started in late 2013. 0005 Cosmetics, household products

and paints Rash on uns pecified
areas Was sensitized in 2006 and

h as a F acebook page devoted to this problem. 0006 Toilet paper, hand soap Hives Has to carry own toilet paper and soap in purse to avoid hives. 0007 Cleaning supplies, dish and

laundry soaps, flushable wipes Rash on f ace and neck Wants product banned.

0008 Residues on linens, napkins,

clothing, shopping carts, table tops and phones Rash similar to poison oak which lasts a week or more. Also experienced rash from

makeup residue on telephone

. 0009 H air products, soaps, clothing,

linens, bedding. Itching, cracking and ble eding of skin. 0010 Linens, towels, sunscreen

residues in pools and spas Poison oak type reaction 0011 Face Wash and Lotion,

Roommates laundry detergent Rash on face then full body Also can’t use pools and

medical hand cleaning soaps 0012 Baby Wipes Rash on h ands and face Also make

- up, shampoos,

cleaning products 0013 Personal Hygiene products 0014 Shampoo Hair loss 0015 Personal care products and

dishwashing detergent Rash on f ace, neck and arms Wants product banned in

all products sold in the US. 0016 Duplicate of comment # 000 7Docket Number EPA

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Page 60 of 60 Comment # Use E ffects Comment 0017 Carpet Cleaner Heart effects, short term memory loss, muscle spasms Improved after removal

from home.

0018 Hand soap at public toilets Rash on h ands and face 0019 Baby Wipes 0020 Bottom wipes and sunscreen Rash on b uttocks and face 0021 Hand soap at public toilets Rash on face 0022 Baby Care products Rash on f ace and body 0023 Duplicate of c omment # 0022 0024 Skin Creams 0025 Duplicate of comment #0010 Widespread rash Equestrian 0026 Not Specified Widespread rash Patch test also caused blistering 0027 Not Specified Patch tested positive Want chemical regulated 0028 Baby Wipes Rash on h ands 0029 Product Changed formula Rash on f ace Also reacted to medical

tape 0030 Baby Wipes Rash on b uttocks 3 year old 0031 Facial Serum, Hair Conditioner Rash on h ands and face 0032 Vaginal Cream (Prescription) Rash on vagina 0033 Washing Potatoes Rash on h ands Chemical allergy to triclosan and MIT 0034 Soap, detergent, wipes, paint,

paper Ras h on h ands and
arms Smallest contact causes

immediate reaction 0035 All products including hand

soaps Sensitive to multiple products 0036 Household products, hand

soaps, laundry detergent, toilet paper, baby wipes, sunscreen Severe allergy

0037 Hand soaps, laundry detergents Swelling in e yes, lips, tongue 0038 Not Specified Rash on h ands and feet 0039 Household cleaning products Rash on e ye lids , face, neck, arms and legs 0040 Baby Wipes m outh, eye lids 0041 Baby Wipes Hands Also shampoos, lotions, laundry and dish detergents 0042 Personal Care and Cleaning

products Two Comments from C.A. Niemi 0043 Dishsoap, Countertop Spray,

Body Wash Hands