Page 2 of 56

Methylisothiazolinone /Chloromethylisothiazolinone Registration Review Team

Human Health & Environmental Effects Pat Jennings Srinivas Gowda James Breithaupt David Bays Jonathan Chen Tim Dole Zoë Cavinder Don Wilbur

Risk Management SanYvette Williams James Parker Eric Miederhoff

Office of General Counsel Philip RossDocket Number EPA

- HQ

- OPP

- 2013

- 060

www.regulations.gov

Page 3 of 56 TERMS, ABBREVIATIONS AND SYMBOLS

AD Antimicrobials Division A.I. or a.i. active ingredient aPAD a cute p opulation a djusted d ose ASRI a ctivat ed sludge r espiration i nhibition
atm

- m 3 /mole a tmospheric pressure

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

- of

- c oncern cPAD c hronic p opulation a djusted d ose CS 2 c arbon disulfide DCI data call

- in EC 50 m edian (or 50 percent) e ffect c oncentration EC 05 5 p ercent e ffect c on centration ECOTOX ECOTOXicology EDI e stimated daily i ntake EDSP E ndocrine Disruptor Screening Program E

- FAST Exposure and Fate Assessment Screening Tool EPI Suite Estimation Program Interface Suite EPA Environmental Protection Agency FDA Food and Dr ug Administration FFDCA Feder al Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FWP Final Work Plan g/mol g rams per mole GLN guideline number HPV h igh production v olume IDS Incident Data System Koc o rganic carbon normalized soil

- water partition coefficient Kd s oil

- water partition coefficient Kow o ctanol

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

- o bserved

- a dverse

- e ffect

- c oncentration LOEC l owest

- o bserved

- e ffect

- c oncentration LOAEL lowest

- observed

- adverse

- e ffect

- l evel Log K ow l ogarithm of the octanol

- water partition coefficient
μg m icrogram ml/g m illiliter p er g ram mg/kg m illigram p er k ilogram mg/kg/day m illigram p er k ilogram p er d ay mg/L m illigram p er l iter mm Hg m illimeter of mercuryPage 4 of 56

MOE m argin of e xposure MRID Master Record Identification Number MRL m aximum r esidue l imit N/A n ot a pplicable

nm n anometers NOAEC no

- observed

- adverse

- effect

- c oncentration NOAEL n o

- o bserved

- a dverse

- e ffect

- l evel OCSPP Office of Chemical Safety and Pollution Prevention OECD Organization for Economic Co

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

- 10 logarithm of the acid

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

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

actor SSTS Section Seven Tracking System SO 2 s ulfur dioxide TEP t ypical e nd

- u se p roduct TGAI t echnical grade active i ngredient TMDL total maximum daily l oads UF uncertainty factor UV/VIS ultraviolet/v isible light a bsorption % w / w p ercent weight per weight. WP w ettable powder WWTPs w astewater treatment plantsPage 5 of 56



### Table of Contents
1 Introduction

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

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

................................ ................................ ................................ .................. 9 1 .3 Chemical Identification and Properties

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

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

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

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

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

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

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

................................ ................................ ................................ ......... 12 1.6.2 Ecological

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

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

................................ ................................ ........................... 15 3.1 Existi ng Toxicological Endpoints

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

................................ ................................ ................................ ............ 15 3.2.1 Food

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

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

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

................................ ................................ .............. 16 3.3.2 Residential Handler Exposures

................................ ................................ ............... 17 3.3.3 Residential Post

- Application Exposures

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

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

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

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

................................ ................................ ........................... 18 4.1 Environmental Fate Assessment

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

...... 19 4.1.2 Water and Sediment

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

................................ ................................ ................................ .......................... 20 4.1.4 Air

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

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

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

................................ ................................ ................ 21 4.3 Ecological Effects Assessment

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

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

................................ ...................... 22 4.4 Expos ure Analysis Plan

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

................................ ............. 24 4.4.2 Screening Level Down

- the

- Drain Analysis

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

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

................................ ................................ . 24 6 Optional Label Changes

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

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

................................ ................................ ................................ ... 25 7.1.1 Trade Irritants

................................ ................................ ................................ .......... 25Page 6 of 56

7.1.2 Water Quality

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

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

................................ ................................ ............. 26 7.1.5 Additional Information

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

................................ ................................ ................................ ............................. 27 9 References

................................ ................................ ................................ ............................. 28

Appendix A T oxicology Profile

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

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

................................ ................................ .......................... 47 Appendix D Screening Lev el Down

- the

- Drain Analysis

................................ ......................... 53 Appendix E Product Chemistry

................................ ................................ ............................... 54

List of Tables Table 1

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

..................... 8 Table 2

– Anticipated Registration Review Schedule

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

– Chemical Identif ication of MIT/CMIT

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

– Physical

- Chemical and Environmental Fate Properties for MIT/CMIT

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

– Summary of MIT/CMIT R egistered Uses

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

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

................. 14 Table 7

– Toxicological End

- P oints for Assessing for MIT/CMIT ORE Exposures

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

– Toxicological End

- Points for Assessing MIT/CMIT Dietary Exposures

..................... 15 T able 9

– Occupational Handler Exposure Scenarios for MIT/CMIT

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

– Residential Handler Exposure Scenarios for MIT/CMIT

................................ ........... 17 Table 11

– Residential Post

- Application Exposure Scenarios for MIT /CMIT

............................. 18 Table 12

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

. ............. 23Page 7 of 56 

## 1 Introduction

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

. The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about MIT/CMIT

, highlighting anticipated data and assessment needs, identifying the types of information that wou ld be especially useful to the

a gency in conducting the review, and providing an anticipate d 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 a gency intends, by sharing this information in the docket, to inform th e public of what it knows about MIT/CMIT and what types of new data or other inform ation would be helpful for the a gency to receive as it moves toward a decision on MIT/CMIT

. The a gency encourages all interested stakeholders to review the PWP and to provi de comments and additional information that will help the a gency’s decision

- making process for this chemical.



## 1.1 Statutory and Regulatory Authority
The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distribu ted 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 pr ogram 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. Change s in science, public policy, and pesticide use practices will occur over time. Through the re gistration review program, the a gency periodically reevaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely. Infor mation on this program is provided at http://www.epa.gov/oppsrrd1/registration_review/

.
The a gency is implementing the registration review program pursuant to Section 3(g) of the Federal Inse cticide, 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. Th e a gency 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 a gency’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. After reviewing and responding to comments and data received in the docket during th is initial comment period, the

a gency will develop a F inal W ork P lan (FWP) and anticipated schedule for the MIT/CMIT Case.

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

- HQ

- OPP

- 2013

- 060 5

. Tables 1 and 2 below summar ize the issues relevant to this registr ation review ca se and the anticipated registration review schedule.Page 8 of 56

Table 1

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

Risk Assessment Assessment

Necessary to Support Registration Review Date of Most

Rece nt 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 a nd Residential Handler Yes 12/1995 Updated Immunotoxicity Dermal Exposure Inhalation Exposure

Residental Post Application

- Incidental Oral and Dermal Yes 12/1995 Updated Immunotoxicity Indoor Surface Residue Dissipation

Residental Post Application

- Inhalation Yes None New Immunotoxicity Inhalation Exposure Chamber Study Aggregate Yes None New Same as above

Cumulative No N/A None None

Ecological 1 Yes 10/98 N ew Honeybee acute contact Toxicity of residues to honeybees

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 app licable

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 Close Pu blic Comment Period 2014

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

- 12 Issue Data Call

- In (DCI) 2015

- 12 Receive Data to be Considered in Risk Assessment 2017

- 12 Open 30

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

- 06 Close Public Comment Period 2019

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

- Day Public Comment Period for Pro posed Decision 2019

- 12 Close Public Comment Period 2020

- 02 Issue Final Decision 2020

- 06 Begin Post

- Decision Follow

- up 2020 Total (years) 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).Page 9 of 56



## 1.2 Case Overview

The registration revi ew docket for MIT/CMIT ( c ase 3092 ) has been established at http://www.regulations.gov in docket number EPA

- HQ

- OPP

- 2013

- 0605

. 

## 1.3 Chemical Identification and Properties

Table 3 presents the active 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

– Ch emical 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 Methylisothiazol 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

- 49.5oCPage 10 of 56

Guideline No. Parameter Mixture of 2 AIs (3:1 ratio) SF 886Technical (EPA Reg. No. 707

- 234):

 5

- Chloro

- 2

- methyl

- 3(2H)

- isothiazolone : 70 .1 %

 2

- Methyl

- 3(2H)

- isothiazolone : 26%

Total: 96 .1 % AI 2

- Methyl

- 3(2H)

- isothiazolone 96% AI Kordek 573T (EPA Reg. No. 707

- 255)

830.7220 Boiling point N/A, this product is a semi solid a t 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 C

830.7370 Dissociation

constant (pKa) Not applicable, the active ingredients i n 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) CMI T (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



## 1.4 Use/Usage Description

1.4.1 Registra tions

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 currently registered products in approxi m 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 anPage 11 of 56

active ingredient without CMIT. All of the products containing MIT and MIT/CMIT are formulated as ready to use solutions, flowable concentrates and liquid soluble concentrates.



### 1.4.2 Summary of Registered Uses

Table 5 presents a listing of the registered uses of MIT/CMIT including some that have been registered since the 2007 RED . All of these uses will be assessed during registration review

. MIT/CMIT can be applied by the following application methods : open pour addition, pressure treatment, spray, dip , mop, wipe, brush /roller or air less sprayer

.

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 systems R everse osmosis water system S econdary oil recovery injection water S ewage systems W et

- end additives/ind ustrial 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 Po ur, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump 3 to 14 1 to 153 3 to 14 1 to 20 3 to 14 3 to 13 9 to 12 1 to 153 3 to 14 1 to 153 3 to 14 1 to 153 2 to 14 11 to 153 3 to 153 1 to 34 3 to 14 16 to 300
Material Preservative
Adhesives, industrial Coatings, industrial Electrical supplies/equipment Emulsions, resin/latex/polymer Fuels/oil storage tank bottom water additive Household cleanin g 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 P ump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump Open Pour, Meter Pump 1 to 400 1 to 400 19 to 439 1 to 400 1 to 34 1 to 1470 60 1 to 444 1 to 400 7 to 1400 7 to 150 25 to 250 55 7 to 400
Wood Preservative

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 378Page 12 of 56



## 1.5 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
approv ed 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.



### 1.5.1 Toleranc e 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 substa nce by FDA and four food contact notifications (FCNs) have been granted to Thor GmbH and Thor GmbH, Germany. FCN No. 999 was granted to Thor GmbH for use as an an timicrobial agent for finished coating formulations and additives used in the manufacture of paper and paperboard including fillers, binders, pigment slurries, and sizing solutions. FCN No. 704 was granted to Thor GmbH, Germany for use as a preservative in resinous and polymeric coatings for polyolefin films

. FCN No. 675 was granted to Thor GmbH , Germany for use as a preservative in aqueous coatings formulated. FNC No. 569 was granted to Thor GmbH for use as an antimicrobial agent in polymer latex solutions intended for use in adhesives. FCN No. 999 was effective 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, 2 006 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% (2 2.5 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 a ctive) ingredients as pesticide formulations applied 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.



## 1.6 Inci dents

1.6.1 Human Health

Incidents that are rated as moderate (HC) or higher are reported in individual reports which include information regarding the causes of the incident and symptoms experienced. There are 4 2 individual incident reports listed in the OPP Incident Database System (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 inci dent involved two employees of a paper mill who developed skin rashes in the year 2000 after a MIT/CMIT product was introduced. One of the employees recovered with treatment while the other also experienced respiratory symptoms. Thirty eight of the HC/H incidents involved dermal exposure in the workplace and most of these incidents were caused by directPage 13 of 56

contact with the product due to equipment failure, spills or lack of PPE. These exposures resulted in skin rashes, blisters and burns, some of which requ ired 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

re ports which are listings of the incidents for a manufacturer or distributer over a certain time period (often quarterly). Typically these reports only contain basic information such as the date, location and product involved and more detailed information such the cause of the incident or symptoms experienced are not included. There are 216 aggregate incident reports listed in the IDS for MIT/CMIT. Two hundred and eleven of these cases are rated as minor (HD) and the remaining five cases are not rated (H E).



### 1.6.2 Ecological

No 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 anticipate d as being needed to support this registration review.Page 14 of 56

Table 6

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

GLN Study Name Test Substance Time Frame

(Measured in months from DCI Receipt) Risk

Assessmen t(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 Se e Tables 9 and 10

875.1700 Product Use

Information TGAI 12 All All All

875.2300 Indoor Surface

Residue Dissipation TGAI 24 Residential Wood Household Cleaning products See Table 11

875.2500 Inhalation

Exposure Chamber Study TGAI in

Paint 24 Occupational and Residential Paint Handler and Post Application 850.3020 Honeybee acute

contact TGAI 12 Ecological Effects Wood preservative Used in hive construction 850.3030 Toxicity of

residue to honeybees TGAI 12 Ecological Effects Wood preservative Used in hive constructionDocket Number EPA

- HQ

- OPP

- 2013

- 060

www.regulations.gov

Page 15 of 56 

## 3 Human Health Risk Assessment

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

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



## 3.1 Existing Toxicological Endpo int s

The a gency’s Office of Pesticide Program Health Effects Division Toxicity Endpoint Selection Committee established endpoints to be used for assessing occupational and residential exposures (ORE) in the 1998 RED

. These endpoints are listed in Table 7.

Table 7

– Toxicological End

- Points for Assessing for 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 tur binates (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 wi ll 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 Toxicologica l 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 4314 0701) based on microscopic lesions in the stomach at 6 mg/kg/day.



## 3.2 Dietary Exposure

The a gency 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 pesticidePage 16 of 56

preservatives, adhesives, coatings, emulsions, paper/paper products, and household cleaning products. With respect to drinking water exposure, several approved uses a s 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 dietary 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 household 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 conducte d 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, t he environmental fate data on degradation indicate that MIT and CMIT are non

- persistent and will biodegrade rapidly
to form straight

- chain nitrogenous carboxylic acids that eventually mineralize to carbon dioxide and formic acid. Therefore, residues of the se compounds are not expected to be found in drinking water.



## 3.3 Occupational and Residential Exposures

The a gency anticipates the need to revise the occupational and residential (ORE) assessment (US EPA, 1995 ) that was conducted in support of the 1998 RED . Th e ORE assessment will need to be revised to account for the toxicology studies that were submitted after the RED and to utilize the exposure data that is anticipated to be needed for registration review. The occupational and residential assessment will co nsider 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 injecti on fluid and drilling mud, cooling towers, pulp and paper) as well as representative material preservation uses (paints and metal working fluids). The inhalation exposures were assessed using the NOA E L of 0.00034 mg/liter (0.049 mg/kg/day) from a 90 day i nhalation toxicity study (MRID 00148418) and the resulting MOEs ranged from 190 to 25,000 which were greater than the target MOE of 100. The dermal exposures were not assessed due to the corrosivity of MIT and gloves were specified by the RED instead

.Page 17 of 56

T he occupational handler scenarios as listed in Table 9 will need to be assessed during registration review . Scenarios 1 and 2 were assessed in RED and will need to be reassessed to account for the toxicology studies that were submitted after the RED and t o utilize the exposure data that is anticipated to be needed for registration review. Scenarios 3 through 6 were not assessed in the RED due to a lack of exposure data and will be assessed utilizing the exposure data that is anticipated to be needed for r egistration review. Dermal exposures do not need to be assessed for S cenarios 1 and 6 because these scenario involve the use of end use products and the
exposures are mitigated the use of chemical resistant gloves as required by the product labels

.

Table 9

– Occupational Handler Exposure Scenarios for MIT/CMIT

Scenario Exposure Route(s) Duration 1. Open Pour Addition for Industrial Process/Water Systems Treatment and Material Preservation Inhalation Short and Inte rmediate Term

2. Brush/Roller Application of preserved p aints Dermal

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

, Inhalation Short and Intermediate Term

4. Machinist Exposure to preserved MWF Der mal

, Inhalation Short and Intermediate Term

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

, Inhalation Short and Intermediate Term

6. Wood Pressure Treatment Inhalation Short and Intermediate Term



### 3.3.2 Residential Handler Exposures Residential handler inhalation exposures to MIT were assessed in the RED for brush/roller application of MIT treated paints. The inhalation MOE for brush/roller application was 25,000 and w as not of concern because it exceeded the target MOE of 30. Inh alation exposures during airless sprayer application or mop wipe and spray application of preserved cleaning products were not assessed in the RED due to the lack of exposure data and will need to be assessed during registration review

.
The residential h andler scenarios as listed in Table 10 will need to be reassessed during registration review to account for the toxicology studies that were submitted after the RED and
to u tilize the exposure data that are anticipated to be needed for registration review.

Table 10

– Residential Handler Exposure Scenarios for MIT/CMIT

Scenario Exposure Route(s) Duration
Brush/Roller and Airless Spray 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 TermPage 18 of 56



### 3.3.3 Residential Post

- Application Exposures Residential post application exposures were not assessed in the RED due to the lack of available data. The residential post application scenarios as listed in Table 11 will need to be reassessed during registration review to account for the toxicology studies that were submitted after the RED and to u tilize the exposure data that are anticipated to be neede d 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 hou sehold cleaning solutions. Dermal Incidental Oral Short and Intermediate

Term
Post application exposure to treated wood Dermal Incidental Oral Short and Intermediate

Term Post application exposure to MIT vapors in rooms painted with preserved pai nts Inhalation Short and Intermediate Term



## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures EPA anticipates the need to revise the aggregate assessment conducted in support of the 1995 RED. Upon a reevaluation and selection of toxicological endpoin ts, 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 Exposu res 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 substa nces and MIT and CMIT do not appear to produce a toxic metabolite produced by other substances. For the purposes of this registration review, therefore, EPA has not assumed that MIT and CMIT have a common mechanism of toxicity with other substances. For in formation 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/pestici des/cumulative/

. 

## 4 Environmental Risk Assessment

The a gency 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 numerous

uses of CMIT, potentia l 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 fro m pressure

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

. Even though there are potential pathways by which CMIT and MIT can reach the aquatic environment, these chemicals degrade very rapidly via biotic processes. CMIT and MIT by in

- service use to wastewater treatment plants would not be expected to be persistent enough to enter surface waterPage 19 of 56

downstream of WWTPs. Any CMIT and MIT that leach out of products and are subsequently transported to surface water via runoff wou ld 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 uses are limited to the terrestrial environment, relea ses 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 ecological risk assessment.



## 4.1 Environmental Fate Assessment
Even though there are potential pathways by which CMIT and MIT can reach the aquatic environment, these chemicals degrade very rapidly via biotic processes. CMIT and MIT by in

service use to wastewater treat ment plants would not be expected to be persistent enough to enter surface water downstream of WWTPs. Any CMIT and MIT that leach out of products and are subsequently transported to surface water via runoff would not be expected to persist in the
terrestr ial 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 MIT, the a gency 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 mine ralize to carbon dioxide and formic acid. The low log Kow of CMIT and MIT indicate that sorption to soil, sludge, and sediments and bioconcentration in aquatic organisms are expected to be limited. CMIT and MIT present in aqueous media are not likely to partition into air based on the low Henry’s Law constants (of 5.4 x 10

- 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 cleavage to form the straight

- chain degradate

, N

- methyl malonamic acid (NMMA). NMMA is a low

- molecular weight n itrogenous carboxylic acid compound that undergoes demethylation and loss of CO 2 (decarboxylation) by biotic processes to eventually form the terminal degradates

, formic acid and CO 2

. However, NMMA is stable to abiotic degradation (MRIDs 42086901, 4375320 3,

- 04 and

- 05)

.


### 4.1.1 Leaching ( Wood/Paint/ Antifoulant Paint/

Plastic/ Textiles/ e.g., treated article ) CMIT and MIT are expected to leach from treated wood into water, but no leaching stud ies have been submitted to the a gency for the paint and textile uses . The registrant conducted a wood leaching study using Southern Yellow Pine and five water types

, including separate treatments of distilled, deionized (DI) water, artificial seawater, and pH 5, 7, and 9 buffer solutions. For all treatments, approximately 55 % of CMIT and MIT leached in first 5 days and approximately 75

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

Even though leaching studies have been submitted for the paint and textile uses, the agency is not planning on requiring them because the leaching from treated wood is expected to create the highest exposure. Also, CMIT and MIT degrade rapidly by biotic processes in the environment (MRIDs 42086901, 43753203,

- 04,

- 05).



### 4.1.2 Water and Sediment

CMIT and MIT are both miscible in water (Table 6) and are expected to preferentially partition to the water phase of the aqueous environment rather than to sediment , air, and fish

. For CMIT,
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 MIT is expected to be an unstable degradate and data on CMIT represents both parent CMIT and the degradate MIT. The experimentally

- determined Koc values , which represent the potent ial for sorption to the organic carbon portion of soil and sediment, ranged from 30

- 310 L/kg in five soils (MRID 42086902, OCSPP 835.1230). Based on these Koc values, CMIT is expected to be mobile to moderately mobile based on the FAO classification syste m. 1 CMIT and MIT have Henry’s Law constants of 10

- 9 to 10

- 8 atm m 3 mol

- 1 , indicating that partitioning to air from aqueous media is not a significant route of dissipation (Table 6). 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 occ urs at pH 9 with half

- lives ranging from 13

- 17 days for hydrolysis in four studies (MRIDs 43971801, 44700501, 42681301, and 42578401 ) and 6.6 days for photodegradation in water (MRID 43753201). The half

- life for photodegradation in water for M I T was 12.3 days (MRID 43753202). For both hydrolysis and photodegradation

, apparent 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 r egistration 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 (OCS PP 835.4300 , MRID 43753204 )

. In these aquatic metabolism studies, no major degradates ( > 10 % of applied parent compound) were detected

. These aquatic metabolism studies have not been formally

- reviewed and will be reviewed during the registration review p rocess

. Based on these results, microbial degradation in the aquatic environment is expected to rapidly degrade CMIT and MIT.



### 4.1.3 Soil

The registrant has submitted data for CMIT for aerobic soil metabolism (OCSPP 835.4100). CMIT was reported to degrade wit h a half

- life of 5.4 hours in aerobic soil but did not form any

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

significant non

- volatile degradates, indicating that mineralization of these degradates was occurring

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

. Data on a naerobic soil metabolism (OCSPP 835.4200) have not been submitted to the a gency , but the registrant has submitted anaerobic aquatic metabolism data (MRID 43753203) which have not been reviewed. If the anaerobic aquatic metabolism data are reviewed and fou nd to satisfy the 835.4400 data requirement, then anaerobic soil metabolism would not be anticipated to be required.



### 4.1.4 Air
CMIT and MIT are both miscible in water (Table 6)

. CMIT and MIT have Henry’s Law constants of 10

- 9 to 10

- 8 atm m 3 mol

- 1 , indicating th at partitioning from water into air is not a significant route of dissipation (Table 6). 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 Transport 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 5). 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, 4375320 3,

- 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

. 

## 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 a gency has determined that products that contain CMIT and its degradate

, MIT
, can be released to the

2 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_3 03d?p_cause_group_id=885

3 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_polluta nt_group_id=885&p_pollutant_ group_name=PESTICIDES

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

terrestrial and aquatic environment fro m 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

- 0.4 9 for CMIT and M I T, respectively (Table 5)

. Even though biotic degradation is a significant route of dissipation for CMIT and MIT , abiotic degradation (hydrolysis and photodegradation) is not (MRIDs 43971801, 44700501, 42681301, 42578401, 43753201, and 43 753202) . Sorption to soil and sediment is not expected to be significant for CMIT and MIT based on experimentally

- determined low Freundlich adsorption coefficients of 0.08

- 4.9 L/kg (MRID 42086902)

. 

## 4.3 Ecological Effects Assessment

MIT is moderately toxic t o practically nontoxic to avian species, but highly toxic to freshwater fish and invertebrates. MIT is moderately toxic to highly toxic to marine/estuarine species. A risk assessment will not be completed on aquatic non

- target species based on a lack of exposure due to a lack of persistence because of microbial degradation. However, a risk assessment on honeybees will need to be completed because of the wood preservative uses of MIT. The anticipated studies

, honeybee acute cont act study (850.3020) and t oxicity of residues to honey bee study (850.3030)

, will need to be completed and submitted by the registrant. Once these data ha ve been submitted to the a gency, 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 to xicologically 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 a gency’s files from MIT studies submitted by

re gistrants 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 us ed 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 b e minimal. In addition, CMIT and MIT form straight

- chain nitrogenous carboxylic acids that eventually mineralize to carbon dioxide and formic acid. Ecotoxicity endpoints will be needed for honeybees because of the wood preservative use pattern.Page 23 of 56

Table 12

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

Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference

Freshwater fish Rainbow trout Acute 96

- h 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 requi red 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 Subacut e

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 accumu late 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 concer n.

D For the MIT use patterns, exposure to plants is not expected because of rapid degradation in the environment

. In addition, CMIT and MIT form low

- molecular weight, straight

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

.Page 24 of 56



## 4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available OPP models will be used to determine the estimated environmental concentration (EECs) in the aquatic environment if an exposure assessment is necessary. However, the agency does n ot 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 a nd 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 assessment p hase 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 Devel opment, 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 f

rom exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints w hich 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 hazar d assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of reregistration decision for MIT /CMIT , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), MIT /CMIT is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed th e EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrato r

5 http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/endangered_species_reregistration_work group/esa_evaluation_open_literature.htmPage 25 of 56

may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or th yroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

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

Under FFDCA sec tion 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. MIT /CMIT is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for MIT /CMIT

. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http ://www.epa.gov/endo/

. 

## 6 Optional Label Changes

The a gency invites comment on any label amendments that could be considered to eliminate the anticipated need for EPA to require certain data, reduce the possibility that EPA’s planned risk
assessments overest i mate risk due to reliance on conservative assumptions, and/or improve label clarity.


## 7 Guidance for Commenters

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



### 7.1.1 Trade Irritants Through the registration review process, the a gency intends to solicit information o n trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The a gency will work to harmonize tolerances and international maximum residue limits (MRLs) and may modify tolerance levels to do so, when possible. Stakeho lders are asked to comment on any trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the nature of the concern.Page 26 of 56



### 7.1.2 Water Quality The agen cy invites submission of water quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP ’s Registration Review Risk Assessment and Management Process 6 in order to ensure they can be used quantitatively or qualitatively in pesticide risk assessments.



### 7.1.3 Environmental Justice EPA seeks to achieve environmental justice, the fair treatment and mean ingful involvement of all people, regardless of race, color, national origin, or income, in the development, implementation, and enforcement of environmental laws, regulations, and policies. To help address potential

env ironmental justice issues, the a genc y seeks information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to MIT /CMIT compared to the general population. Please comment if you are a ware of any sub

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



### 7.1.4 Structure Activity Relationships EPA must rely upon information of appropriate quality and reliability for each decision made by the a gency. In the OPP, the evaluation process for a pesticide chemical traditionally begins with the applicant’s submission of a set of studies conducted with the specific pesticide chemical of interest. The use of the results of such testing (measured data) is a logic al, scientifically rigorous process that identifies the physical, chemical, and environmental fate properties of the pesticide, as well as the dose and endpoints at which an adverse effect can occur in various animal species.

Today, there is significant i nterest in alternative techniques, i.e., techniques other than data generation that could significantly inform the a gency’s decision

- making process. Recently, OPP has made increasing use of structure activity relationship (SAR) as part of its regulatory de cision

- making process. In the SAR process, a chemical's molecular structure is compared to that of other chemicals for which data are available. These structural similarities are then used to make predictive judgments about a chemical’s physical, chemical, and biological properties. Thus, the chemical’s physical, chemical, and biological properties are a function of (or directly related to) the chemical’s molecular structure. Quantitative SAR is referred to as QSAR. To develop a QSAR, a selected set of meas ured data on a single physical, chemical, or biological property is used to derive a model (an equation) to predict the value of that property.

Since SAR assessments and QSAR modeling are another set of tools that are available to a gency scientists, OPP h as begun a process shift that envisions shifting from the current study

- by

- study approach to an approach in which the use of predicted data, generated using validated models, is considered along with information from open literature and studies specificall y generated under Part 161 requirements. All relevant information would be considered as part of a weight

- of

- the

evidence evaluation.

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

At this time, EPA believes that for certain endpoints, especially physical/chemical and fate properties, that SAR and QSA R might be effectively utilized to fulfill these data requirements for many antimicrobial pesticide chemicals. When considering biological properties, at this time, EPA believes that SAR and QSAR can be most effectively utilized in the evaluation of chemic als that exhibit lower toxicity for human health and/or ecotoxicity parameters. This is appropriate because the risk assessment for lower toxicity chemicals can be stream

- lined, i.e., a screening

- level assessment procedure rather than multiple tiers of ass essments with progressively more data requirements.

If stakeholders believe that submission of predicted data can fulfil l one of the data needs for the MIT /CMIT case , then the a gency invites submission of this information. The submitter would be expected to supply a rationale describing the utility of the information and provide documentation on the scientific validity of the information. The determination that the predicted data fulfills the data requirement would be at the sole discretion of the Agency. Pre

- submission consultation with the Agency is encouraged.



### 7.1.5 Additional Information

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

- speci fic ecologic al effects determinations. The a gency is interested in receiving the following information:

1. Confirmation on the following label information: A. Sites of application B. Formulations C. Application methods and equipment D. Maximum application rates E. Fre quency of application, application intervals and maximum number of applications F. Geographic limitations on use 2. Use or potential use distribution 3. Use history 4. Usage/use information for non

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

- target plant damage and avian, fish, reptilian, amphibian and mammalian mortalitie s) not already reported to the a gency 8. Monitoring data


## 8 Next Steps

After the 60

- day comment period cl oses in August 2014 , the a gency will review and respond to any comments received in a timely manner, and then issue a Final Work Plan for the MIT /CMIT

case.Page 28 of 56



## 9 References

U.S. Environmental Protection Agency (EPA). 2002. ECOTOX User Guide: ECOTOXicology D atabase System. Version 3.0. Available: http://www.epa.gov/ecotox/

. U.S. Environmental Protection Agency. High Production Volume Information System (HPVIS). http://www.epa.gov/hpvis/

.Page 29 of 56 

# Appendix A T oxicology Profile

Acut e T oxicity 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 irri tation to skin (Toxicity category I). Methylisothiazolinone is a dermal sensitizer.

Table A1 Methylisothiazolinone Acute Toxicity Data

Guideline No./ Study Type Result Toxicity Category (MRID #) 870.1100/ Acute oral toxicity Rats: Both Sex = 105 mg/kg II 86091

870.1200/ Acute dermal toxicity Rabbit: Both Sex = 200 mg/kg I 86092

870.1300/ Acute inhalation toxicity Rat: 0.33mg/L II 41963501 42360901 42360902

870.2400/ Acute eye irritation

- Rabbit Corrosive I 86092

870.2500/ Acute dermal irritati on 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 f ood consumption (all of which were minimal), and water consumption

. Although differences in several parameters were observed (decreased cholesterol in females, increased SGOT in females, decreased BUN, foci of erosion and focal blunting of the superficial epithelium of the glandular mucosa of the stomach in both sexes), there were no toxicologically significant effects observed in either sex. The NOEL is 75 ppm (males 6.3 mg/kg/day; females 10.8 mg/kg/day). The LOEL is 225 ppm (males 16.3 mg/kg/day; female s 24.7 mg/kg/day), based on microscopic findings (focal blunting) in the stomach in both sexes.Page 30 of 56

90 Day Inhalation

- Rat; 148418

In a subchronic inhalation toxicity study, the exposure of 16 Crl:CD(SD)BR rats/sex/group to methylisothiazolinone (14% a.i.) at dose levels of 0.34, 1.15, or 2.64 mg/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. The re 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, which consisted of eosinophilic droplets in the anterior respiratory mucosa (2.64 mg/m3) and rhinitis in the lining of the anterior portion of the nasal cavity (1.15 and 2.64 mg/m3). These are consistent with a no rmal 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 signific ant 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 4346200 5), dermal administration of methylisothiazolinone [13.9% formulation] to Crl:CD(SR)BR rats [10/sex/group] for 13 weeks at dose levels of 0, 0.75, 3.75 and 18.75 mg/kg/day resulted in skin effects at all dose levels in females and at the mid

- and high

- dose levels in males. There were no adverse effects on survival, body weight gain, food consumption, hematology, clinical chemistry, urinalysis, ophthalmoscopy, gross and microscopic lesions [except skin] at any dose level in either sex. The dermal LOAEL is < 0 .75mg/kg/day based on skin effects

. The NOAEL for systemic effects can be set at 18.75 mg/kg/day, the highest dose tested . This subchronic study is classified Acceptable , and it satisfies the guideline requirement [82

- 3] for a subchronic dermal toxicity study in the rat. 

## Developmental Toxicity

There are two acceptable

- guideline developmental toxicity studies in rat and rabbit, respectively.

Rat

Exposure of Sprague

- Dawley CR® rats (25 dams/group) to methylisothiazolinone (14% a.i.) via gavage (days 6

- 15 of gestation) at dose levels of 0 (distilled 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 i n 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 gro ups. 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/kg/day, based on decreased body

- weight gains, with support from the dose

- related increase in deaths. ThePage 31 of 56

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

- 3(a); MRID #78831).

Rabbi t
In a developmental toxicity study, dose levels of 0.5, 2, 8, or 20 mg methylisothiazolinone (13.4% a.i.)/kg body weight per day to presumed

- pregnant New Zealand white rabbits (16/group) during days 7 through 19 of gestation resulted in: (1) death and gr oss pathological lesions of the stomach at the highest dose (all animals either died or were sacrificed moribund by day 15 of gestation); (2) scant or no feces and diarrhea at the 8 and 20 mg/kg/day dose levels; and (3) decreased overall body

- weight gain ( 70% of control), corrected body weight (92% of control), and food consumption at the 8 mg/kg/day dose level. The numbers of implantations, live fetuses, resorptions, dead implants, and dead fetuses per doe were comparable among the groups, and fetal body w eight (combined and per sex) was comparable among the groups. Although there were no statistically significant differences in the incidence of any fetal alteration (external, visceral or skeletal malformations, variations, or 13 retarded development), ther e 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, c orrected body weight, food consumption, and scant/no feces and diarrhea. The developmental toxicity NOEL is 2 mg/kg/day. The developmental toxicity LOEL is 8 mg/kg/day, based on the slight increase in fetal alterations (GDLN 83

- 3(b); MRID #42311701). 

## Repr oductive Toxicity

There are three acceptable two generation reproductive toxicity studies: two tested with 3:1 CMIT and MIT mixture solution and one tested with MIT solution only.

Rat

– (MRID 44656101 )

– Testing with methylisothiazolinone (3 :1 CMIT and MI T )

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 based on per cent active ingredient of the test article. The salt control group received water containing 15.88% magnesium nitrate and 6.19% magnesium chloride, equivalent to the concentrations of these salts in the high dose group . One litter was produced in each generation. Premating doses were 2.8, 8.5, and 22.7 mg/kg/day, respectively, for 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 wee ks before mating within the same dose group. All animals were continuously exposed to test material either in the drinking water or during gestation and lactation until sacrifice.

Several intercurrent deaths of the F 0 males were considered incidental to treatment. No
treatment

- related clinical signs of toxicity were observed in males or females of either generationPage 32 of 56

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

Body weights and body weight gains of the low

- and mid

- dose P males and females and of all treated 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 the high

- dose P males were significantly (95

- 96% of control; p  0.05) less than the water control group, but not different from the salt control group, during weeks 2

- 4. Cumulative weight gains by the high

- dose P males we re 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 ga ins 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 significantly (p  0.05) less than one or both contro l groups throughout the premating interval. As compared to one or both control groups, water consumption by the mid

- and high

- dose groups was 70.5

- 91.9% and 65.5

- 73.8%, respectively, by P males, 63.3

- 83.3% and 49.4

- 68.2%, respectively, by P females, 74.4

- 91.7% and 63.5

- 79.7%, respectively, for 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 gest ation 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 findings were observed in the stomachs of the high

- dose parental animals of both generations: focal superficial erosions, edema and inflammation in the submucosa of the glandular and non

- glandular areas (except 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. Other lesions, in both sexes and generations seen at the mid dose levels were comparable to the controls.

Therefore, the LOAEL for parental toxicity is 100 ppm [8.5, 11.8 mg/kg/day, P males/females ] based on reduced water consumption and histopathological lesions in the stomach of P and F 1 males an d females. The systemic toxicity NOAEL is 30 ppm [2.8/4.4 mg/kg/day, P males/females ] . No treatment

- related effects were noted on maternal body weights, body weight gains, or food consumption during gestation and lactation. Mating, fertility, gestation, and parturition indices, mean precoital interval, and mean gestation length were similar between the treated and control groups of both generations. Mean litter size, live births, and pup survival were also similar between the treated and control groups f or both generations. No treatment

- related clinical signs of toxicity were observed in the F 1 or F 2 pups during lactation.Page 33 of 56

Mean pup body weights during lactation were similar between the treated and control groups for both generations. Gross necropsy of the pups was unremarkable. No histological lesions in the stomach were observed in the pups.

Therefore, the NOAEL for reproductive toxicity is  300 ppm (HDT) [22.7/ 28.0, P males/females ]; the reproductive toxicity LOAEL was not identified.

This study is classified as Acceptable/guideline and satisfies the requirements for a reproduction study (83

- 4) in rats.

Rat

– (MRID 48444412)

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

In the 2

- generation reproductive toxicity study (MRID 48444412)

, methyl isothiazolinone ( 14.62 % a.i., batch # 

### 080310 ) was administered to 25 Wistar rats /sex/dose in distilled water by
gavage at dose levels of 0, 5, 20, or 80 mg/kg/day. Vehicle control group animals were administered distilled water alone

.
The parental animals (P) were given test diets for 10 weeks before they were mated . Treatment for the P females continued through mating, pregnancy, and up to weaning of their offspring. The 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 ma ximum of 8 pups/litter ( 4/ sex/litter, as nearly as possible. )

Parental toxicity was observed at the high dose. Signs of toxicity included decreased body weights, decreased body weight gains, and decreased food consumption; these changes were observed in m ales 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. These effects were attributed to the local irritation po tential 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 generation, 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 ppmPage 34 of 56

(corresponding to dose levels of 4, 15 or 69 mg/kg/day in P males; 7, 22 or 93 mg/kg/day in P females; 5, 19 or 86 mg/kg/day in 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 toxicity in either the P or F1 parental rats. For the pre

- mating p eriod, 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 was decreased significantly for gestation days 14

- 17, 17

- 20, and 0

- 20 at the 1000 ppm dose level and during lactation days 7

- 14 at the 1000 ppm dose level. Food consumption was significantly decreased in P parental rats at the 1000 ppm dose level by 5

- 11% and in 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 pare ntal animals, reproductive performance (including male and female mating indices, male fertility index, and female fertility index) were not affected by treatment with the test article at any dose level. No test article

- related effects were noted on the nu mber 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 males per litter were similar among all groups and no statisti cally 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 identified 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 significantly decreased at the 1000 ppm dose in males and was stat istically 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 wei ght 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 level. Relative weight of the brain was significantly increase d 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 gain, and organ weight changes. The parental systemic NOAEL is 200 ppm (15/22 mg/kg/day in P males/females; 19/26 mg/kg/day in F 1 males/females).Page 35 of 56

Offspring litter parameters were unaffected by treatment at any dose level. Body weight and body weight gain in both F 1 and F 2 pups was significantly decreased at the 10 00 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 significantly decreased at the 1000 ppm dose level. The abso lute weight of the spleen and thymus was also observed to be significantly decreased in F2 male and female pups at the 1000 ppm dose level. However, there were no corresponding macroscopic or microscopic changes to these organs.

The LOAEL for offspring t oxicity 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 ma les/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 du ration 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 i n P males/females; 86

- 115 mg/kg/day in F1 males/females). 

## Mutagenicity

Methylisothiazolinone was positive in the reverse gene mutations in Salmonella typhimurium TAl 00 in three independent studies (MRIDs #78827, 96692, and 105044). The response has been observed both in the absence and the presence of S9 activation; however, concentrations 5 x 10 X higher are required to induce mutagenicity when S9 activation is incorporated into the assay with this bacterial strain. Similarly, forward gene mutations hav e 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 perform ed 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 t he 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, mus t 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 ass ay). Using these new criteria, in order for test material to be considered positive, the IMF must show an increase over the solvent control background frequency + the GEF developed for the mouse lymphoma assay by the International Workshop on Genotoxicity Testing (IWGT, 2005). When the data were revisited and the new criteria were applied, results from RH

- 81RC

- 153 (1981) can no longer be considered positive; however the findings of MRID 43419617 remain positive. CMIT/MIT was also clastogenic in human lympho cytes at S9Page 36 of 56

activated concentrations that induced ≤ 50% decrease in the mitotic index. In vivo, three studies (either mouse micronucleus or chromosome aberrations) were negative; however, none of these studies were conducted up to the maximum tolerated dos e and are, therefore, unacceptable. Two in vivo unscheduled DNA synthesis assay rat hepatocytes were also submitted; these studies, which were negative up to doses causing overt animal toxicity, were also guideline/acceptable. Nevertheless, the lack of an acceptable bone marrow cytogenetic assay precludes the ruling out of a mutagenicity concern.

MIT was not mutagenic in the S. typhimurium tester strain battery and also in strain TA102; it was negative for forward mutations up to cytotoxic concentrations in CHO cells. Although chromosome aberrations were observed in CHO cells, this clastogenic effect was confined to non

- activated and S9

- activated concentrations that were severely cytotoxic. Similarly, MIT neither induced micronuclei in mouse bone marrow u p to the lethal doses nor UDS in rat hepatocytes up to the highest dose tested (308 mg/kg); higher doses were lethal. Accordingly, there was no mutagenicity concern.

CMIT caused ≥ 2

- fold increases in revertant colonies of S. typhimurium TA 100 in the p resence of S9 activation; no other assays were performed with this biocide. No further testing was submitted.



## Chronic / Carcinogenicity Toxicity

There is one acceptable drinking water cancer study (MRID 43140701). Under the condition of the study, exposu re 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 consumption at all dose levels in both sexes throughout the study. Decreased body weight (95

- 98% of control) and body weight gain (87% of control at week one, from 91

- 98% thereafter) were observed in the high

- dose males, although statistical significance was not always attained. Females displayed an equivocal decrease in body weight throughout the study, with the mid

- (93

- 96% of control) and high

- dose (87

- 96% of control) groups showing comparable decreases that were not always dose

- related. During the second year, body

- weight gains of the high

- dose females were significantly decreased (83

- 88% of control). High

- dos e 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

e vident. 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 a ttributed to the decrease in water consumption. With the exception of the stomach, none of the gross and non

- neoplastic lesions observed could be attributed to treatment. An increased incidence in hyperplasia and hyperkeratosis of the squamous mucosa of th e stomach was observed at the mid

- and high

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

- glandular mucosa of the forestomach on gross examination. Additionally, there was an increased incidence of necrosis of the glandular mucosa in the mid

- dose females and in both sexes at the high

- dose level. There was no treatment

- related increase in the incidence of any tumor in either sex. The corrosive properties of methylisothiazolinone imposed limitations on thePage 37 of 56

dose levels tested. The NOAEL is 30 ppm (males 2.0 mg/kg/day; females 3.1 mg/kg/day). The LOEL is 100 ppm (males 6.6 mg/kg/day; females 9.8 mg/kg/day), based on microscopic lesions (hyperplasia/hyperkeratosis in both sexes, necrosis of g landular mucosa in females) in the stomach

. 

## Immunotoxicity

There is currently no existing immunot oxicity study for m ethylisothiazolinone

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

. 

## Metabolism Studies

The toxicokinetics and metabolism of 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 appea r in the urine, bile or feces. Excretion occurs predominately within 24 hours. There is no evidence that CMIT or MIT or its metabolites bioaccumulate in tissues. CMIT and MIT is initiated through nucleophilic attack on the sulfur

- nitrogen bond of the isoth iazolone 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

se condary 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 metabol ites 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).Page 38 of 56 

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of CMIT and MIT

T his environmental fate assessment addresses the p ersistence and mobility of the parent compound 5

- chloro

- 2

- methyl

- 4

- isothiazolin

- 3

- one (CMIT) and the dechlorinated CMIT degradate (MIT), both of which contain an intact isothiazolone ring. It also addresses the persistence and mobility of the low

- molecula r 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 th e chemical and physical properties (Table 6) and environmental fate properties (Table B1 ) of CMIT and MIT, both compounds are highly water soluble, stable to chemical degradation (hydrolysis and photodegradation), rapidly degraded by metabolism in the

en vironment , unlikely to volatize from water into air, and will be present mostly in water in the presence of sediment.

The straight

- chain degradates are also highly water

- soluble include N

- methyl malonamic acid, N

- methyl acetamide, N

- methyl oxamic acid, ma lonamic 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 scre ened but not 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 major degradate as pH 9 was N

- methyl malonamic acid which did not degrade in the studies (MRIDs 43971801, 44700501, and 42681301). In a separate study using the degradate MIT (methyl

- 3(2H)

- isothiazolone, dechlorinated parent as a parent compoun d), was stable to hydrolysis at pH 5, 7, and 9 (MRID 42578401).

The presence of hydrolysis of MIT as a degradate and the absence of hydrolysis of MIT as a parent compound appear to be contradictory. However, CMIT (parent compound in the hydrolysis studies ) is an alkyl halide with a high concentration of negative charges located near the negatively

- charged chlorine, and these electrical charges destabilize the ring structure. As aPage 39 of 56

result, negatively

- charged hydroxyl ( 1

- OH) groups can attack the ring and br eak it. The hydrolysis of MIT in the studies is consistent with Lyman et al. (1990) which states that alkyl halides are potentially susceptible to hydrolysis. 7 The absence of hydrolysis of MIT as a parent compound (starting compound) in the study is con sistent with the fact that MIT does not have the high concentration of negative charges at one point in the ring, and Lyman et al. (1990) states that aromatic amines (e.g. MIT) are generally resistant to hydrolysis 8

. Aqu eous Photoly s is

Parent CMIT degraded with a reported half

- life of 6.6 days to form the degradates N

- methyl malonamic acid (NMNA) acid and 5

- chloro

- 3

- methyl

- 4

- thiozolin

- 2

- one (CMT). Both degradates increased throughout the study period and were presumed to be stable. NMNA increased to 30

- 31 % and CMT increased to 38 % of applied parent compound (MRID 43753201)

. This study has been screened but not reviewe d . It will be reviewed during the registration review process.
The dechlorinated parent compound MIT degraded with a reported half

- life o f 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 r eviewed during the registration review process.
Aerobic Aquatic Metabolism

CMIT degraded with a reported half

- life of 9.5 hours in a 7

- day study

. Significant quantities of aqueous, sediment

- extractable residues, and non

- extractable sediment residues were present throughout the study but carbon dioxide was not formed in significant amounts. Therefore, complete mineralization to carbon dioxide was not occurring in the 7

- day study duration. The registrant did not quantify the degradates because they were s o substantially similar, but provided a degradation pathway (Figure 11, p. 48). Parent CMIT degrades to straight

- chain, low molecular

- weight compounds such as N

- methyl malonamic acid which eventually degrade to formic acid, formaldehyde, and carbon dioxid e (MRID 4375320 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 residue s 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 d egradates 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 d ioxide (MRID

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

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

- 4Page 40 of 56

4375320 5 ). This study has been screened but not reviewed . It will be reviewed during registration review process

.

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

ext ractable residues but did not form significant non

- volatile degradates . Based on these results, mineralization of parent compound and these degradates was occurring

. By 7 days (end of study) , aqueous and sediment

- extractable residues were <10 % of applie d 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

CMIT was mobile to moderately mobile with a dsorption K f v alues 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 42 086902). 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. 9

Aerobic Soil Metabolism

CMIT degraded with a half

- life of 5.4 hours but did not form any signific ant 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 a gency. However, the registrant has submitted anaerobic aquatic metabolism data (MRID 43753203) which have not been reviewed. If the anaerobic aquatic metabolism data are reviewed and found to satisfy the 835.4400 data requirement, then anaerobic soil metabolism data would not be anticipated to be required.

Leaching from Treated Wood

The registrant conducted a wood leaching study using Southern Yellow Pine and five water types. Leaching studies included separate treatments of distilled, deionized (DI) water, artificial seawater, and pH 5, 7, and 9 buffer solutions. For all treatments, approximately 55 % of CMIT and MIT leached in first 5 days and approximately 75

- 80 % leached in 28 days (MRID 43478401).

9 http://www.fao.org/docrep/003/x2570e/x2570e06.htmPage 41 of 56

Bioconcentration in Fish

CMIT is not like ly to bioconcentrate in fish to a significant degree based on reported BCF values of 41

- 54X (MRID 44113102) . This lack of bioconcentration is consistent with the low log Kow (0.401) 10 , which is less than the level of concern (log Kow of 3 or greater). 11 CM IT also has a high water solubility of 659,600 mg/l , but compounds that have a tendency to bioconcentrate generally ha ve low water solubility values . However, this study has been screened but not reviewed . It will be reviewed during registration review process

. Fate and Transport in WWTP

Activated Sludge Sorption Isotherm

Data on activated sludge sorption isotherm (ASSI) were not submitted but are not required because the log Kow values of CMIT and MIT are 0.40 and

- 0.4 9 , which are less than three. Ac cording to the Final 158W Rule, ASSI data are not required if the log Kow is <3 (Footnote 19)

. Activated Sludge Biodegradation

Data on activated sludge biodegradation (Ready Biodegradability) were not submitted and are required based on the registered use pa t terns.
Table 1. Status of Methylisothiazolinone Environmental Fate Studies 12

Test Guideline (parent compound unless stated) OCSPP

Guideline No. Study result Significant Degradation Products 13 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 14 Acceptable 43971801

25 o C

Shamim,

January 6, 1998

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

- methyl

malonamic acid inc reased to 64.5 % of parent by Acceptable 44700501

42681301

10 Table 6

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

. 12 Pare nt methylisothiazolone is 5

- chloro

- 2

- methyl

- 3(2H)

- isothiazolone, CMIT

. 12 Pare nt methylisothiazolone is 5

- chloro

- 2

- methyl

- 3(2H)

- isothiazolone, CMIT

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

. 14 No degradates formed at > 10 % of applied compound.Page 42 of 56 42 days (end of study) 25 o C

Gowda, September 1, 2000

Hydrolysis

Degradate

(methyl

- - 3(2H)

- i sothiazolone study)) 835.2120 Stable at pH 5, 7, and 9 None 15 Acceptable

(in RED) 16 42578401

24.1 o C

De chlorinated parent compound 17

Photodegradation in water by sunlight 835.2210 6.6 days (parent) N

- methyl

malonamic acid increased to 30

- 31 % of parent by 15 days (end of study)

5

- chloro

- 3

- methyl

- 4

- thiozolin

- 2

- one increased to 37.6 % by 15 days Will be

reviewed during reregistration review 43753201 (parent)

pH 7 for 15 days at 24.8 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 reregistration review 43753202

Degradate MIT
, dechlorinated parent

15 Degradates cannot form if parent compound is stable.
16 RED lo cated at http://www.epa.gov/oppsrrd1/REDs/3092.pdf

. 17 Methyl

- 3(2H)

- Isothiazolone, MIT, dechlorinated parent compound.Page 43 of 56

Aerobic soil metabolism 835.4100 5.4 hours No major non

volatile degradates formed Acceptable

(in RED)

Look i n file to find review 42086901

25 o C

~90 % degraded by 2 days

Anaerobic aquatic metabolism 835.4400 5.3 hours No major non

volatile degradates formed Will be

reviewed during reregistration review 43753203

25 o C

Aerobic aquatic metabolism 835.4300 9.5 h ours (parent) No major non

volatile degradates formed Will be

reviewed during reregistration review 43753204

25 o C

8.8 hours (degradate) N

- methyl

malonamic acid Will be

reviewed during reregistration review 43753205

25 o C

Leaching

Adsorption

Desorpt ion (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 org anic 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 reregistration review 44113102

Leaching from treated wood AWPA E11

-

12 84 % le ached

from treated Southern No degradat ion

at pH 5 and 7 but significant degradation occurred in the Acceptable in

RED 43478401

Kathon WTPage 44 of 56 Yellow Pine in 28 days

55 % leached in first 5 days pH 9 solution.

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

methyl

malonamic acid (NMMA) based on hy drolysis study ( MRIDs 44700501, 42681301)Page 45 of 56

References

Food and Agriculture Organization of the United Nations ( FAO ) . 1987. Soil Quality Considerations in the Selection of Sites for Aquaculture. http://www.fao.org/docrep/field/003/ac172e/AC172E05.htm (partial document), http://www.fao.org/docrep/field/003/AC172E/AC172E00.htm (whole document)
Gowda, Srinivas. September 1, 2000. Review of 5

- chloro

- 2

- methyl

- 4

- isothiazolin

- 3

- one (RH 651) hydrolysis studies.

Lyman, W.J., W.F. Reehl, and D.H. Rosenblatt. 1990. Handbook of Chemical Property Estimation Methods. American Chemi cal Society. ISBN O

- 8412

- 1761

- 0

. Shamim, Najm. January 6, 1998. Review: Hydrolysis data submitted in support of registration. Review of Lucas, 1996. DP Barcode D228642

.
42086901

. Wang, W. (1991) Aerobic Soil Metabolism of carbon 14|

- RH

- 651: Lab Proje ct Number: XBL 90020: XBL RPT0045: RH TECH. 34

- 91

- 03. Un

- published study prepared by XenoBiotic Labs, Inc. 73 p.

42086902

. Wang, W. (1991) Adsorption and Desorption of carbon 14

- RH

- 651 in Four Soils and One Sediment: Lab Project Number: XBL 90024: RPT 0046: RH TECH. 34

- 91

- 09. Unpublished study prepared by XenoBiotics Labs, Inc. 86 p.

42578401

. Marx, M.; Castle, S.; Shepler, K. (1992) Hydrolysis of (carbon 14)

- RH

- 573 at pH 5, 7 and 9: Lab Project Number: 223W

- 1: 223W: 34

- 92

- 63. Unpublished study prepa red 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. Un published study prepared by Pharmacology and Toxicology Research Laboratory

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 Ha as 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. Unpubli shed 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: 3 4P

- 90

- 09: 34

- 94

- 78. Unpublished study prepared by PTRL West, Inc. and Rohm and Haas Co. 101 p.Page 46 of 56

43753203

. Liu, P.; Reynolds, J. (1994) Anaerobic Aquatic Metabolism of (Carbon 14)

- RH

- 651: Lab Project Number: XBL90022: RPT00169: 34P

- 90

- 60. Unpublished stud y prepared by XenoBiotic Labs, Inc. 112 p.

43753204

. Reynolds, J. (1994) Aerobic Aquatic Metabolism of (Carbon 14)

- RH

- 651: Lab Project Number: XBL90021: RPT00172: 34P

- 90

- 59. Unpublished study prepared by XenoBiotic Labs, Inc. 122 p.

43753205

. Reynolds, J . (1994) Aerobic Aquatic Metabolism of (Carbon 14)

- RH

- 573: Lab Project Number: XBL91006: RPT00170: X117. Unpublished study prepared by XenoBiotic Labs, Inc. 143 p.

43971801

. Lucas, T. (1996) (Carbon

- 14) ACTICIDE 14: Hydrolytic Stability: Final Report: Lab Project Number: 1154

- 043: CHE 1154

- 043. Unpublished study prepared by Corning Hazleton GmbH. 104 p.

44113101

. Reynolds, J. (1996) Aged Leaching of (carbon 14)

- RH

- 651 in Four Soils: (Final Report): Lab Project Number: XBL90023: RPT00171: 34P

- 90

- 27. Unpubl ished 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., Biocides Research Labs. 117 p.

44700501

. Mazza, L. (1998) Identification of Hydrolytic Degradates of (carbon

- 14)

- RH

- 651 at pH 9: Supplemental Report to MRID 42681301: Lab Project Number : TR

- 98

- 039: 24P

- 97

- 004: 13

- 98

- 045TR. Unpublished study prepared by Rohm and Haas Company. 141 p.Page 47 of 56 

# Appendix C Ecotoxicology Profile

Toxicity to Terrestrial Receptors

Ecological Toxicity Data Ecological effects toxicity testing was performed using a formulation i ntermediate (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 o f the technical grade is indicated, due to the inherent instability of the active ingredients at higher percentages.

Birds, Acute Toxicity

In order to establish the acute toxicity of methylisothiazolinone to birds, the following test is required using the technical grade material: one avian single

- dose oral (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 characterize methylisothiazolinone as moderately toxic to avian species on an acute oral basis. The guideline requirement is fulfilled. (MRID #41719501)

Birds, Subacute Toxicity

In order to establish the subacute toxicity of methylisothiazolinone to birds, the following test is required using the technical grade material: one subacute dietary study (LC 50 ) on one species of waterfowl or upland game bird (preferably the mallard duck or bob white quail).

TABLE C1

- Avian Subacute Dietary Toxicity Findings

Species % 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 sup plemental because the analytical methodology may not have followed GLP procedures

.
There is sufficient information to characterize methylisothiazolinone as moderately toxic to practically non

- toxic to avian species on a subacute dietary basis (Table 4). B oth avian subacute dietary toxicity studies are considered to be supplemental because GLP compliance was not evident. However, the guideline requirement is considered fulfilled. (MRID #41719502 and #41719503)Page 48 of 56



## Toxicity to Aquatic Receptors

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 (preferabl y 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 High ly 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 bo th cold and warmwater fish (Table 5). The guideline requirements for freshwater fish acute toxicity are fulfilled. (MRIDs #41718802 and #41718801, respectively)

Freshwater Fish, Chronic Toxicity

In order to establish the chronic toxicity of methylisothia zolinone 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 freshwa ter 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 we re reviewed.Page 49 of 56

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.

Ther e is sufficient information to characterize methylisothiazolinone as highly toxic to freshwater invertebrates (Table 6). The guideline requirement for freshwater invertebrate acute toxicity is fulfilled. (MRIDs #42358701 and #41718803)

Freshwater Inverte brates, Chronic Toxicity

In order to establish the chronic toxicity of methylisothiazolinone to freshwater invertebrates, the minimum data required on the technical grade of the active ingredient is an invertebrate life cycle study using the technical mate rial.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 chr onic 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 Catego ry

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

Easter n Oyster Embryo

- larvae 13.9% 0.028 00042558 highly toxicPage 50 of 56 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 guidel ine 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 Mi nnow 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 estuari ne/marine species (Table 7). Certain studies are considered to be supplemental because test organisms were used that are not recommended, nevertheless, these studies are considered to have satisfied the guideline requirements. The guideline requirements for estuarine/marine acute toxicity are fulfilled. (MRID #00042556, #42840301, #00042559, #00042557, and #00042558)Page 51 of 56

References

00042556 Heitmuller, T. (1980) Acute Toxicity of Kathon WT to Sheepshead Minnows, Cyprinodon variegatus: Report No. BP

- 80

- 3

- 53. (Unpublished study received Aug 28, 1980 under 707

- 128; prepared by EG&G, Bionomics, submitted by Rohm & Haas Co., Philadelphia, Pa.; CDL:243239

- A)

.
00042557 Heitmuller, T. (1980) Acute Toxicity of Kathon WT to Fiddler Crabs, Uca pugilator: Report No . BP

- 80

- 3

- 52. (Unpublished study received Aug 28, 1980 under 707

- 128; prepared by EG&G, Bionomics, submitted by Rohm & Haas Co., Philadelphia, Pa.; CDL: 243238

- A)

.
00042558 Hollister, T.A. (1980) Acute Toxicity of Kathon WT to Embryo Larvae of Eastern O ysters, 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 Kat hon 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) Tox icity 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, Oncorhynch us mykiss: Lab Project Number: 9003

- RH: 89RC

- 0343. Unpublished study prepared by Resource Analysts Inc., Envirosystems Div. 250 p.

41718803 Ward, T.; Boeri, R. (1990) Acute Flow Through of Kathon 886 Biocide to the Rainbow Trout, Oncorhynchus mykiss: Lab Project Number: 9001

- RH: 89RC

- 0345. Unpublished study prepared by Resource Analysts Inc., Envirosystems Div. 209 p. 41741401 Derbyshire, R. (1990) Product Chemistry (of) Kathon 886F Microbiocide: Lab Project Number: 1770.02. Unpublished study prepared by Rohm and Haas Co. 518 p.

41719501 Pedersen, C. (1990) Kathon 886 Biocide: 21

- Day Acute Oral LD50 Study in Bobwhite Quail: Lab Project Number: 90 QD148: 89RC

- 0339

. Unpublished study prepared by Bio

- Life Associates, Ltd. 45 p. 41719502 Pederson, C. (1990) kathon 886 biocide: 8

- Day Acute oral LD50 Study in Bobwhite Quail: lab project number: 90 QC148: 89RC

- 0340. Unpublished study prepared by Bio

- life Associates, Ltd. 45 p.Page 52 of 56

41719503 Pedersen, C. (1990) Kathon 886 Biocide: 8

- Day Acute Dietary LC50 Study i n 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: 90 05

- 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: 90 06

- RH: 89RC

- 0348. Unpublished study prepared by Resource Analysts, Inc. 306 p.

42358701 Jop, K. (1992) Kathon WT 1.5 Percent Biocide

-- Acute Toxicity to Cerlodaphnia dubia under Static Conditions: Final Report: Lab Project Number: 92

- 404209: 91RC

- 0196: 86 .0392

- 6152.132. Unpublished study prepared by Springborn Labs, Inc. 36 p.

He. K., J. Huang, C.F. Langenaur, E. Aizenman. (2006). Methylisothialinone, a neurotoxic biocide, disrupts the association of SrC family tyrosine kinases with focal adhesion kinase in developing cortical neurons. J. Pharmacol. Exp. Therap. 317(3): 1320

- 1329.Page 53 of 56 

# Appendix D Screening Level Down

- 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 p erformed.Page 54 of 56 

# Appendix E Product Chemistry

MIT/CMIT product chemistry information is summarized in Table E1 ( MRIDs 43825701, 43825702, 43825703 (MIT), 42261401, 42261402, 42261403 (CMIT) )

.

Table E1

– Product Chemistry of MIT/CMIT

Guideline No. Physical and Chemic al

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)

830.1 550 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

p roduction 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 Reve rse 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 We akly 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).Page 55 of 56

Guideline No. Physical and Chemic al

Properties Mixture of 2 AIs (3:1 ratio) SF

886Technical (EPA Reg. No. 707

- 234):

 5

- Chloro

- 2

- methyl

- 3(2H)

- isothiazolone: 70.1%

 2

- Methyl

- 3(2H)

- isothiazolone: 26%

Total: 96.1% AI 2

- Methyl

- 3(2H)

- isothiazolone 96% AI Kordek 573T (EPA Reg. No. 707

- 255)

Metal, mild steel

- stable (1

- week testing) Metal ions, FeCl3

- slightly unstable (1

- week testing) Sunlight

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

830.6314 Oxidation/Reduction 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 Exploda bility 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/Visib le 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

830.72 20 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 Co nstant 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:

Solubiliti es 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 mlPage 56 of 56

Guideline No. Physical and Chemic al

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)