Page 2 of 73Page 3 of 73

Octhilinone (OIT) Registration Review Team

Human Health & Environmental Effects

Timothy Dole

Don Wilbur

Jonathan Leshin

David Bays

Siroos Mostaghimi

Najm Shamim

Risk Management

SanYvette Williams

Rose Kyprianou

Seiichi Murasaki

Office of Gene ral Counsel

Philip RossDocket Number EPA

- HQ

- OPP

- 2014

- 016 0

www.regulations.gov

Page 4 of 73 TERMS, ABBREVIATIONS AND SYMBOLS

AD Antimicrobials Division

A.I. or a.i. active ingredient

aPAD a cute p opulation a djusted d ose

ASRI a ctivated sludge r espiration i nhibition

atm

- m 3 /mole a tmospheric pressure

- cubic meter per mole

BCF b ioconcentration f actor

°C d egrees Celsius

CAS Chemical Abstracts Service

CFR Code of Federal Regulations

CHO Chinese h amster o vary

CMA Chemical Manufacturers Association

CO 2 c arbon dioxide

COC c oncentration

- of

- c oncer n

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 oncentration

ECOTOX ECOTOXicology

EDI e stimated daily i ntake

EDSP E ndocrine Disruptor Screening Program

E

- FAST Exposure and Fate Assessment Screening Tool

EPI Suite Estimation Program Interface Suite

EPA Environmental Protection Agency

FDA Food and Drug Administration

FFDCA Feder al Food, Drug, and Cosmetic Act

FGD f

lue

- g as d esulfurization

FIFR A 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 p artition 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 b served

- 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 illig ram p er l iter

mm Hg m illimeter of mercuryPage 5 of 73

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 eve l

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 ercen t

PC Code Pesticide Chemical Code

PCF p ounds p er c ubic foot

pH power of h ydrogen or power of the con centration of the hydrogen ion

PHED Pesticide Handler’s Exposure Data

PIS primary i rritation s core

pKa p ower of the acid dissociation constant or negat ive base

- 10 logarithm of the acid

dissociation constant of a solution

ppb p arts p er b illion

ppm p arts p er m illion

PWP Preliminary Work Plan

QSAR q uantitative s tructure

- a ctivity r elationship

RED Rere gistration Eligibility Decision

SAR s tructure a ctiv ity r elationship

SF s afety f

actor

SSTS Section Seven Tracking System

TEP t ypical e nd

- u se p roduct

TGAI t echnical grade active i ngredient

TMDL total maximum daily l oads

UF uncertainty factor

UV/VIS ultraviolet/v isible light a bsorption

% w / w p ercent weight per weight.

WP w ettable powder

WWTPs w astewater treatment plantsPage 6 of 73



### Table of Contents

1 Introduction

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

1.1 Statutory and Reg ulatory Authority

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

1.2 Updates to the Final Work Plan

................................ ................................ ..................... 10

1.3 Case Overview

................................ ................................ ................................ ............... 10

1.4 Chemical Identification and Properties

................................ ................................ .......... 11

1.5 Use/Usage Description

................................ ................................ ................................ ... 12

1.5.1 Registrations

................................ ................................ ................................ ........... 12

1.5.2 Summary of Registered Uses

................................ ................................ .................. 12

1.5.3 Usage Information

................................ ................................ ................................ .. 14

1.6 Regulatory H istory

................................ ................................ ................................ ......... 14

1.6.1 Tolerance Information

................................ ................................ ............................ 14

1.7 Incidents

................................ ................................ ................................ ......................... 14

1.7.1 Human Health

................................ ................................ ................................ ......... 14

1.7.2 Ecological

................................ ................................ ................................ ............... 15

2 Anticipated Data Needs

................................ ................................ ................................ ........ 15

3 Human Health Risk Assessment

................................ ................................ ........................... 19

3.1 Existing Toxicological Endpoints

................................ ................................ .................. 19

3.2 Dietary Exposure

................................ ................................ ................................ ............ 20

3.2.1 Food

................................ ................................ ................................ ........................ 20

3.2.2 Drinking Water

................................ ................................ ................................ ....... 21

3.3 Occupational and Residential Exposures

................................ ................................ ....... 21

3.3.1 Occupational Handler Exposure

................................ ................................ ............. 21

3.3.2 Residential Handler Exposures

................................ ................................ ............... 22

3.3.3 Residential Post

- Application Exposures

................................ ................................ . 23

3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 24

3.4.1 Aggregate Exposures

................................ ................................ .............................. 24

3.4.2 Cumulative Exposures

................................ ................................ ............................ 24

4 Environmental Risk Assessment

................................ ................................ ........................... 24

4.1 E nvironmental Fate Assessment

................................ ................................ .................... 25

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

........ 25

4.1.2 Wate r and Sediment

................................ ................................ ................................ 25

4.1.3 Soil

................................ ................................ ................................ .......................... 25

4.1.4 Air

................................ ................................ ................................ ........................... 25

4.1.5 Water Quality

................................ ................................ ................................ .......... 25

4.2 Conceptual Models for Environmental Exposure Pathways

................................ .......... 26

4.3 Ecological Effects Assessment

................................ ................................ ....................... 26

4.3.1 Mode of Action

................................ ................................ ................................ ....... 26

4.3.2 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 26

4.4 Exposure Analysis Plan

................................ ................................ ................................ .. 27

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............ 27

4.4.2 Screening Level Down

- the

- Drain Analysis

................................ ............................ 27

4.5 Effects Analysis Plan

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

5 Endocrine Disruptor Screening Program (EDSP)

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

6 Optional Label Changes

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

7 Next Steps

................................ ................................ ................................ ............................. 29Page 7 of 73

8 References

................................ ................................ ................................ ............................. 30

Appendix A Public Comments

................................ ................................ ................................ ..... 35

Appendix B Environmental Fate

................................ ................................ ................................ .. 57

Appendix C Epi Suite (Version 3.12) Ecotoxicity Profile

................................ ............................ 59

Appendix D Screening Level Down

- the

- Drain Analysis

................................ ............................. 71

Appendix E Product Chemistry

................................ ................................ ................................ .... 72

Appendix F Public Comments

................................ ................................ ................................ ...... 73

List of Tables

Table 1

– Summary of Anticipated Risk Assessments and Data Needs: OIT

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

Table 2

– Anticipated Registration Review Schedule

................................ ................................ .. 10

Table 3

– Chemical Identification of OIT

................................ ................................ ..................... 11

Table 4

– Physical

- Chemical and Environmental Fate Properties for OIT

................................ .. 11

Table 5

– Summary of OIT Registered Uses

................................ ................................ ................ 13

Table 6

– Studies Anticipated as Needed for the Registration Review of OIT

............................ 16

Table 7

– Toxicological Endpo ints for Assessing for OIT ORE Exposures (2007 RED)

............ 19

Table 8

– Occupational Handler Exposure Scenarios to be assessed in Registration Review

..... 22Page 8 of 73



## 1 Introduction

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

Agency ”) Final Work Plan ( F WP) for Octhilinone (OIT). The F WP document explains what

EPA's Office of Pesticide Programs (OPP) knows about OIT, highlighting anticipated data and

assessment needs, identifying the ty pes of information that would be especially useful to the

agency in conducting the review, and providing an anticipated timeline for completing OIT’s

review. This work plan also addresses the public comment received concerning the Preliminary

Work Plan (P WP) which was posted in the OIT registration review docket (EPA

- HQ

- OPP

- 2014

- 0160). Further, this document makes final the work plan for the OIT registration review process.



## 1.1 Statutory and Regulatory Authority

The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All

pesticides distributed or sold in the United States generally must be registered by the USEPA

based on scientific data showing that they will not cause unreasonable risks to human health or

the environment when used as directed on product labeling. The registration review program is

intended to make sure that, as the ability to assess risk evolves and as policies and practices

change, all registered pesticides continue to meet the statutory standard of no unreaso nable

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

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

periodically reevaluates pesticides to make sure that as chan ge occurs, products in the

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

http://www2.epa.gov/pesticide

- reevaluation

.

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

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

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

registration. The regulations governing registration review begin at 40 CFR 155.40. The a genc y

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

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

agency ’s opportunity to state what it knows about the pesticide and what a dditional risk analyses

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

comment period for the preliminary work plan (PWP), published June 25, 2014, closed on

August 25, 2014. As stated in Appendix F, a let ter from the Physician Committee for

Responsible Medicine (PCRM) was submitted to the docket regarding the following studies: 1)

acute inhalation toxicity study; 2) the chronic oral toxicity and carcinogenicity studies and 3) the

21/28 day dermal toxicity study. In response to this comment, changes are addressed in “Table 6

– Studies Anticipated as Needed for the Registration Review of OIT ”

. Additionally, the agency

has determined that guideline 850.3030 ( honeybee toxicity to residues ) is not necessary for risk

assessment and has been deleted from Table 6

.

Documents as sociated with the registration review of OIT, including the PCRM letter, can be

viewed at http://www.regulations.gov in docket EPA

- HQ

- OPP

- 2014

- 0160. Tables 1 and 2 b elow

summar ize the issues relevant to this regis tration review case and the anticipated registration

review schedule

.Page 9 of 73

Table 1

– Summary of Anticipated Risk Assessments and Data Needs : OIT

Risk Assessment Assessment

Necessary to

Support

Registration

Review Date of Most

Recent

Assessment Type of

Assessment

Required

(New/Updated) Data Anticipated as Needed

(See Table 6 for detail s)

Dietary (food) Yes N/A New Chronic Oral Toxicity

Carcinogenicity

– 2 species

Acute neurotoxicity

Immunotox icity

Dietary (drinking water) Yes N/A New Chronic Oral Toxicity

Carcinogenicity

– 2 species

Acute neurotoxicity

Immunotoxicity

Occupational Handler Yes 9/17/2007 Updated Chronic Oral Toxicity

Carcinogenicity

– 2 species

Acute neurotoxicity

Immunotoxic ity

Dermal and Inhalation

Exposure

– Indoor

Acute inhalation toxicity

Residential Handler Yes 9/17/2007 Updated Acute neurotoxicity

Immunotoxicity

Dermal and Inhalation

Exposure

– Indoor

Acute inhalation toxicity

Residental Post

Application

- Inciden tal

Oral and Dermal Yes 9/17/2007 Updated Acute neurotoxicity

Immunotoxicity

Indoor Surface Residue

Dissipation

Aggregate Yes 9/17/2007 Updated Chronic Oral Toxicity

Carcinogenicity

– 2 species

Acute neurotoxicity

Immunotoxicity

Cumulative No None None None

Ecological Yes 3/7/2007 Updated Aquatic invertebrate life

- cycle

Fish early

- life stage

Honeybee acute contact

Leaching from treated wood

Leaching from fabrics

Ready Biodegradability

Activated sludge Respiration

Inhibition (OECD ) or Modified

Sludge R espiration Inhibition or

one of the three biodegradation

in activated sludge simulation

tests

N/A = Not applicablePage 10 of 73

Table 2

– Anticipated Registration Review Schedule

Anticipated Activity Target Date * Completion Date

Phase 1: Op ening the Docket

Open Docket and 60

- Day Comment Period for Preli minary Work Plan 2014

- 06 2014

- 0 6

- 25

Close Public Comment Period 2014

- 08 2014

- 08

- 25

Phase 2: Case Development

Issue Final Work Plan 2014

- 12 2014

- 12

Issue Data Call

- In (DCI) 2015

- 12

Receive Data to be Considered in Risk Assessment 2018

- 12

Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 2020

- 06

Close Public Comment Period 2020

- 07

Phase 3: Registration Review Decision and Implementation

Open 60

- Day Public Comment Period for Pro posed Decision 2020

- 12

Close Public Comment Period 2021

- 02

Issue Final Decision 2021

- 06

Begin Post

- Decision Follow

- up 202 1

Total (years) 7

* The anticipated schedule will be revised as necessary ( e.g

., need arising under th e Endocrine Disruptor Screening Program with

respect to the active ingredients in this case).



## 1.2 Updates to the Final Work Plan

 Updated Table 2

– Anticipated Registration Review Schedule to reflect completion date.

 Clarified in Table 6 that s tudies which are designed to simultaneously fulfill the

requirements of both the chronic oral and carcinogenicity studies (i.e., a combined study)

may be conducted

.

 Removed the 21/28 day dermal toxicity study (OPPTS 870.3200) from Table 6.

 Removed the honeybee toxicity r esidues study (OPPTS 850.30 3 0) from Table 6 and

Appendix C under Beneficial Insects section.

 In Table 6, moved the Wastewater Treatment Plant and Biodegradation studies ( OPPTS

835.3110 and 850.3300) from the “Studies That Were Required through the Post RED

DCI” section to the “Stud ies Anticipated To Be Required Through T he Registration

Review DCI” section since they were not part of the Post

- RED DCI

. OPPTS 835.3220,

835.3240 and 835.3280 are listed individually and are part of the biodegradability study

OP PTS 835.3110 requirement

.

 Deleted “Guidance for Commenters” section.

 Updated format, corrected typographical errors and made other editorial changes.



## 1.3 Case Overview

The docket for Octhilinone (OIT) (case# 2475 ) has been established at

http://www.regulations.gov in docket number EPA

- HQ

- OPP

- 2014

- 0160

.Page 11 of 73



## 1.4 Chemical Identification and Properties

Table 3 presents the active ingredient to be assessed in case 2475: OIT (PC Code 099901).

Table 3

– Chemi cal Identification of OIT

Chemical Name 3(2H)

- Isothiazolone, 2

- Octyl

Other names 2

- Octyl (2H)

- Isothi a zolone (OIT)

2

- Octyl

- 3 2(H)

- isothiazolone (OIT)

2

- Octyl

- 2H

- isothiazol

- 3

- one (OIT)

Octhilinone

KathonTM 893T

Chemical Classification Isothiazolone

PC Cod e 099901

CAS Number 26530

- 20

- 1

Molecular Formula C 11 H 19 NOS

Molecular Weight (grams/mole) 213.34

Molecular Structure

The octhilinone product chemistry information (MRID 41687801) relevant to risk assessment is

summarized in Table 4

.

Table 4

– Physical

- Chemical and Environmental Fate Properties for OIT

Guideline # Parameter Octhilinone

Physical/Chemical Properties

830.7000 pH Not applicable. The test material is <0.1% soluble in water and the

test material does not dissocia te into Bronsted Acid

- Base ions (no

measurable pH). Because of these reasons, this test is not

applicable to the test material.

830.7050 UV/Visible Absorption Absorption max. at 280 nm

.

830.7200 Melting point ( o C) Not applicable. The test material is a liquid at room temperature.

830.7220 Boiling point ( o C) 133 ° C at 2.3 x 10

- 2 Torr ; No degradation.

116°C/0.005 mm Hg; 128

- 130°C /0.4 mm Hg

.

830.7300 Density 1.036 g/ml

830.7370 Dissociation constant (pKa) This test is not applicable since the test subst ance does not

dissociate into ions.

830.7550 Octanol

- water partition

coefficient at 25 o C (Log K

ow ) 4.4 (PAI)

830.7840 Solubility in water (mg/L) at 25oC 481 mg/L (481 ppm)

830.7860 Solubility in organic solvents at

25oC Most organics

- 50% (aromatics, alcohols, ethers, etc.)

Ethyl acetate

- 940g/L

Methanol

- 840 g/L

Toluene

- 800 g/LPage 12 of 73

Guideline # Parameter Octhilinone

Hexane

- 640 g/L

830.7950 Vapor pressure (mmHg) 3.68 x 10

- 5 to 4 x 10

- 6 mm HG at 25 ° C( PAI)

Environmental Fate Properties

Octanol

- air partition coefficient at 25 o C (Log

K OA ) Not Available

Air

- water partition coefficient (Log K AW ) Not Available

Mobility

Organic Carbon Partitioning Coefficient (K

oc ) Kd and Koc values of 1.1

- 10.8 and 604

- 1297 ml/g

Slight to not mobile in four US soils: silt loam, clay, clay loam, and

si lt clay loam (tech report)

Persistence in Water (half

- life)

Hydrolysis at 25 o C: pH 5, 7 &9 (days) Stable under the three pHs: 5, 7, and 9

Aqueous photolysis at 25 o C (days) Half

- life of 16.3 days

Aerobic aquatic metabolism (days) T he submitted data w ill be reviewed when the fate risk assessment

is conducted

.

Anaerobic aquatic metabolism half

- life (days) The submitted data will be reviewed when the fate risk assessment

is conducted.

Persistence in Soil (half

- lifes)

Soil photolysis (days) Data are n ot required.

Aerobic soil metabolism at 25 o C (days) The submitted data will be reviewed when the fate risk assessment

is conducted.

Anaerobic soil metabolism (days) The submitted data will be reviewed when the fate risk assessment

is conducted.

Persist ence in WWTP (% removed)

Ready biodegradation The submitted data will be reviewed when the fate risk assessment

is conducted.

atm

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

millimeters of mercury.

Several metabolism studies have been submitted to the a gency and will be used to support the

registration review risk assessment.



## 1.5 Use/Usage Description

1.5.1 Registrations

OIT was first registered in 1971 . There are 36 end use and four technical products that c ontain

OIT as an active ingredient. The percent of a.i. for the end use products range from 0.18 to 46.5

percent and the percent of the active ingredient for the technical products range from 95 to 99.4

percent.



### 1.5.2 Summary of Registered Uses

Table 5 presen ts a summary of the registered uses of OIT that will be assessed in this registration

review. End use registrations that contain OIT are formulated as liquid soluble concentrates,

pellets and ready to use liquids. OIT end use products can be applied by th e following

application methods: spray, open pour, meter pump, padding and dip. In addition, materialsPage 13 of 73

treated with OIT, such as paints and metal working fluids

, can be applied by brush/roller, airless

sprayer and machine cutting tool cooling nozzles. OIT is not registered for residential use

(although residential handlers may be exposed to OIT via contact with the household items

which were treated with OIT (e.g., carpet, paints and plastics) )

.

Table 5

– Summary of OIT Registered U ses

Use Application Method Application Rate

(ppm a.i. by weight)

Agricultural Premises and Equipment

Mildew c ontrol o n w alls and f loors Surface Spray 1800 ppm (in spray

solution)

Commercial, Industrial, Institutional, Premises and Equipment

Mildew con trol on walls and floors Surface Spray 1800 ppm (in spray

solution)

Food Handling/Storage Establishments Premises and Equipment

– Indirect Food Contact

Mildew control on walls and floors Surface Spray 1800 ppm (in spray

solution)

Industrial Processes and Water Systems

Air Washer Water Systems

Water Cooling Systems

Paper Mill Water Systems Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump Not Specified*

Not Specified*

500

– 1350 ppm

Material Preservative

Adhesives, Industrial

Coating s, Industrial

Emulsions, resin/latex/polymer

Leather Processing Liquors

Leather hides and products

Metalworking Fluids

Paints

Paper/paper products

Plastic products

Rubber products

Household cleaners, dishwasher and

laundry products

Textiles Open Pour, Mete r 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

Pad, Dip or Spray 250

– 2 700 ppm

250

- 2800 ppm

250

– 1500 ppm

17 ppm

36

- 630 ppm

78

– 80 ppm

250

– 2800 ppm

168

– 520 ppm

990

– 3700 ppm

2000 ppm

7 5

- 1400 ppm

9.9

– 2000 ppm

Medical Premises and Equipment

Mildew Control On Walls, Floors Surface Spray 1800 ppm (in spray

solut ion)

Residential and Public Access Premises and Equipment

Mildew Control On Walls, Floors Surface Spray 1800 ppm (in spray

solution)Page 14 of 73 Use Application Method Application Rate

(ppm a.i. by weight)

Wood Preservative

Sapstain Treatment Spray or Dip 2400

– 2500 ppm

(treatment solution)

* These uses are only inc lud ed on one label (6836

- 326). The water treatment uses are included on the formulator section of the

label and the application rates are not listed.



### 1.5.3 Usage Information

According to the Kline Biocides Report for 2004/2005 (Kline, 2005), the major uses of OIT a re

paints and coatings, plastics and resins, metal working fluids and adhesives and sealants.



## 1.6 Regulatory Histor y

There are no recent or pending regulatory actions for products containing OIT as an active

ingredient. The agency signed the reregistration eligibility decision (RED) for OIT (2

- Octyl

3(2h)

- isothiazolone) on September 28, 2007. A dietary exposure assessment was not conducted

to support the OIT RED because there were no dietary uses registered at that time

. A

comprehensive ecological and occu pational/residential exposure assessment was conduc ted to

support the RED decision

.



### 1.6.1 Tolerance Information

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

in raw agricultural commodities or processed food and feed products under FFDCA Section 408

. However, OIT is listed as a food contact substance by FDA and two food contact notifications

(FCNs) have been granted to Thor GmbH, Germany under FFDCA 490(h)(1)(C)

. These FCNs

represent food contact substances that have been demonstrated to be safe for their intended use.

They are for use as an an timicrobial active ingredient in industrial technical formulations for use

in preserving polymeric latex emulsion products destined for use in the manufacture of paper and

paperboard. The first (FCN No. 698) was effective June 15, 2007 at a maximum level of 35 ppm.

The second (FCN No. 788) was effective March 14, 2008 and increased the maximum level to

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

notification.



## 1.7 Incidents

1.7.1 Human Health

Individual Incident Reports

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 experi enced. In the case

of OIT, four human health individual incident reports are listed in the OPP Incident Data System

(IDS) for the years 2007, when the RED was written, to the present (search conducted on

2/24/14)

. All of these incidents are classified as human moderate (HC).Page 15 of 73

Two of the incidents involved dermal exposure when workers were handling concentrated

product s at packing plants and shipping facilities. This dermal exposure resulted in hives,

blisters and burns on the exposed area.

One inciden t involved exposure to a sapstain treatment mixture that contained OIT as well as the

related compounds MIT and CMIT. The worker got some of this mixture on his arm while he

was cleaning out a storage tank and experienced blisters, burns and swelling.

The fourth case involved a factory worker who drank from a bottle that contained an OIT

product. This bottle had been previously used to store drinking water. The worker experienced

burns in the throat and esophagus which required hospitalization.

Aggregate Incident Reports

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

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

period (often quarterly). Typically these repo rts 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. In the case of OIT, there are five aggregate incidents

listed in the IDS for the years 2007, when the RED was written, to the present (search conducted

on 4/23/14)

. All five of these incidents are classified as human minor (HD). One of these

incidents involved dermal irritation experienced by firefighters who responded t o fire in a

storage facility where OIT, as well as other chemicals, were stored. There is no information

regarding the other four incidents.



### 1.7.2 Ecological

No OIT ecological incidents have been reported in the a gency ’s Ecological Incident Information

System (EI I S) for the time period spanning 2005 to 2013

.



## 2 A nticipated Data Needs

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

review.Docket Number EPA

- HQ

- OPP

- 2014

- 016 0

www.regulations.gov

Page 16 of 73 Table 6

– St udies Anticipated as Needed for the Registration Review of O IT

GLN Study Name Test

Substance Time Frame

(Measured in

months from DCI

Receipt) Risk Assessment(s) Data

Will Support Use Site(s) Triggering

Anticipated Data

Requirement Applicable Exposure

Scen ario

Studies Anticipated to be Required through the Registration Review DCI

870.1300 Acute Inhalation TGAI 12 Occupational and

Residential All All potential

inhalation exposures

870.4100 5 Chronic Oral Toxicity TGAI 36 Occupational, Dietary, and

Drinking Water Metal Working Fluid, Wood

Preservative, Paper products

and materials preservative Machinist exposure to

metal working fluids,

chronic dietary

870.4200 5 Carcinogenicity

– 2

species TGAI 36 Occupational, Dietary, and

Drinking Water Metal Working Fl uid, Wood

Preservative, Paper products

and materials preservative Machinist exposure to

metal working fluids,

chronic dietary

87 0 .6200 Acute neurotoxicity TGAI 12 Occupational and

Residential All All potential

exposures

870.7800 Immunotoxicity TGAI 24 Oc cupational and

Residential All All potential

exposures

875.1 2 00

875.1 4 00 Dermal and Inhalation

Exposure

– Indoor TGAI or

surrogate 24 Occupational and

Residential Mold Preventative Spray and

household cleaners Low pressure

handwand application

of mold pr eventative

surface spray ;

mop/wipe/spray for

household cleaners

875.2300 Indoor Surface Residue

Dissipation TGAI 24 Residential Carpet Cleaners and Floor

Cleaners Child contact with

floors and carpets

cleaned with OIT

preserved cleaning

products

850.130 0 Aquatic invertebrate

life

- cycle TGAI 24 Ecological Effects Industrial processes and

water systems Wastewater

discharges into water

bodies

850.1400 Fish early

- life stage TGAI 24 Ecological Effects Industrial processes and

water systems Wastewater

dischar ges into water

bodies

850.3020 Honeybee acute

cont act TGAI 12 Ecological Effects Wood preservative Wooden structuresPage 17 of 73

GLN Study Name Test

Substance Time Frame

(Measured in

months from DCI

Receipt) Risk Assessment(s) Data

Will Support Use Site(s) Triggering

Anticipated Data

Requirement Applicable Exposure

Scen ario

850.3300 4 Activated Sludge

Respiration Inhibition

test TGAI 12 Fate and persistence in

WWTP, down

- the

- drain

assessment Paints, Material

P reservatives, Drilling Muds

and Flooding Fluids,

Textiles Toxicity to WWTP

organisms

835.3110 3 Ready biodegradability TGAI 12 Fate and persistence in

WWTPs Down the drain

assessment Paints, Material

Preservatives, Drilling Muds

and Flooding Fluids,

Te xtiles Toxicity to WWTP

organisms

835.3220 3 Porous Pot test TGAI 12 Fate and persistence in

WWTPs Down the drain

assessment Paints, Material

Preservatives, Drilling Muds

and Flooding Fluids,

Textiles Toxicity to WWTP

organisms

835.3240 3 Simulation tes t

–

Aerobic sludge TGAI 12 Fate and persistence in

WWTP, down

- the

- drain

assessment Paints, Material

Preservatives, Drilling Muds

and Flooding Fluids,

Textiles Toxicity to WWTP

organisms

835.3280 3 Simulation test

–

Biodegradation TGAI 12 Fate and persist ence in

WWTP, down

- the

- drain

assessment Paints, Material

Preservatives, Drilling Muds

and Flooding Fluids,

Textiles Toxicity to WWTP

organisms

SS

- 1099 Leachibility from

treated wood EUP 12 Environmental Fate Wood preservative Treated wood

SS

- 1221 Textil es leaching EUP 12 Environmental Fate Material preservative Treated Textiles

Studies That Were Required through the Post

- RED DCI

870.3465 90

- Day Inhalation

Toxicity Study TGAI 24 Occupational and

Residential All

875.1100

875.1200 Dermal Exposure

–

Ou tdoor and Indoor TGAI or

surrogate 24 Occupational and

Residential All See Notes 1 and 2

875.1300

875.1400 Inhalation Exposure

–

Outdoor and Indoor TGAI or

surrogate 24 Occupational and

Residential All See Notes 1 and 2Page 18 of 73

GLN Study Name Test

Substance Time Frame

(Measured in

months from DCI

Receipt) Risk Assessment(s) Data

Will Support Use Site(s) Triggering

Anticipated Data

Requirement Applicable Exposure

Scen ario

875.1700 Product Use

Information T GAI 12 All All All

875.2300 Indoor Surface Residue

Dissipation TGAI 24 Residential Textiles, Mattresses

875.2500 Inhalation Exposure

Chamber Study TGAI in Paint 24 Occupational and

Residential Paint Unknown

875.2800 Description of Human

Activity TGAI 2 4 All All All

1The exposure scenarios include: Open pour for material preservation and leather processing, sapstain treatment, machinist ex posure to MWF, and brush/roller and airless sprayer application of paints.

2 It may be possible to use proprietary surrogate exposure data if data compensation issues are appropriately and adequately addressed.

3 The results of the ASRI test will determine which of these four biodegradation tests is/are anticipated to be required. If th e ASRI test EC50 is less than or equal to 20 mg/L, then either the (i)

Biodegradation in Activated Sludge Study or (ii) Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units or (iii) the Porous Pot Test is expected to be required. If the ASRI test EC50 is

greater than 20 m g/L, then the registrant would likely be required to conduct either: (i) Ready Biodegradability or (ii) a) Biodegradation in Activated Sludge or b) Simulation Test

– Aerobic Sewage

Treatment: A. Activated Sludge Units or c) the Porous Pot Test. If the Read y Biodegradability study is conducted and passes, then no further testing would be expected to be required. If, however, the

antimicrobial fails the Ready Biodegradability study, then the a) Biodegradation in Activated Sludge or b) Simulation Test

– Aerobi c Sewage Treatment: A. Activated Sludge Units, or c) the Porous Pot

study would likely be required.

4 Data have been submitted to the a gency for review.

5 Studies which are designed to simultaneously fulfill the requirements of both the chronic oral and ca rcinogenicity studies ( i.e. , a combined study) may be conducted

.Page 19 of 73



## 3 Human Health Risk Assessment

The a gency anticipates the need to conduct a human health risk assessment for OIT . The a gency

expects to require additional data for use in conducting the reg istration review and to review data

submitted from the time of the 2007 RED and the current registration review

.



## 3.1 Existing Toxicological Endpoint s

EPA anticipates the need to revise the existing toxicological endpoints as part of this registration

review. T able 7 presents the endpoints used in EPA’s most recent human health risk assessment

in support of the 2007 RED

. As previously stated, toxicological studies were identified as data

gaps in the RED and identified in the registration review as anticipated da ta needs based on

currently registered uses. All available information including existing toxicology studies, valid

scientific literature, and the studies that are expected to be required for registration review will be

considered in establishing the endpo ints to be used in the registration review risk assessment. A

detailed description of the toxicity studies is provided in Appendix A.

Table 7

– Toxicological End p oints for Assessing for OIT ORE Exposures (2007 RED)

Ex posure

Scenario Dose Used in Risk

Assessment

(mg/kg/day) Target Margin of Exposure

(MOE), Uncertainty Factor (UF),

FQPA Safety Factor (SF) Study and Toxicological

Effects

Incidental Oral,

Short

- Term;

Intermediate

- Term

(1

- 30 days; 30 days

6 months) Systemic

NOAEL= 5

mg/kg/day MOE= 100 (ST)

(10x inter

- species

variation; 10x

intra

- species

variation)

MOE= 300 (IT)

(10x inter

- species

variation; 10x

intra

- species

variation; 3x for

extrapolation to

intermediate

- term

from short

- term

end point) Developmental toxicity study

(MRID

41482508)

Systemic : Mortality, decreased

body weight

and body weight gain, decreased

food consumption

Dermal Exposure,

Short

- Term

(1

- 30 days)

[5 x 7 cm

application

area] Dermal Irritation

NOAEL= 10

mg /kg/day

(0.0674 mg/cm 2 ) Dermal Irritation

MOE= 10 (ST) a

MOE= 30 (ST/IT)

(3x inter

- species

variation; 3x intraspecies

variation) 14 Day Dermal Study (MRID

43935705)

Dermal : Dermal irritation in

both sexes.

Systemic : No systemic effects.

Dermal Ex posure,

Intermediate

- Term

(30 days

- 6

months)

[4 x 5 cm

application ] Systemic

NOAEL= 5.95

mg/kg/day MOE= 100 (IT)

(10x inter

- species

variation; 10x

intra

- species

variation) 90 Day Dermal Study (MRID

42007301)

Systemic : Decreases in H GB,

HCT, RBC, albumin, and total

protein. Decrease in body

weight gain in the male.Page 20 of 73

area]

Dermal Exposure,

Long

- Term

(>6 months) Not Selected Not Selected Not Selected

Inhalation

Short

- Term;

Intermediate

- Term

(0

- 30 days)/ (30

days

to 6 months) 2 hr H EC: 0.29 mg/m 3

4 hr HEC: 0.15 mg/m 3

6 hr HEC: 0.10 mg/m 3

8 hr HEC: 0.073

mg/m 3

MOE = 30 b MOE= 30 (ST/IT) 90 Day Inhalation Toxicity

(MRID 41544701)

Clinical signs (rales, dyspnea)

decreases in body weight gain,

fluid in uterus and pulmonary

and n asal cavity pathology.

Chronic/Carcinogen

icity No chronic/cancer data available

.

Prenatal

developmental

toxicity

– rat and

rabbit Systemic

NOAEL= 5

mg/kg/day MOE= 100 (ST)

(10x inter

- species

variation; 10x

intra

- species

variation) Developmental t oxicity study

(MRID

41482508)

Systemic : Mortality, decreased

body weight and body weight

gain, decreased food

consumption.

Mutagenicity Not mutagenic

. Immunotoxicity No immunotoxicity data available

.

a The use of dermal irritation is applied only for the short

- term dermal exposure scenario. A margin of exposure

(MOE) of 10 is used for the short

- term assessment (3x inter

- species variation, 3x intra

- species variation).

b Human Equivalent Concentrations (HECs) were calculated using the Regional Deposited Dose Ratio (RDDR) for

nonhygroscopic particles and the study NOAEL of 0.64 mg/m3 Where, HEC = RDDR x NOAEL x (6h r (rats

exposure time in study) /hr (worker exposure time ))

.



## 3.2 Dietary Exposure

The a gency will need to conduct dietary exposure (food and drinking water ) assessment s to

support registration review since no previous dietary assessments have been conducted for OIT.

Uses of OIT that may r esult in d ietary exposure (food) include paper products/wrappings as well

as dishwashing detergents

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

mat erial preservative may result in OIT being discharg ed in waste water or leached from

preserve d materials and subsequently running off into surface water.



### 3.2.1 Food

Since the 2007 RED, a new use as a materials preservative for dishwashing detergents was

granted by the a gency (3/2011) and FCNs for latex emulsions to be used in paper/paper products

have b een issued by FDA. Since these can contribute to dietary (food) exposure, the a gency will

need to conduct both acute and chronic dietary exposure assessments for all population

subgroups to support registration review. In an effort to determine if additi onal residue data will

be required to conduct these assessments, a screening level analysis was conducted for both the

dish detergent use and the latex emulsion paper products use. Both of these screens used FDA

methodology (FDA, 1993) where appropriate a s well as relied on high

- end assumptions to be

protective of human health. These include: all of the daily food consumed will come into contactPage 21 of 73

with paper treated with the latex emulsion containing the active ingredient; all of the dishes used

will have b een washed with the dish detergent containing the active ingredient; and 100% of the

residue on the paper/dishes will transfer to food items. The toxicological point of departure used

for the analyses, although not selected at the time of the RED, is from a developmental toxicity

study with a NOAEL of 5 mg/kg/day. A 100x uncertainty factor was applied in order to account

for intra

- and interspecies variation.

The screening level analyses based on latex emulsions for use in paper products as well as the

di shwashing detergent use indicate that no further residue data will be required when the current

toxicological information available is used to conduct the assessment. The exposure

contributions from these two scenarios will be considered in the aggregate assessments

conducted during registration review. It is important to note that if the toxicological point of

departure for either the acute or chronic scenario changes based on data received during the

registration review process, additional residue chemi stry data may be required.



### 3.2.2 Drinking Water

A drinking water assessment has not been conduc ted for OIT in the past. However, for several

approved uses (including some plastics, household cleaners , textile, paints, stains, adhesives, and

water cooling systems ) the a gency cannot rule out the potential for OIT to enter surface water

during incorporation into treated materials and/or leaching from in

- service use of treated

materials and to subsequently be present in drinking water . Since the residues of concern in

drinking water, the magnitude of these potential residues concern, their mammalian toxicities,

how persistent they will be, and if they are likely to pass through a wastewater treatment plant

(WWTP) is unknown, the a gency anticipates needing certain env ironmental fate data listed in

Section 4 of this PWP

. These data will be useful to determine whether, and to what extent,

residues of OIT pass through a WWTP. The a gency anticipates using these data and/or other

sources of information during the risk ass essment stage of this r egis tration r eview to determine

the potential for discharged or leached residues of OIT to result in human dietary exposure via

drinking water, which may trigger a drinking water assessment.



## 3.3 Occupational and Residential Exposures

The a gency anticipates the need to revise the previous Occupational Residential Exposure (ORE)

assessment s. These assessments include the ORE assessment that was written for the OIT RED

(EPA, 2007) and the ORE assessment that was written to evaluate the new use of OIT for

treating walls and interior surfaces (EPA, 2013). The ORE assessments will need to be revised to

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

data that were called in during the RED or subm itted after the post

- RED DCI or to be submitted

during the registration review DCI.



### 3.3.1 Occupational Handler Exposure

Exposures assessed for the RED

Occupational handler exposures were assessed in ORE Assessment for the RED (US EPA, 2007)

for materials preser vation, wood preservation sapstain treatment, leather processing and use of

preserved products such as me tal working fluids and paint. Both dermal and inhalation exposuresPage 22 of 73

were assessed

. The short

- term dermal irritation concerns for workers were mi tigated by

specifying chemical resistant gloves, where applicable. Some of the inhalation MOEs indicated

risks of concern. In particular, the inhalation MOEs of 2 to 14 for materials preservation and the

inhalation MOE of 1 for airless sprayer application of pres erved paint were of concern because

they were much lower than the target MOE of 30. To address these inhalation risks, the RED

specified the use of PF10 respiratory protection for all of the material preservation uses and a

reduction of the application rat e from 0.23% to 0.14% for the paint use. In addition, the RED

stated that additional toxicology studies would be required to refine the inhalation POD.

Handler Exposures Assessed for the New Use as an Interior Surface Spray

Occupational handler exposures were assessed in Risk Assessment for the New Use of Algicid

Plus for Treating Walls and Exterior Surfaces (US EPA, 2 013 ) for brush/roller and low pressure

sprayer application. This assessment used the same endpoints that had been used for the RED

and b ot h dermal and inhalation exposures were assessed. The dermal MOEs of 12 and 10, for

brush roller and low pressure sprayer, respectively, were of concern if gloves were not worn

because they did not exceed the target MOE of 100; however, if gloves were wo rn the MOEs

were 930 and 2400 and were not of concern

. The inhalation MOEs of 34 and 71 were not of

concern at baseline PPE (i.e. respirators not worn) because they exceeded the target MOE of 30.

Handler Exposures to be a ssessed during Registration Revie w

The occupational handler exposures will need to be assessed to account for the toxicology

studies and exposure data that were submitted after the post

- RED DCI or that will be required

via the registration review DCI . The scenario s that are anticipated t o be assessed for registration

review are listed in Table 8

.

Table 8

– Occupational Handler Exposure Scenarios to be assessed in Registration Review

Scenario Exposure Route(s) Duration

Open pour appl ication for material preservation and leather

processing. Dermal

, Inhalation Short and Intermediate

T erm

Sapstain treatment Dermal

, Inhalation Short and Intermediate

Term

Brush/ r oller and airless sprayer application of OIT preserved paints Dermal

, Inhalation Short and Intermediate

Term

Machinist exposure to treated MWF Dermal

, Inhalation Short and Intermediate

and Long Term

Low pressure handwand sprayer application of mold preventive

surface spray Dermal

, Inhalation Short and Intermediate

Ter m



### 3.3.2 Residential Handler Exposures

Residential Handler Exposures assessed during the RED

Residential handler dermal and inhalation exposures to OIT were assessed in the RED for

brush/roller and airless sprayer application of OIT treated paints. The inha lation MOEs for

brush/roller application ranged from 60 to 180 and were not of concern because they exceededPage 23 of 73

the target MOE of 30. The inhalation MOEs for airless sprayer application; however, ranged

from 1 to 2 and were of concern. The dermal MOE was 10 , which is target MOE and thus was

not of concern. As discussed above for occupational handlers, the RED stated that additional

toxicity studies would be required and also specified an application rate reduction to address the

inhalation risks for airless sprayer paint application.

Residential Handler Exposures Assessed for the New Use as an Interior Surface Spray

Residential handler exposures were assessed in Risk Assessment for the New Use of Algicid

Plus for Treating Walls and Exterior Surfaces (US EPA, 2 013 ) for brush/roller and low pressure

sprayer application. This assessment used the same endpoints that had been used for the RED

and b oth dermal and inhalation exposures were assessed. The dermal MOEs of 60 and 280 for

brush roller and low pressure spra yer, respectively, were not of concern because they were

greater than the target MOE of 100

. The inhalation MOEs of 170 and 1200 were not of concern

at baseline PPE (i.e. respirators not worn) because they were greater than the target MOE of 30.

Residenti al Handler Exposures to be a ssessed during Registration Review

The residential handler exposures will need to be assessed to account for the toxicology studies

that were submitted after the post

- RED DCI or that will be required via the registration review

DCI

. The scenario s that will need to be assessed for registration review are listed in Table 9

.

Table 9

– Residential Handler Exposure Scenarios To Be Assessed During Registration

Review

S cenario Exposure Route(s) Duration

Brush/Roller and Airless Spr ay a pplication of preserved p aints Dermal

, Inhalation Short Term

Mop/Wipe/Spray for household cleaners Dermal, Inhalation Short Term



### 3.3.3 Residential Post

- Application Exposures

EPA anticipates the need to revise the residential post

- application assessment co nducted in

support of the 200 7 RED. Residential post

- application dermal and incidental oral exposures to

residues arising from contact with treated carpeting, vinyl flooring, clothing, and mattress covers

were assessed . The MOEs for exposure to clothing and mattress covers were of concern when

using the default residue transfer rate of 100 percent

, however they were not of concern when

using a refined transfer rate of 5 percent. The MOEs for treated carpet s remained above the

agency’s LOC , even when usin g the refined transfer rate of 5 percent.

Based on these concerns, the RED label table specified that the labels be changed to indicate that

only carpet backing, and not carpet fibers, could be treated with OIT. This label change has not

been implemented and many of the OIT labels still allow OIT to be used on carpet fibers. The

agency plans to update the OIT carpet labels during the registration review process. In addition

, OIT is used to preserve household general purpose and carpet cleaners.

The reside ntial post application exposures will need to be assessed to account for the toxicology

studies and exposure data that were either submitted after the post

- RED DCI or that will bePage 24 of 73

required via a registration review DCI. The scenarios that will need to be assessed for

registration review are listed in Table 10.

Table 10

– Residential Post

- Application Exposure Scenarios for OIT

S cenario Exposure Route(s) Duration

Treated carpet

- child Dermal and Incidental Oral Short and Intermediate Term

Vinyl flo oring

– child Dermal and Incidental Oral Short and Intermediate Term

Clothing

– child and adult Dermal and Incidental Oral Short Term

Mattress covers

– child and adult Dermal Short and Intermediate Term

Plastics

– child Incidental Oral 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 200 7

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

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 and drinking

water ) exposures and residential exposure s.



### 3.4.2 Cumulative Exposures

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

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

common mechanism of toxicity finding as to OIT and any other substances and OIT d oes not

appear to produce a toxic metabolite produced by other substances. For the purposes of this

registration review, therefore, EPA has not assumed that OIT has a common mechanism of

toxicity with other substances. For information regarding EPA’s effor ts to determine which

chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such

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

.



## 4 Environmental Risk Asses sment

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

species determination for OIT. The ecological risk assessment planned during registration

review will allow the a gency to determine potential acute and chr onic risks to aquatic organisms

exposed to OIT that are transported from treatment sites into the aquatic environment. Such sites

include sapstain treatment of wood and industrial processes and water systems. The risk

assessment also will allow the a genc y to determine whether each use of the OIT has 'no effect' or

'may affect' federally listed threatened or endangered species (listed species) or their designated

critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a listed s peciesPage 25 of 73

or its designated critical habitat, the a gency will consult with the U.S. Fish and Wildlife Service

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



## 4.1 Environmental Fate Assessment

A number of fate studies have been submitted, but not all of these studies have been formally

reviewed. The studies will be reviewed at the time the agency conducts the fate assessment of

OIT. Some of the reviews previously completed show: Octhithilone is hydrolytically stable at

environmental pHs 4, 5, 7, and 9. In aqueous medium it photolyzes with a half

- life of 16 days

indicating that in surface water it is not likely to persist (MRID 48358617) . In an aqueous

photolysis study, four photodegradates were identified: Octhilinone

- sulfoxide, N

- (n

oct yl)acetamide,3

- (n

- octyl)

- 4

- thaizolin

- one and N(n

- octyl) malonamic acid + N

- (n

- octyl)formic

acid. It is not ready biodegradable.



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

Plastic/ Textiles/ e.g., treated

article

Octhilinone (OIT) is widely used in paints and tex tiles as a materials preservative and as an

antisa pstain paint on wood surfaces. For the fate assessment, wood leaching and textile studies

are expected to be required.



### 4.1.2 Water and Sediment

A preliminary review of submitted data shows OIT binds strongly on t he soil surfaces, with little

tendency to migrate

.



### 4.1.3 Soil

OIT did not degrade rapidly in aerobic soil metabolism studies with a half

- life of >120 days.



### 4.1.4 Air

OIT’s vapor pressure is low (< 10

- 6 mm Hg) and is not likely to volatilize from water surfaces.



### 4.1.5 Water Quality

Octhilinone (OIT) is not identified as a cause of impairment for any water bodies listed as

impaired under section 303(d) of the Clean Water Act, based on information provided at the

a gency ’s National Pesticides Cause of Impairment of Waters websi te (searched March 25,

2014 ) 1 as a pesticide use or as synthetic organic or toxic organic. In addition, no Total

Maximum Daily Loads (TMDL) have been developed for OIT, based on information provided at

the a gency ’s National Pes ticide TMDL web site (sea rched March 25, 2014). 2 More information

on impaired water bodies and TMDLs can be found at http://www.epa.gov/owow/tmdl/

.

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

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

group_name=PESTICIDESPage 26 of 73



## 4.2 Conceptual Models for Environmental Exposure Pathways

Based on the summary of reg istered uses of OIT presented in Table 5, physical/chemical

properties and environmental fate data presented in Table 4 and Appendix B, the a gency believes

that there are several uses which may result in aquatic exposures including WWTP exposure

from surfa ce applications to walls, floors and equipment, sapstain treatment of wood and

materials preservatives. Further there may be industrial water treatment from manufacturing as

well as direct discharge and leaching from treated materials, textiles and wood. OIT is stable to

hydrolysis and has a 16 day photolysis half

- life. Chemicals that are released down

- the

- drain can

typically take from a few to several hours to reach wastewater treatment plant intakes following

their discharge and from several hours to r oughly a day following their discharge down

- the

- drain

to subsequently be discharged from wastewater treatment plants to surface water. OIT would be

expected to enter wastewater treatment plants as a result of down

- the

- drain discharges. OIT is

not known to be biodegradable and therefore, aquatic organisms in surface water downstream of

both direct and indirect sources of discharge may be exposed to OIT. There are aquatic and soil

metabolism studies which have been submitted to the a gency , but these stud i es have not yet been

reviewed.



## 4.3 Ecological Effects Assessment

OIT has use patterns that could lead to exposure to non

- target organisms. The w ood p reservative

use could lead to exposure to honeybees from structures built with wood containing OIT. In

ord er to complete a risk assessment, an acute honeybee study (850.3020) is anticipated to be

required. The i ndustrial p rocesses and w ater s ystems use and material preservative use could

lead to the exposure of non

- target aquatic organisms from wastewater rel ease from industrial

plants into water bodies. Therefore, two chronic aquatic studies (850.1300 and 850.1400) are

anticipated to be required for a down

- the

- drain assessment. The wood preservative and materials

preservative uses could also lead to potenti al water exposures.



### 4.3.1 M ode of Action

The specific toxic mechanism of action of OIT to fungi and bacteria is presumed to be the

disruption of DNA/RNA synthesis.



### 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data in Table 11 are used as me asures of effects to aquatic and terrestrial

organisms. All available ecotoxicity endpoints in the a gency ’s files from product studies

submitted by registrants or other interested parties, federal laboratory data, or from the public

literature are tabulat ed along with the anticipated data requirements and data gaps. The most

sensitive values for each receptor group are used for the risk assessment. These selected

endpoints will be updated during the risk assessment phase based on any additional submitted

data or data found in the public literature.Page 27 of 73

Table 11

– Ecological Effects Endpoints Selected for Assessing Risks for OIT

Receptor

Group Surrogate Species Risk

Scenario Toxicity Endpoint Reference

Freshwater fish Ra inbow Trout Acute 96

- h LC 50 = 0.047 mg/L 41608051

Chronic None

Freshwater

invertebrates Acute 48

- h EC 50 = 273 ug/L 48358616

Chronic None

Estuarine/marine fish Sheepshead Minnow Acute LC 50 =0.16 mg/L 41608007

Estuarine/marine

invertebra tes Mollusk Acute LC 50 =>0.057 mg/L 41700701

Shrimp Acute LC 50 =0.071 mg/L 41608008

Algae Nonlisted IC 50 = 0.61ug/L 48557405

Listed NOAEC = <0.143 48557405

Aquatic vascular

plants Duckweed Nonlisted IC 50 = 280 ug/L 48557404

Listed NOAE C = <62 ug/L 48557404

Seedling Emergence Nonlisted I C 25 = 14 mg a.i./kg 48358620

Listed NOAEC = 22 mg a.i./kg 48358620

Birds Bobwhite Quail Acute LD 50 = 384 mg/kg 44859001

Mallard duck Subacute

dietary LC 50 > 3267 mg/L 41608002

Mammals Acute LD 5 0 = 794 mg/kg 00070456

Chronic NOAEL = 5 mg/kg/day 41482500

Nontarget insects Honey bee Acute R equired

--



## 4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available OPP models will be used to determine the estimated environ mental concentration

(EECs) in the aquatic environment . Resulting exposure estimates will be compared to the

toxicity endpoints to determine if levels of concern are exceeded for each receptor group.



### 4.4.2 Screening Level Down

- the

- Drain Analysis

The Down

- the

- Drain (DtD) module of E

- FAST (Exposure and Fate Assessment Screening Tool)

was used as a screen to determine the potential for aquatic organisms downstream of domestic

wastewater treatment plants that receive discharges from end

- use of Octhilinone (OIT) to be

exposed to OIT and its degradates. The results of the DtD module runs are expressed as number

of days of exceedance of concentrations of concern (COC) for aquatic organisms. A detailed

description of derivation of data for input parameters selected t o run the DtD module and of the

theoretical basis for this model is presented in Appendix E. A 0% removal was assumed for this

model run.Page 28 of 73

The DtD analysis for OIT was intended to serve two purposes: (1) to demonstrate the maximum

WWTP influent volume of OIT that would trigger potential concerns for aquatic organisms

exposed to OIT downstream of domestic wastewater treatment plants and (2) to evaluate

potential exposures based on the assumptions that the total production volume of OIT enters

domestic wast ewater treatment plants. A key purpose of the DtD analysis for OIT is to

determine the lowest maximum annual WWTP influent volumes of OIT that would trigger

potential concerns for aquatic organisms downstream of domestic WWTPs.

The screening DtD model pre dicted E xceedences of concentrations of concern for acute, chronic

and endangered aquatic organisms.

This screening level analysis assumes that OIT is released to domestic wastewater treatment

plants. Based on registered uses of OIT presented in Table 8 of this PWP, there are some use s

, such as commercial and industrial cooling water systems and paper mill water systems, for

which discharges may enter industrial WWTPs rather than domestic WWTPs prior to entering

surface water. Different methods and tools for assessing potential exposures and associated

ecological risks will be applied for these other types of uses.

There is considerable uncertainty regarding the amount of OIT that could be expected to enter

domestic wastewater treatment plants. Current pr oduction volume information is needed to

refine the assessment. There is also uncertainty about the potential for exposure to aquatic

organisms from OIT entering industrial wastewater treatment plants as a result of industrial uses

of OIT. The a gency does not have high quality data on the toxicity of OIT to activated sludge

microorganisms in wastewater treatment plants and does not have high quality data on

biodegradation of OIT during wastewater treatment. Consequently, the Agency anticipates

requiring t oxicity to activated sludge microorganisms and biodegradation of OIT studies during

registration review

. Additional information is in Appendix D of this document.



## 4.5 Effects Analysis Plan

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

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

the data reviewed following the a gency ’s policy for reviewing public literature for use in

assessing risks from pesticides. Those ecotoxicity values found in the public literature to be

more sensitive than those currently in OIT and or which satisfy an existing data gap(s) will be

used during the risk assessment phase of OIT. ECOTOX was created and is maintained by the

USEPA, Office of Researc h and Development, and the National Health and Environmental

Effects Research Laboratory's Mid

- Continent Ecology Division

.



## 5 Endocrine Disruptor Screening Program (EDSP)

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

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

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

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

susceptible to endocrine influence, including effects on endocrine target organ histopathology,Page 29 of 73

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

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

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

taxonomic groups. As part of its reregistration decision for OIT , 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), OIT is subject to the

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

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

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

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

may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

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

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

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

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

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

testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

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

Under FFDC A section 408(p), the a gency must screen all pesticide chemicals. Between October

2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals,

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

identified for EDSP screening was published on June 14, 2013 3 and includes some pesticides

scheduled for registration review and chemicals found in water

. Neither of these lists should be

construed as a list of known or likely endocr ine disruptors.

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

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

website

. 3



## 6 Optional Label Changes

To eliminate th e anticipated need for EPA to require certain data, reduce the possibility that

EPA’s planned risk assessments overesti mate risk due to reliance on conservative assumptions,

and/or improve label clarity

, registrants may consider amending product labeling.



## 7 Next Steps

After the Final Work Plan has been posted to the docket in December 2014 at EPA

- HQ

- OPP

2014

- 0160, the agency will continue its registration review and anticipates issuing a data call

- in

for the OIT case by December 2015

.

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

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.Page 30 of 73



## 8 References

010890 (T ox ID No.): Copley, M. (1994) Octhilinone, W a iver Request for a Der m al of

Sensitization Study; Unpublished study prepared by the U.S. EPA, ID 099901

- 000707, Apr. 8,

1994.

00046403 (MRID) Powers, M.B. (1971) Final Report: Teratology Study

- Rats: Project No.

417

- 349. (Unpublished study received May 25, 1971 under unknown admin. no.; prepared by

Hazleton Laboratories, submitted by Rohm & Haas Co., Philadelphia, Pa.; CDL:107967

- A).

00058029 (MRID) Powers, M.B. (1970) Final Report: Teratology Study

- Rabbits: Pro ject No.

417

- 346. (Unpublished study received Feb 3, 1977 under 984

- 67; prepared by Hazleton

Laboratories, Inc., submitted by Whitmoyer Laboratories, Inc., Myerstown, Pa.; CDL:229345

- A).

00063214 (MRID) Powers, M.B. (1970) Final Report [f o r Octhininone]: Acute Oral

- Rats;

Draize Eye Irritation

- Rabbits; Pri m ary Skin Irritation

- Rabbits; Skin Sensitization

- Guinea

Pigs; Acute Inhalation Exposure

- Rats: Projects No. 417

- 323, No. 417

- 324, No. 417

- 325, and

No. 417

- 326, 417

- 327. (Unpublished study, receiv ed Jul 18, 1978 under 707

- 127; prepared by

Hazleton Laboratories, Inc., Philadelphia, Pa.; CDL: 234400

- C).

00070456 (MRID) Powers, M.B. (1970) Final Report [f o r Octhininone]: Acute Oral

- Rats; Acute

Der m al

- Rabbits; Acute Eye Irritation

- Rabbits; Acute Inhalation Exposure

- Rats: Projects No.

417

- 306, No. 417

- 307, No. 417

- 308, and No. 417

- 310 and 417

- 310. (Unpublished study,

received April 4, 1978 under 707

- 143 prepared by TR W

, Inc. sub m itted by Rohm & Haas Co.,

Philadelphia, Pa; CDL:233428

- B).

0013652 4 (MRID) Powers, M.; Kundzin, M.; Ferrell, J. (1970) Three

- month Dietary Ad

ministration

- Rats: RH

- 893 (Technical): Project No. 417

- 320. Final report (Unpublished study

received Feb 9, 1971 under 707

- 100; prepared by Hazleton Laboratories, Inc., submitted by

Rohm & Haas Co., Philadelphia, PA; CDL:004372

- H).

00136525 (MRID) Powers, M.; Ferrell, J. (1970) Three

- month Dietary Administration

- Dogs:

RH

- 893 (Technical): Project No. 417

- 334. Final report (Unpublished study received Feb 9,

1971 under 707

- 100; pre pared by Hazleton Laboratories, Inc., submitted by Rohm & Haas

Co., Philadelphia, PA; CDL:004372

- I).

00136526 (MRID) Powers, M.; Kwapien, R. (1970) Three

- week Dermal Application

- Rabbits:

RH

- 893

- 50%: Project No. 417

- 321. Final report (Unpublished study rec eived Feb 9, 1971

under 707

- 100; prepared by Hazleton Laboratories, Inc., submitted by Rohm & Haas Co.,

Philadelphia, PA; CDL:004372

- J).

00136527 (MRID) Hiddemen, J.; Ferrell, J. (1971) Subacute Inhalation Study

- Rats: RH

- 893

- 50%: Project No. 417

- 345. Fin al report (Unpublished study received Feb 9, 1971 under 707

- 100; prepared by Hazleton Laboratories, Inc., submitted by Rohm & Haas Co., Philadelphia,

PA; CDL:004372

- K).Page 31 of 73

00136528 (MRID) Powers, M. (1970) Teratology Study: Rabbits: RH

- 893 (Technical):

Projec t No. 417

- 346. Final report (Unpublished study received Feb 9, 1971 under 707

- 100;

prepared by Hazleton Laboratories, Inc., submitted by Rohm & Haas Co., Philadelphia, PA;

CDL: 004372

- L).

00139417 (MRID) Piccirillo, V.J.; Smith, J.M.; Larson, P.S.; et al . (1975) Eighteen Month

Study on the Carcinogenic Potential of RH

- 893 in Mice. (Unpublished study received Jun 4,

1975 under 5F1632; prepared by Medical College of Virginia, Health Sciences Center, Dept.

of Pharmacology and Medical Univ. of South Carolina, Dept. of Pathology, submitted by

Rohm & Haas Co., Philadelphia, Pa.; CDL: 094944

- B).

00139419 (MRID) Hennigar, G.R.; Larson, P.S. (1974) Eighteen

- Month Study in Which RH

893 Is Being Added to the Diet of Mice: Monthly Reports. (Unpublished study receive d Jun 4,

1975 under 5F1632; prepared by Medical Univ. of South Carolina, Dept. of Pathology and

Medical College of Virginia, Health Sciences Center, Dept. of Pharmacology, submitted by

Rohm & Haas Co., Philadelphia, Pa.; CDL: 094944

- D).

00139484 (MRID) Pi ccirillo, V.J.; Smith, J.M. (1975) Eighteen Month Study on the

Carcinogenic Potential of RH

- 893 in Mice. (Unpublished study received Feb 3, 1977 under

984

- 67; prepared by Medical College of Virginia, Toxicology Research Dept., submitted by

Whitmoyer Labora tories, Inc., Myerstown, Pa.; CDL:229346

- A).

40647502 (MRID) Foxall, S. (1986) Skane M

- 8 HQ Microbicide CHO/HGPRT Gene Mutation

Assay: Report No. 86R

- 055. Unpublished study prepared by Rohm and Haas Co. 49 p.

40647504 (MRID) Sames, J.; Frank, J. (1987) Skane M

- 8 HQ In vivo Cytogenic Study in Rats:

Report No. 86R

- 218: Protocol No. 86P

- 360. Unpublished study prepared by Rohm and Haas Co.

74 p.

40647505 (MRID) Muller, G. (1986) Skane M

- 8 HQ Microbiocide in vitro Unscheduled DNA

Synthesis Assay: Report 86R

- 0018. Unpublished study prepared by Rohm and Haas Co. 29 p.

41482505 (MRID) Murphy, M. Chen, P. (1983) RH

- 893

- A Study of the Concentrated

Dependent Delayed Contact Hypersensitivity study in Guinea Pigs; Lab Project Nu m ber: 83R

143. Unpublished study prep ared by Rohm and Haas Co. 48 p.

41482507 (MRID) Bonin, R; Murphy, M. (1983) RH

- 893 Process Variation A Study of the

Concentrated

- Dependent Delayed Contact Hypersensitivity study in Guinea Pigs; Lab Project

Nu m ber: 83R

- 025. Unpublished study prepared by Ro hm and Haas Co. 36 p.

41482508 (MRID) Powers, M. (1970) Teratology Study: Rabbits: RH

- 893 (Technical): Project

No. 417

- 346. Final report (Unpublished study received Feb 9, 1971 under 707

- 100; prepared by

Hazleton Laboratories, Inc., submitted by Rohm & Ha as Co., Philadelphia, PA; CDL: 004372

- L).

41482509 (MRID) Solomon, H.; Lutz, M. (1987) Skane M

- 8 HQ Industrial Mildewcide: OralPage 32 of 73

(Gavage) Developmental Toxicity Study in Rabbits: Lab Project Number: 87R

- 019: 86P

- 504.

Unpublished study prepared by Rohm and Haas Co. 178 p.

41544701 (MRID) Hagan, J.; Kulwich, B.; Fisher, J. (1989) Skane M

- 8 HQ Microbicide:

Thirteen

- Week Inhalation Toxicity Study in Rats: Protocol No. 86P

- 196: Report No. 87R

- 013:

Lab Project Number: 87R

- 013: 86P

- 196. Unpublished study prepar ed by Rohm and Haas Co.

521 p.

42007301 (MRID) Bernacki, H.; Hamilton, J. (1991) RH

- 893 HQ Technical: Three

- Month

Dermal Toxicity Study in Rats: Lab Project Number: 90P

- 031: 90R

- 031. Unpublished study

prepared by Rohm and Haas Co. 374 p.

43935705 (MRID) Zuehlke, U. (1995) N

- Octylisothiazolone (OIT) 96%: 14

- Day Dermal

Subacute Toxicity Study in the Rat: Final Report: Lab Project Number: 1247

- 1154

- 052:

1154

- 052. Unpublished study prepared by Hazleton Deutschland GmbH. 145 p.

43935706 (MRID) Zuehlke, U. (1 995) N

- Octylisothiazolone (OIT) 94 +/

- 3% 90

- Day

Dermal Subchronic Toxicity Study in the Rat: Final Report: Lab Project Number: 1282

- 1154

-

051: 1154

- 051. Unpublished study prepared by Corning Hazleton GmbH. 403 p.

43935707 (MRID) Fuchs, A. (1995) N

- Octylis oth i azolone (OIT) 96%: 14

- Day Oral (Gavage)

Dose Range

- Finding Study in the Fe m a le Rat: Final Report: Lab Project Nu m ber: 1248

- 1154

-

050: 1154

- 050. Unpublished study prepared by Hazleton Deutschland G m bH. 108 p.

43935708 (MRID) Ballantyne, M. (1995) N

- Oct ylisothiazolone (OIT) 94 +/

- 3%: Reverse

Mutation in 5 Histidine

- Requiring Strains of Salmonella typhimurium: Final Report: Lab Project

Number: 1154/53. Unpublished study prepared by Hazleton Europe Ltd. 49 p.

43935709 (MRID) Clements, J. (1995) N

- Octylis othiazolone (OIT) 94 +/

- 3%: Mutation at the

Thymidine Kinase (TK) Locus of Mouse Lymphoma L5178Y Cells Using the Microtitre

Fluctuation Technique: Final Report: Lab Project Number: 1154/54. Unpublished study prepared

by Corning Hazleton (Europe). 44 p.

4 3935710 (MRID) Riley, S. (1995) N

- Octylisothiazolone (OIT) 94 +/

- 3%: Induction of

Micronuclei in the Bone Marrow of Treated Mice: Final Report: Lab Project Number: 1154/55.

Unpublished study prepared by Corning Hazleton (Europe). 36 p.

43944401 (MRID) Fu chs, A. (1995) N

- Octylisothiazolone (OIT) 94+/

- 3%: Oral (Gavage)

Teratogenicity Study in the Rat: Final Report: Lab Project Number: 1272

- 1154

- 049: 1154

- 049.

Unpublished study prepared by Hazleton Europe GmbH. 189 p.

47107004 (MRID) Lutz, M.; O'Hara, G. (1 993) RH

- 893 in Dioctyl Phthalate Skin Irritation

Study in the Rabbit: (Kathon 893T): Final Report. Project Number: 92R/176, 92P/176.

Unpublished study prepared by ROHM & HAAS Co. 13 p.Page 33 of 73

47107006 (MRID) Wagner, V.; VanDyke, M. (2006) Skane M8 (2

- n

- octyl

- 4

- is othiazolin

- 3

- one):

Bacterial Reverse Mutation Assay in E. coli: (Kathon 893T): Final Report. Project Number:

AB21HG/503/BTL, 05P/079, 05RC/079. Unpublished study prepared by Bioreliance. 40 p.

47107007 (MRID) Sames, J.; Frederick, C. (2001) 2

- n

- Octyl

- 4

- iso thiazolin

- 3

- one: Micronucleus

Assay in CD

- 1 Mouse bone Marrow Cells: (Kathon 893T). Project Number: 00R/198.

Unpublished study prepared by ROHM & HAAS Co. 35 p.

47107012 (MRID) Lohse, K. (1982). Skane TM M

- 8: Microbial mutagen test. Rohm and Haas,

Toxicolog y Department, Spring House, Pennsylvania. Laboratory Project ID 82R

- 207A, August

5, 1982. MRID 47107012. Unpublished.

47107014 (MRID) Nemec, M. (1987) A Range

- Finding Teratology Study in Rats with Skane M

8 HQ: (Kathon 893T). Project Number: WIL/91002, 86R C/0078B, 86P/339. Unpublished study

prepared by WIL Research Laboratories, Inc. 116 p.

47181001 (MRID) Wenker, I. (2006) Dermal Absorption Study with 2

- N

- Octyl

- 4

- [4,5

- (carbon

14)]Isothiazolin

- 3

- One in the Wistar Rat: Acticide OIT. Project Number: 397856. U npublished

study prepared by Notox V.O.F. 44 p.

47198002 (MRID) Black, C.; Wederbrand, K.; Goldman, P. (1991) (Carbon 14)

- RH

- 893: In

Vitro Dermal Absorption Study in Male Rat Skin. Project Number: 87R/076, 86P/423, 87P/002.

Unpublished study prepared by Ro hm & Haas Co. 109 p.

47198005 (MRID) DiDonato, L.; Hazelton, G. (1990) (Carbon 14)

- RH

- 893: Effect of Vehicle,

Formulation or Occlusion on Dermal Bioavailability in Male Guinea Pigs. Project Number:

88P/308, 88R/206. Unpublished study prepared by Rohm & Haa s Co. 58 p.

47315011 (MRID) Otterdijk, F. (2007) 90

- Day Dietary Toxicity Study with Acticide OIT (2

- N

Octyl

- 4

- Isothiazolin

- 3

- One) in the Rat. Project Number: 397788, 136656/A. Unpublished study

prepared by Notox B.V. 361 p.

47315012 (MRID) Otterdijk, F. ( 2007) 90

- Day Oral Dietary Toxicity with Acticide OIT (2

- N

Octyl

- 4

- Isothiazolin

- 3

- One) in Male and Female Beagle Dogs. Project Number: 397801,

136656/A. Unpublished study prepared by Notox B.V. 486 p.

47815801 (MRID) Beekhuijzen, M. (2006) Two

- Generation R eproduction Toxicity Study with

Acticide OIT by Dietary Administration in Wistar Rats. Project Number: 397823, 136656/A,

05044. Unpublished study prepared by Notox B.V. 997 p.

47985502 (MRID) Wenker, I. (2008) Absorption, Distribution, Metabolism and Excre tion of 2

- (n

- Octyl)

- 4

- [4,5

- (Carbon 14)]Isothiazolin

- 3

- One in Bile

- Cannulated Wistar Rats. Project

Number: 439605, 08RC/1001. Unpublished study prepared by Notox B.V. 210 p.

48175501 (MRID) Wenker, I. (2007) Absorption, Distribution, Metabolism and Excretio n of 2

-

N

- Octyl

- 4

- [4,5

- (Carbon 14)] Isothiazolin

- 3

- One in the Wistar Rat. Project Number: 397845,

141309/A, 136656/A. Unpublished study prepared by Notox B.V. 328 p.Page 34 of 73

48358628 (MRID) Stankowski, L. (2011) In vivo/in vitro Unscheduled DNA Synthesis in Rat

Pri mary Hepatocyte Cultures at Two Timepoints with a Dose Rangefinding Assay with OIT 100:

Amended Final Report. Project Number: 6736/188, 29151/0/494OECD, 071084. Unpublished

study prepared by Covance Laboratories, Inc. 93 p.Page 35 of 73 

# Appendix A Public Comments

A cute Toxicity for Product Labeling

As listed in Table A1, OIT exhibits moderate oral and inhalational toxicity (toxicity category

III). Acute dermal toxicity is category II. For primary eye irritation, OIT is severely irritating

(toxicity category I). OIT is corrosive to the skin and is a dermal sensitizer. An acceptable acute

inhalation study is anticipated to be required

.

Table A1

– Acute Toxicity Studies for OIT

Guideline No./ Study

Type MRID No. Results Toxicity

Category

870.1100/

Acute oral toxicit y 00070456 LD50 = 794 mg/kg (M)

LD50= 681 mg/kg (F) III

870.1200/

Acute dermal toxicity 00070456 LD50 = 1.83 gm/kg* (combined) II

870.1300/

Acute inhalation toxicity 00070456 LC50 >200 mg/kg III**

870.2400/

Acute eye irritation 00070456 Severely Irritating I

870.2500/

Acute dermal irritation 47107004 Corrosive I

870.2600/

Skin sensitization 41482505,

41482507,

010890 Dermal Sensitizer

-

*Notes: Octhilinone has a density of 1.03 gm/mL. = LD50 = 1.83 gm/kg

. **Acute inhalation study is unacce ptable

.



## Subchronic Toxicity

For subchronic oral toxicity, the database includes three studies, an acceptable non

- guideline

14

- day study in rats (MRID 43935707) and two unacceptable 90

- day oral toxicity studies, one

in rats (MRID 00136524) and another in dogs (MRID 00136525). For subchronic der m al

toxicity, the database includes four studies: an acceptable 14

- day der m al toxicity study in rats

(MRID 43935705); an unacceptable 21

- day der m al toxicity study in rabbits (MRID 00136526);

and two 90

- day der m al toxicity studies in rats ( M RID’s 42007301 and 43935706) that are

classified as acceptable and supple m ental, respectively. For subchronic inhalation toxicity, the

database includes an unacceptable non

- guideline 10

- day inhalation toxicity study in rats (MRID

00136527) and an acceptable 90

- day inhalation toxicity study in rats (MRID 41544701). There

are two additional subchronic oral studies, one in rats (MRID 47315011) and one in dogs (MRID

47315012) which need to be evaluated for the risk assessment.Page 36 of 73

Non

- G uideline 14

- Day Oral Toxicity (Rat)

In a repeated dose oral toxicity study (MR I D 43935707), N

- octylisothiazolone (OIT 96%, Batch

No. K1217) was ad m i nistered by intragastric intubation to eight fe m ale Sprague Dawley

rats/dose at dose levels of 0, 10, 60, or 120 m g/kg bw/day for 14 days. The purpose of this study

was for selection of doses for a develop m ental toxicity study in the rat.

Clinical observations and gross pathology findings i ndicated dose

- related signs of toxicity in all

treat m e nt groups. Observa tions of salivation and abnor m a l position increased in incidence and

frequency of occurrence with increasing dose level. Piloerection, soft feces, and excessive

urination were also noted in the 120

- m g/kg/day ani m als. Treat m e nt

- related gross pathology

findi ngs included a pro m inent lobular pattern in the liver (≥ 10 m g/kg/day), and whitish

- colored

and thickened fundus of the sto m ach (≥ 60 m g/kg/day). Gastric he m orrhages of the fundus were

also noted in one 120

- m g/kg/day rat. Body weight gain and food consu m ption were reduced at

≥ 60 m g/kg/day. However, body weight gain was not statistically different from controls due to

large standard deviations, and food consu m ption was only significantly reduced at the Day 1

- 3

treat m e nt interval. This study had nu m erous deficiencies in m eeting criteria for a repeat dose

oral tox icity study in rodents. However, because the purpose of this study was for dose selection

for a rat develop m ental toxicity study and not for fulfill m ent of a specific guideline, the

infor m ation contained in this study m a y be scientifically useful for exa m i ning toxic effects from

short

- term oral exposure. Based on the results of this study, doses of 5, 30, or 60 m g/kg/day were

suggested for the rat develop m ental toxicity study.

The LOAEL for N

- octylisothia z olone (OIT) 96% is 10 mg/kg/day, based on clinical signs of

salivation and gross pathology in the liver. A NOAEL could not be defined for this study.

This 14

- day repeated dose oral toxicity study is classified as ACCEPTABLE NON

GUIDELINE and does not satisfy the Guideline require m e nts (OPPTS 870.3050; OE CD 407)

for a 28

- day oral toxicity study in rodents. Although there are m a jor deficiencies in the

guideline require m ents, the study is scientifically acceptable for the dose range

- finding purpose

f or which it was intended.

870.3100 90

- Day Oral Toxicity (R at)

In a 90

- day oral toxicity study (MRID 136524), RH

- 893 (octhilinone, % a.i. not reported, lot no.

SW 70/0293) was ad m i nistered to 10 albino rats/sex/dose in the diet at dose levels of 0, 100,

500, or 2000 ppm (equivalent to 0, 7.0, 34.6, and 139.9 m g/k g bw/day, respectively). There was

no effect on survival, feed efficiency, urinalysis, or gross and m i croscopic pathology.

Body weight, body weight gain, and feed consu mption were low during the first week of

treat m e nt for high

- dose m a les and fe m a les, but were co m parable to the respective control groups

for the re m a inder of the study. The results for he m a tology, clinical che m istry, and organ weight

were equivocal because of the high variability, low nu m ber (5 rats/sex/treat m e nt group for

clinical che m istry and he m a tology), inconsistency between the sexes, and lack of a dose

response. The results, however, suggest a possible decrease in he m oglobin and RBCs in all

fe m a le treat m e nt groups, which was acco m panied by an increase in serum carbon dioxide levels.

Si m ilar results were not observed in the m ales. There was a decrease in total W BC in the high

dose group at 13 weeks for both sexes and at 4 weeks in fe m a les. There also were so m e changesPage 37 of 73

in the differential leukocyte counts with an increase in the percent of seg m ented neutrophils

acco m panied by a decrease in the percent of ly mphocytes in all m a le (4 weeks only) and fe m a le

(13 weeks only) treat m e nt groups. All treated m a les and fe m a les also had increases in absolute

and relative thyroid weight.

The deficien cies in this study were nu m erous with several being sufficiently severe enough to

co m pro m i se the overall integrity of the study. These deficiencies are m a inly due to the age of

the study, having been perfor m e d prior to the i m ple m entation of Good Laboratory Practices

(GLP). These de f

i ciencies include high variability in the data (which could be a result of the

variability in the initial body weight or an artifact of the strain); the lack of any analyses on the

dose f or m ulation to indicate that ho m ogeneity, s tability, or adequate concentrations were

achieved and m a intained throughout the study; an inadequate nu m ber of ani m als (only 5

ani m als/sex/treat m e nt) used for he m a tology, clinical che m istry, and histopathology

exa m inations; and the lack of nu m erous m easur ed para m e ters (e.g., neurological exa m s). The

deficiencies in this study are such that n e ither a LOAEL nor NOAEL could be

determined.

This 90

- day oral toxicity study in the rat is UNACCEPTABLE/NOT UPGRADABLE and

does not satisfy the guideline require m e nt for a 90

- day oral toxicity study (OPPTS 870.3100;

OECD 408) in rodents. There were no analyses perfor m e d on the dose for m ulation to deter m ine

ho m ogeneity, stability, or concentration of the test co m pound. In addition, only 5 of the 10 rats

per sex and dose group were exa m ined for he m a tology, clinical che m istry, and histopathology

endpoints.

870.3150 90

- Day Oral Toxicity (Dog)

In a 90

- day oral toxicity study (MRID 136525 )

, RH

- 893 (octhilinone, Lot no. S W 70/0293;

purity assu m e d to be 100%) was ad m i nistered to 4 Beagle dogs/sex/dose in the diet at dose

levels of 0, 100, 500, or 2000 ppm (equivalent to 0, 3.5, 16.8, and 60.2 m g/kg bw/day,

respectively, based on the assu m ption that the dose for m

ulation was ho m ogeneous, stable,

and at the correct concentration).

Data were highly variable, even at the initial m easure m ent, m a king it di ff i cult to deter m ine

treat m e nt

- related e ff

ects. The results indicate the f ollowing as possibly related to the

ad m i nistration of RH

- 893: reduced body weight gain in 500

- ppm m a les and 2000

- ppm m a les

and fe m ales, with reduced food efficiency in these groups; slightly reduced he m atocrit and

he m oglobin and increased alkaline phosphatase in the high

- dose groups; decreased total

protein in high

- dose m a les and all fe m a les, acco mpanied by so m e disruption in the protein

electrophoresis; increased relative liver weight (high

- dose m a les only); increased relative

kidney weight (high

- dose f e m a les only); and decreased relative testis weight with an increase

in slight to m oderate epididy m itis in high

- dose m a les. The m a jor deficiency in this study was

the co m plete lack of analyses on the dose for m ulation. Because there was high variability in

the results, coupled with very little apparent affects, this beco m e s a great deficiency. The

ani m als had such va riability initially in their body weights and the m ajority of the other

m easured para m eters that it cannot be deter m ined if there is an inadequate ho m ogeneity,

stability, or concentration in the dose f or m ulation or if there were just great variability in t hePage 38 of 73

ani m als. Given the great variability, the slight differences between the groups, and the lack

of infor m ation on the dose for m ulations, it cannot be deter m ined what effects are actually

related to the treat m ent. Although it is possible that higher doses m a y have yielded m ore

definitive results, this would again largely depend on the ho m ogeneity, stability, and accuracy

of the dose for m

ulations. The deficiencies in this study are so great that neither a LOAEL

nor NOAEL can be assigned.

This 90

- day oral to xicity study in the dog is UNACCEPTABLE/NOT UPGRADABLE and

does not satisfy the guideline require m e nt for a 90

- day oral toxicity study (OPPTS 870.3150;

OECD 409). This study is unacceptable because ho m ogeneity, stability, and concentration of the

dose for m

ulations were not m easured. Additionally, the ani m als were not rando m ized and were

possibly of different ages or older than 9 m onths prior to dosing. These and other nu m erous

deficiencies discussed in this review m a ke the study not upgradable.

Non

- Guideli ne 14

- Day Dermal Toxicity (Rat)

In a 14

- day der m al toxicity study (MRID 43935705), N

- octylisothiazolone (OIT) 96% was

applied to the shaved skin of 5 Sprague Dawley rats/sex/dose at dose levels of 0, 10, 100, or

1000 m g/kg bw/day for 6 hours/day during a 14

- day period.

There were no treat m e nt

- related effects in m ortality, clinical signs, and food consu m ption.

Der m al irritation was observed at ≥ 100 m g/kg/day in both m a les and fe m a les at W eeks 1 and 2.

Slight to m oderate erythe m a

, ede m a, atonia, and desqua m a tion were observed in 100

- m g/kg/day

treated rats. The severity of der m al irritation increased to m oderate to severe in the 1000

-

m g/kg/day treated rats. So m e 1000 m g/kg/day fe m a les also exhibited slight to m oderate fissures

at W eek 1 (1/5) and W eek 2 (3/5 ). In addition to these observations, scabbing was observed at

≥ 100 m g/kg/day at W eeks 1 and 2, and scabbing with exfoliation was observed at 1000

m g/kg/day in m a les and fe m a les at W eek 2. There were no statistically

- significant findings for

body weight and body weight gain data. Body weight gain, however, was reduced in 1000

m g/kg/day m a les and fe m a les at W eek 2 and in overall weight gain. The lowered weight gain

was greater in m a les than in fe m a les. Food consu m ption data did not provide an explanation for

the reductions observed in body weight gain. There were no sta tistically

- significant effects in

m ean food consu m

ption in treated rats throughout the study. Macroscopic findings reported at

necropsy were generally insignificant. A der m al

- related finding of subcutaneous redness in the

neck and indurated skin in the tre ated area was observed in one 1000 m g/kg/day m a le. The

lo w est

- observable

- adverse

- effect level (LOAEL) for N

- octylisothia z olone (OIT) 96% is

100 mg/kg/day based on dermal irritation in both males and females. A NOAEL of 10

mg/kg/day is established based on no effects observed at this dose.

This 14

- day subacute der m al toxicity study is ACCEPTABLE

- NONGUIDELINE. Although

a nu m ber of deficiencies were noted for m eeting the guideline require m e nts for a 28

- day der m al

toxicity study (OPPTS 870.3200; OECD 410), the study is acceptable as a range

- finding study.Page 39 of 73

870.3200 21

- Day Dermal Toxicity (Rabbit)

In a 21

- day der m al toxicity study (MRID 136526 )

, RH

- 893

- 50% (purity assu m e d to be 100.0%

a.i. by study authors; however, the test article’s na m e is RH

- 893

- 50%, lot an d/or batch # not

provided) was applied to the shaved skin of 10 New Zealand W hite albino rabbits/sex/dose at

dose levels of 1 or 10%, 6 hours/day for 5 days/week during a 21

- day period at a dose volu m e of

1.0 m L/kg body weight/day; sub

- groups of 5/sex/dose were abraded or the skin was left intact.

The vehicle controls 5/sex/dose were treated with 1% Tween 80/distilled water solution, sub

groups were 3 m a les with abraded skin and 2 m a les with intact shaved skin 2 fe m a les with

abraded skin and 3 fe m a les with intact shaved skin. Dose volu m e for vehicle treated ani m als

was 2.0 m L/kg body weight/day for the first 4 days of treat m e nt, propylene glycol for the fifth

day and 1.0 m L/kg body weight/day of 1% Tween 80/distilled water solution f or the rest of the

study duration. Undiluted co m pound at a dosing volu m e of 0.25 m L/kg body weight/day was

applied for the first four days of W eek 1; these ani m als were then given a 10% dilution of RH

893

- 50% in a 1% Tween 80/distilled water solution for the rest of the study du ration. The

control and 1% ani m als’ vehicle was 1% Tween 80/distilled water solution except on the f i f t h

day of treat m e nt when propylene glycol was applied to the rabbits; all subsequent doses were in

the 1% Tween 80/distilled water solution vehicle.

Ther e were no treat m e nt

- related e ff ects on m ortality, appearance, and behavior. The 10%

treat m e nt effected der m al clinical findings, body weight, body weight gain, he m a tological

para m e ters (leukocytes, seg m ented neutrophils, and ly m phocytes) and histological f indings of

the skin (acanthosis, hyperkeratosis, der m atitis, pseudoepithelial hyperplasia, pustular

epider m itis [ m ales ]

, ulcerations, f olliculitis [ m ales ] ) with the abraded ani m als displaying a

slightly m ore severe skin lesions but with the s m all nu m ber of intact skin ani m als exa m ined at

necropsy co m

parisons were difficult. The 1% ani m a l s, displayed clinical signs of der m al effects,

decreases in body weight gains ( m ales with a greater effect noticed in m a les with abraded skin),

and histological findings of the skin (acanthosis, leukocyte infiltration, hyperkeratosis,

der m atitis, and pustular epider m itis) with the abraded ani m als displaying a slightly m ore severe

skin lesions but with the s m all nu m ber of intact skin ani m als exa m ined at necropsy co mparisons

we re difficult.

In addition, a 10% dose

- m a le, had severe hepatic necrosis and infla mm a tion and suppurative

hepatitis; these changes cannot be fully attributed to dosage due to the low nu m ber of control

ani m als for co m

parison but cannot be ruled at as incide ntal.

The LOAEL is 1% based on dermal irritation (clinical findings and microscopic findings)

in both males and females. A NOAEL cannot be determined.

The systemic LOAEL is 10% in females (body w eight gain) and 1% in males (body w eight

gain). A NOAEL is 1% in females and cannot be determined in males.

This 21

- day der m al toxicity study in the New Zealand W hite albino rabbits is

UNACCEPTABLE

- NONGUIDELINE and does not satisfy the guideline require m e nt for a

21/28

- day der m al toxicity study (OPPTS 870.3200; O E CD 410) in rodents. The experi m ental

design of this study appears to be one of rang e

- finding, where dose volu m es, vehicles, and areaPage 40 of 73

of application were altered during the course of the study. Deter m ining if a change was treat m e nt

related was difficult d ue to low sa m ple size, variability of the blood che m istry and he m atology

data, and variation in experi m ental design during the study. Several he m atological para m eters,

clinical che m istry, and several organs were not exa m ined. These and other nu m erous

defic iencies m a ke the study not upgradable.

870.3250 90

- Day Dermal Toxicity (Rat)

In a der m al subchronic toxicity study ( M RID 42007301), doses of 1 m L/kg of RH

- 893 HQ

Technical (99.1% a.i.) were applied to the shaved skin of ten young adult Cr1:CDBR CD

rats/s ex/dose at dose levels of 0, 2.97, 5.95, or 14.87 m g/kg/day for 6 hours/day for 5 days/week

for 13 weeks. Skin irritation occurred in all treat m e nt groups in a dose

- related m a nner. The

LOAEL for dermal irritation is 2.97 mg/kg/day a nd a NOAEL could not be established.

No m ortality or treat m e nt

- related signs of clinical toxicity were observed during the study.

Treat m e nt

- related m i croscopic changes observed in the treated area of the skin of m a le and

fe m a le rats in Groups 3, 4, and 5 and in m a le rats in Grou p 2 (vehicle control) include

hyperkeratosis, acanthosis, foci of necrosis, and eschar for m ations in the epider m i s and chronic

infla mm a tion and sebaceous gland hyperplasia in the der m is. No statistically significant effects

on food consu m

ption or food effi ciency were observed in Groups 2, 3, or 4 of either sec. In

Group 5 m a les, food consu m ption and decreased body weights were observed. No changes in

absolute organ weights or organ/body weight ratios for m a les or fe m a les were considered to be

treat m e nt

- rela ted. The only treat m e nt

– related changes in he m a tology para m e ters observed in the

high

- dose fe m a les, a slight but statistically

- significant decrease in red blood cell count,

he m a tocrit, and he m oglobin were observed; t h e biological significance of this effe ct is

questioned because of the low m a gnitude of the effect and because the effect was only observed

in f e m a les. Likewise, statistically

- signif i cant treat m e nt

- related changes in clinical che m istry

patterns were observed in the high dose ani m als, including decreases in albu m in, glucose, and

total protein in fe m a les and an increase in alkaline phosphatase and a decrease in triglycerides in

m a les; the biological significance of these effects is also questioned because of the low

m a gnitude of the effects and b ecause they were not observed in both sexes.

The systemic NOAEL for this study is 5.95 mg/kg/day and the LOAEL is 14.87 mg/kg/da y

, based on decreases in HGB, HCT, RBC, albu m in, glucose, and total protein in fe m a les and a

decrease in body weight and body w eight gain in m a les.

This der m al subchronic toxicity study is classified as Acceptable because it satisfies the

require m e nts for a repeated dose der m al toxicity study (§82

- 3). Minor deficiencies noted in the

study report include: the test site was not occ luded after dose ad m i nistration, and data for the

differential leukocyte counts were not provided.

870.3250 90

- Day Dermal Toxicity (Rat)

In a der m al subchronic toxicity study (MRID 43935706), N

- octylisothiazolone (94 ± 3% ai, Lot#

K1217) was applied to t he shaved skin of ten young adult Sprague

- Dawley CD rats/sex/dose at

dose levels of 0, 5, 25, or 125 m g/kg/day for 6 hours/day for 90 days.Page 41 of 73

Male and fe m a le rats in the 125 m g/kg treat m e nt groups exhibited slight to m oderate ( m ean

score ≤ 2.l on a scale o f 0 to 3) erythe m a

, ede m a, atonia, desqua m a tion, and fissures, and lesions

described as squa m ous cell hyperplasia, sebaceous cell hyperplasia, folliculitis, der m atitis, and

he m orrhages at the site of treat m e nt. Body weight gains of m a le rats in the 125 m g/ kg treat m e nt

group were 21% less than rats in the control group after 90 days of treat m e nt; the depressed

weights were first noted at 22 days. The body w e ight and body weight gains of fe m a le rats in

the 125 m g/kg treat m e nt group were unaffected. Male and f e m a le rats in the 25 m g/kg treat m e nt

groups were found to have m i ni m a l ( m ean scores ≤ 1) erythe m a

, ede m a, and atonia; no lesions

were observed. No der m al irritation was observed in the 5 m g/kg treat m e nt group during the

study. Body weights of rats in the 5 and 25 m g/kg treat m e nt groups were si m ilar to the controls.

For all treat m e nt groups, food consu mption was si m ilar to the controls. There were no

treat m ent

- related differences in ophthal m ology, he m atology para m eters, clinical blood

che m istry, urine che m ist ry and appearance, organ weights, or m acroscopic or m i croscopic organ

m orphology (with the exception of treated skin in the high dose rats) between rats in the treated

and the control groups. No neoplastic tissue was observed. However, the investigator fai led to

m i croscopically exa m ine sa m ples of tissue from the treat m e nt sites in the m i d

- and low

- dose

groups. Da m a ge to the treat m e nt sites was not assessed. Therefore, the NOEL/LOEL cannot

be determined.

This der m al subchronic toxicity study is classified u nacceptable/upgradable and does not

satisfy the guideline require m e nt for a repeated dose der m al toxicity study (§82

- 3). The study

m a y be upgraded once m i croscopic exa m ination of the treat m e nt sites in the lower dose groups is

conducted.

Non

- Guideline 10

- Day Inhalation (Rat)

In a 10

- day inhalation toxicity study ( M RID136527), RH

- 893

- 50% (octhilinone, Lot and Batch

no. not provided; purity assu m ed to be 50%), was ad m i nistered to 10 Sprague

- Dawley albino

rat/sex/dose, in an aerosol under dyna m i c conditions at no m inal concentrations of 0, 1%, or

10% with a target cha m

ber concentrations of 2.0 m g/L for 1 hour per day, for a total of 10 days.

The vehicle was propylene glycol; the control ani m als received the vehicle control as an aerosol.

All exposures were who le body exposures. After 10 days of exposure, 5 rats/sex/dose were

sacrificed in the 1% and 10% exposure groups and necropsied on Day 12. The rest of the

surviving ani m als were sacrificed and necropsied on Day 26, after a 1 4 th day recovery period.

Ani m als in the 10% exposure group were found dead or sacrificed due to m oribundity 9/10

m a les and 7/10 fe m a les died as early as Day 3. Clinical signs of toxicity related to treat m e nt

were nose shuffling (1% and 10%), dried red m a terial around the eyes (10%), gasp ing (10%),

lacri m ation (10%), red nasal exudate (10%), and coughing (10%); preening, hypoactivity, wet

hair, excessive water consu m ption, and wheezing were exhibited in control and treated ani m als.

Data were highly variable, m aking it difficult to deter m in e treat m ent

- related effects. W eight loss

was observed in the 10%

- RH

- 893

- 50% m a les and fe m a les; however, only 1 m a le rat and 3

fe m a le rats survived to Day 8 so the body weights on Days 8, 12, and 26 could not be

statistically co m

pared to controls. By the en d of the recovery period the 10%

- RH

- 893

- 50%

group had gained weight; however, the surviving 10%

- treated m a le displayed a weight gain of

69% of control, the 1% m a les a weight gain of 26% of control, 10%

- treated fe m a le displayed aPage 42 of 73

weight gain of 86% of contr ol; the 1% fe m a les a weight gain of 91% of control. Blood was only

taken on Day 26 from the surviving ani m als and not on Day 12, after exposure ter m ination, it is

difficult to deter m ine treat m e nt

- related effects. Analysis of he m a tological data de m onstrated a

decrease in total white blood cells (10% m ales and fe m ales; 1% fe m ales), an increase in

seg m ented neutrophils (1 and 10% m a les and fe m a les), and a decrease in ly m phocytes (10%

m a les and fe m a les; 1% m a les), which m a y indicate an irritation response. Howe ver, without

data from Day 12 this is speculation. A significant decrease in glucose was observed in the high

dose m a le. Clinical pathology data does not correlate to this change; therefore, it could be an

incidental change. W ithout data from Day 12 when the treat m e nt was ter m inated it is i mpossible

to m a ke a conclusion as to the relevance of this finding. An increase in aspartate

aminotransferase levels was observed in the 10% ani m als; however due to data variability and

the fact that only 1 m a le and 3 fe m a les re m a ined after treat m e nt, these values were not

statistically

- significant. These changes m a y have corresponded with gross pathology findings of

m ottled liver; however, without clinical che m istry data from Day 12 when the treat m e nt was

ter m inated it i s i m

possible to m ake a conclusion as to the relevance of this finding. Because

there was high variability in the results, coupled with very little data from the day treat m e nt was

ter m inated, this beco m e s a great deficiency.

Microscopic treat m e nt related e ff ects were li m ited to the respiratory tract and included m ild to

m oderate bronchiolitis in m ultiple 10% RH

- 893

- 50% rats. Additionally, four m a le rats from the

1%

- RH

- 893

- 50% group exhibited severe lung les i ons, which were consistent with chronic

m urine pne u m onia that m a y have been exacerbated by inhalation treat m e nt.

Based on the data in this study, neither a NOAEL nor LOAEL can be determined.

Analytical concentrations of test material in the breathing z one of the rats w ere not

determined. Thus actual dose to the animals cannot be determined.

This 10

- day inhalation toxicity study in rats is UNACCEPTABLE/ NOT UPGRADABLE

and does not satisfy the guideline require m e nt for a subchronic inhalation study OPPTS

870.3465; OECD 413 in the rats. This study is unacce ptable because only two dose groups were

used with 10 rats/sex/dose and satellite groups of 5 rats/sex/dose were kept for a 14

- day recovery

period. The ani m als were only exposed for 1 hour/day for 5 days a week for a total of 10

exposures where the guideli ne states exposure for 6 hours/day, 5 days a week. Ho m ogeneity,

stability, and concentration of the dose f or m ulations were not m easured; test article concentrations

and analytical deter m ination of the test article in the exposure cha m ber were not provided.

Several toxicity testing para m e ters were not m easured. These and other nu m erous deficiencies

discussed in section III.C m a ke the study not upgradable.

870.3465 90

- day inhalation (Rat)

In a subchronic aerosol inhalation (nose

- only) toxicity study (MR ID 41544701), eleven

Crl:CD®BR rats/sex/exposure group were exposed by inhalation (6 hours/day, 5 days/week) for

13 weeks to aerosolized Skane® M

- 8 HQ Microbicide (octhilinone, a.i. 42%, Lot No. SW 85

- 0311) at exposure concentrations of 0 (a m bient air), 0 (propylene glycol, 123 m g/ m 3), 0.05,

0.64 and 6.39 m g of octhilinone/ m 3

. An additional eleven rats/sex/exposure group werePage 43 of 73

assigned to a fourteen

- week recovery period.

The m ean m a ss dia m eter (MMD) and geo m etric m ean (GM) were 2.5 μm and 9.2, respectivel y,

for the propylene glycol exposure group and were 1.4 μm and 5.5, respectively, for all exposure

groups of octhilinone. Three deaths occurred during the study but were not considered related to

the exposures. No clinical signs were observed in the 0, 0 ( PG), 0.05, and 0.64 m g/m 3 groups.

Clinical signs in the 6.39 m g/ m 3 exposure group included: rales [ m ales and fe m a les 5

- 22/22;

weeks 1

- 13]; dyspnea [fe m a les: 3/22: week 4; 3

- 9/22: weeks 7

- 10]; thriftless [( m a les: 3/22:

weeks 8 and 10) and (fe m ales: 9

- 22/22: weeks 7

- 10)]; and red staining of the dropping sheet

[( m a les: 11/22: week 2) and (fe m ales: 6/22: week 8)]. There were statistically significant

decreases (p < 0.05) in body weights (3.3 to 8.8% for weeks 1, 7, and 13) and body weight gains

(11.3 to 68.9% or weeks 1, 7, and 13) in m a le and fe m a le rats in the 6.39 m g/m 3 group. No

clinical che m istry and organ weight changes and deaths were related to the exposures. There

were no gross pathological findings in exposed m a les and fe m ales. Histopathological findi ngs in

the m ale and/or fe m ales from the 6.39 m g/ m 3 group consisted of secretory cell hyperplasia,

squa m ous m etaplasia, infla m m ation, and eosinophilic droplets in the nasal cavity at the 13

- week

sacrifice.

During the recovery period, rales were present in the m a les and fe m a les from the 6.39 m g/ m 3

group. Based upon the clinical signs, the decreased body weights, fluid in the uterus, and the

pul m onary histopathological findings at the ter m inal sacrifice for m a les and fe m a les in the 6.39

m g/ m 3 group, the LOAEL for 13

- w eek inhalation exposure is 6.39 mg/m 3

. The NOAEL is

0.64 mg/m 3 . The study is classified as Acceptabl e

, satisfying the require m e nts for a subchronic

inhalation toxicity study in the rats (§82

- 4).



## Developmental Toxicity

The database includes four develop m ental toxicity studies in rats and two in rabbits. The

develop m ental toxicity studies in rats include three acceptable studies (MRIDs 41482508,

43944401 and 47107014) and one unacceptable study (MRID 00046403). For

develop m ental toxicity in rabbit s, the database includes one acceptable study (MRID

41482509) and one unacceptable study (MRIDs 00058029 and 00136528).

870.3700a Prenatal Developmental Toxicity (Gavage) Study

– Rat

In a develop m ental toxicity study (MRID 41482508), SkaneTM M

- 8 HQ (43% a.i., lot SW 86

6155) was ad m i nistered to 25 Crl:C D ® BR rats/dose by gavage at dose levels of 0, 1, 5, or 30 m g

active ingredien t

/kg bw/day from days 6 through 15 of gestation. Because SkaneTM M

- 8 HQ

contains about 50% propylene glycol; an additional contro l group co m prised of 25 rats was

ad m i nistered propylene glycol at 30 m g/kg/day, a volu m e equal to that of the highest does group.

Maternal toxicity was observed at 30 m g/kg/day. Signs of toxicity at 30 m g/kg/day include: one

death; salivation and decrease d defecation; decreased body weight and body weight gain;

decreased corrected body weight and body weight gain; and decreased food consu m ption. ThePage 44 of 73

investigator also concluded that there was a slight, treat m e nt

- related increase in resorptions/dam

and post

- i mplantation loss at 30 m g/kg/day. Upon further inspection, however, the values

appear co m

parable to control values, as well as other treat m ent groups. Additionally, these

changes did not reach statistical significance. A lthough the investigator concluded that m a ternal

toxicity also was observed at 5 m g/kg/day, this deter m ination does not seem reasonable.

Changes in body weight, corrected body weight and body weight gain, and food consu m ption

observed at the m i d

- dose and dee m ed treat m e nt

- related by the inve stigator were slight, and the

values were not statistically di ff e rent in co m

parison to the control values. The values actually

appear to be co m

parable to control values, especially when standard deviations are taken into

consideration. The findings at the m i d

- dose do not warrant being called a treat m e nt

- related

effect. Consequently, the maternal LOAEL is 30 mg/kg b w /day, based on death,

salivation and decreased defecation, decreased body w e ight and body w e ight gain,

decreased corrected body w e ight and body w e ight gain, and decreased food

consumption. The maternal NOAEL is 5 mg/kg b w /day.

Develop m ental toxicity was not observed at any dose level. The investigator concluded that

develop m ental toxicity was observed at 30 m g/kg/day due to an increased percentag e of litters

and fetuses with any type of m a lfor m a tion (external, visceral, or skeletal). Malfor m a tions

occurred in only three f

e tuses f r om three litters at 30 m g/kg bw/day in co m parison to one control

f e tus f r om one control litter. The di ff e rence was not statistically signi f i cant, and the apparently

high percentage values (1.2% of f e tuses and 17.6% of litters at 30 m g/kg/day; 0.4% of f e tuses

and 5.3% of litters in the control; and 0.3% of f etuses and 4.3% of litters in the historical control)

are m ost like ly an artifact of the very s m all nu m ber of f e tuses and litters available f or evaluation.

In addition, the m a lfor m a tions observed are known to occur spontaneously in this strain of rats

as de m onstrated by the historical data. Consequently, the developmental NOAEL is 30 mg/kg

b w /day.

This develop m ental toxicity study is classified ACCEPTABLE

- GUIDELINE and satis f i es the

guideline require m e nt for a develop m ental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700a Prenatal Developmental Toxicity (Gava ge) Study

– Rat

In a develop m ental toxicity study (MRID 43944401 )

, N

- octylisothiazolone (octhilinone, 94% ai,

Lot# K1217) was ad m i nistered to 25 fe m a le Sprague Dawley rats/dose in corn oil by gavage at

dose levels, of 0, 5, 30, or 60 m g/kg/day from days 6 through 15 of gestation.

Maternal toxicity was de m onstrated by reduced m ean body weight gains on days 6

- 9 of gestation

(14%, co m

pared to controls). No other treat m e nt

- related e ff ects in m ortality, clinical signs of

toxicity, body weight, food consu m ption

, or cesarean para m e ters were noted at any dose level.

The maternal LOEL is 60 mg/kg/day, based on reduced body w eight gains. The maternal

NOEL is 30 mg/kg/day.

There w ere no treatment

- related effects noted in the developmental parameters. A

developmental LOEL w as not observed. The developmental NOEL is 60 mg/kg/day.

This develop m ental toxicity study is classified ACCEPTABLE

- GUIDELINE and satis f i es thePage 45 of 73

guideline require m e nt for a develop m ental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700a Prenatal Developmental Toxicity (Gavage) Study

– Rat

In a developmental range finding toxicity study (MRID 471070

- 14 ), Octhilinone (43% a.i.,

batch/lot SW 86 6155 ), SkaneTM M

- 8 HQ, was administered to 5 female Crl:CD ® BR rats/dose

by gavage at dose levels of 0, 50, 100, 200, or 400 mg active ingredient/kg bw/day 4 from days 6

through 15 of gestation. Because SkaneTM M

- 8 HQ contains about 50% propylene glycol, an

additional control group comprised of 5 rats was administered propylene glycol at 465.1

mg/kg/da y, a dose equal to of the amount of propylene glycol in the highest Skane TM M

- 8 HQ

group.

Signs of toxicity were observed at all dose levels. At the high dose, all dams died prior to

scheduled necropsy. Additional treatment

- related deaths due toxicity i ncluded two 200

- mg/kg/day dams (on gestation day [gd] 7 and 8) and one 50

- mg/kg/day dam (on gd 12). Clinical

signs of toxicity were observed in most animals administered 50, 100, and 200 mg/kg/day and

included, but were not limited to, the following: drie d red material around the nose and mouth;

wet yellow urogential staining; decreased defecation and salivation; and increased frequency of

soft stool and wet anogenital and abdominal staining. Treatment

- related body weight loss and

decreased food consumpti on were observed in all dose groups.

There were no treatment

- related changes to the mean number of viable fetuses, early resorptions,

implantation sites, and corpora lutea. Only one 200

- mg/kg/day dams survived until termination.

This dam had nine ear ly resorptions; this was probably the result of the dam’s severely reduced

food intake and decreased body weight throughout the treatment period. For those dams that

died as a result of treatment (all 400

- mg/kg/day dams; two 200

- mg/kg/day dams; and one 50

- mg/kg/day dam), necropsy findings included reddened intestines with yellow contents, dark red

corticomedullary junction in the kidneys, and separation of the stomach mucosa and submucosa

from the muscular layer with accumulation of serous exudate in the s ubmucosal space.

Additionally, those animals that died due to intubation trauma to the esophagus (2, 2, and 1 dam

in the 50

- , 100

- , and 200

- mg/kg/day dose groups, respectively) exhibited similar findings

including dark red or corroded areas in the stomach and kidney.

The maternal LOAEL is 50 mg/kg bw/day, based on mortality, clinical signs of toxicity,

decreased body weight and body weight gain, decreased food consumption, and treatment

related necropsy findings.

Mean fetal weights were reduced at 50 and 100 mg/kg/day. The one 200

- mg/kg/day dam that

survived until termination had two small fetuses; decreased fetal weight was probably the result

of the dam’s severely reduced food intake and decreased body weight throughout the treatment

period. There were no remarkable external abnormalities. Fetuses were not examined for

visceral or skeletal abnormalities.

The developmental LOAEL is 50 mg/kg bw/day, based on decreased fetal weight.

4 The Skane M

- 8 HQ doses represent mg active ingredient per kg body weight; they were adjusted for an active

ingredient of 43% using an adjustment factor of 2.33

.Page 46 of 73

Based on the results, the study author concluded that a dose leve l of 50 mg/kg/day was excessive

and dosage levels of 0, 1, 5, and 30 mg/kg/day should be selected for subsequent teratology

studies in rats.

This developmental toxicity study in the rat is classified ACCEPTABLE

- NON

- GUIDELINE

and does not satisfy the g uideline requirement for a developmental toxicity study (OPPTS

870.3700; OECD 414) in the rat. This study is classified as such because it is a range finding

study.

870.3700a Prenatal Developmental Toxicity (Gavage) Study

– Rat

In a develop m ental toxici ty study (MRID 00046403), RH

- 893 (octhilinone, lot no. SW 70/0293;

purity assu m e d to be 100% active ingredient) was ad m i nistered to up to 18 fe m a le Charles River

Caesarean

- derived rats/dose in the diet at dose levels of 0, 200, or 1000 ppm from days 6

- 15 o f

gestation. All da m s were sacrificed at gestation day (gd) 19.

There was no m a ternal toxicity observed at any dose level. It should be noted, however, that

there m ay be treat m ent

- related changes in m aternal body weight. Mean m aternal body weight

values s how a slight decrease in body weight at the high dose that is difficult to interpret due to

the lack of individual data, standard deviations, and statistical analysis, as well as the low

nu m ber of ani m als. The maternal NOAEL is 1000 ppm.

There were no dev elop m ental effects attributed to oral exposure to RH

- 893 in the diet; therefore,

the developmental NOAEL is 1000 ppm.

This develop m ental toxicity study in the rat is UNACCEPTABLE/NOT UPGRADABLE and

does not satisfy the guideline require m e nt for a develop m ental toxicity study (OPPTS 870.3700;

OECD 414) in rats. Several m a jor study reporting deficiencies including a lack of ani m al data

would not allow this study to be upgraded.

870.3700b Prenatal Developmental Toxicity (Gavage) Study

– Rabbit

In a develop m ental toxicity study (MRID 41482509), SkaneTM M

- 8 HQ Industrial Mildewcide

(46.3% a.i., lot S W 86

- 6155) was ad m i nistered to 19 New Zealand W hite rabbits via gavage at

dose levels of 0, 5, 20, or 80 m g active ingredient/kg bw/day from days 7 through 19 of

ges tation. Because SkaneTM M

- 8 HQ Industrial Mildewcide contains about 50% propylene

glycol, an additional control group of 19 rabbits was ad m i nistered propylene glycol at 92.8

m g/kg/day, a volu m e equal to that of the highest does group.

Maternal toxicity was observed at 80 m g/kg/day and included clinical signs of toxicity (anorexia

and scant, soft, or no feces), decreased body weight and body weight gains, and increased

nu m ber of abortions. The maternal LOAEL is 80 mg/kg b w /day, based on clinical signs of

tox icity, decreased body w eight and body w eight gains, and increased number of abortions.

The maternal NOAEL is 20 mg/kg b w /day.Page 47 of 73

There was a significant treat m e nt

- related decrease in m a le fetal body weight and total ( m ale and

fe m a le) fetal body weight at 80 m g/kg/day. There were no other treat m e nt

- related signs of

develop m ental toxicity. The developmental LOAEL is 80 mg/kg b w /day, based on

decreased male fetal body w eight and total (male and female) fetal body w eight. The

developmental NOAEL is 20 mg/kg b w /da y.

The develop m ental toxicity study in the rabbit is classified Acceptable (Guideline) and satisfies

the guideline require m e nt for a develop m ental toxicity study (OPPTS 870.3700; OECD 414) in

rabbits.

870.3700b Prenatal Developmental Toxicity (Gavage) St udy

– Rabbit

In a develop m ental toxicity study (MRIDs 00058029 and 00136528), RH

- 893 (100% a.i., lot SW

70/0293) was ad m i nistered to 15 New Zealand W hite rabbits/dose by gavage at dose levels of 0,

6, or 60 m g/kg bw/day. Of the 15 rabbits/group, 8/group w ere designated for Caesarean section

and 7/group were designated for nor m al hutching. Doses were ad m i nistered on gestation days

(gd) 6 through 18 (for fe m a les designated for Caesarean section) or gd 6 through 16 (for fe m a les

designated for nor m a l hutching)

. Treat m e nt was ter m inated two days earlier in da m s designated

f or nor m a l hutching due to high m ortality.

The test m a terial was toxic at both dose levels and resulted in high m a ternal m ortality rates.

Death occurred in 6 low

- dose da m s (3 designated for Ca esarean section and 3 designated for

nor m a l hutching) and 10 high

- dose da m s (6 designated for Caesarean section and 4 designated

for nor m a l hutching). Changes in body weight and food consu m ption appear treat m e nt

- related

with those ani m als dying prior to sc heduled sacrifice exhibiting body weight losses and

decreased food consu m

ption. Ani m als that died prior to study ter m ination also showed gross

pathology findings, with the predo m inate findings being dark, red lungs or chest cavity

ano m alies. There were no apparent treat m e nt

- related changes in the nu m ber of i m plantation

sites co m pared to the nu m

ber corpora lutea. Additionally, there were no apparent treat m e nt

related changes in the nu m ber and place m ent of i mplantation and resorption sites or in the

nu m ber o f live and dead fetuses/pups. The lack of a treat m e nt

- related response could be the

result of too f

e w ani m als available f

or co m parison. Additional data are needed to f ully assess

these endpoints. The maternal LOAEL is 6 mg/kg/day based on mortality, body w eight

loss, decreased food consumption, and gross pathology findings. A Maternal NOAEL w as

not achieved.

There were no apparent develop m ental effects. Fetal and pup body weight and length in treated

groups appeared to be co m parable with the control group s. Skeletal changes occurred m ore

f r equently in high

- dose f

etuses; however, these e ff ects predo m inately occurred in one litter

where one out of f

i ve f e tuses died. There were only two high

- dose litters to exa m ine. Therefore,

it is difficult to draw any m ean ingful conclusions from these data. A developmental NOAEL/

LOAEL could not be determined.

This develop m ental toxicity study is classified UNACCEPTABLE/NOT UPGRADABLE and

does not satisfy the guideline require m e nt for a develop m ental toxicity study (OPPTS 870.3700;Page 48 of 73

OECD 414) due to m a

jor study deficiencies. These include an inadequate nu m ber of da m s per

group, high m a ternal m ortality and abortion, and a lack of individual ani m al data.



## Reproductive Toxicity

There is one reproduction and fertility effect s tudy available (MRID 47815801).

870.3800 Reproduction and fertility effects

– rat

In a two

- generation reproduction study (MRID 47815801 ) Acticide ® OIT (2

- n

- Octyl

- 4

-

isothiazolin

- 3

- one) (95.9%) was administered to Wistar rats (24/sex/dose) in diet at dose levels

of 0, 300, 800, or 1500 ppm (equivalent to 0, 13

- 15, 43

- 51, or 96

- 120 mg/kg bw/day based on

test article recovery).

In the parental P and F 1 generations, no treatment

- related clinical signs were observed. No

mortalities occurred in the P generatio n, but in the F 1 parental generation, one animal in the 300

ppm group was found dead and another in the 800 ppm was killed in extremis. These deaths

were not considered to be treatment

- related. In the first generation, body weights were

statistically sig nificantly decreased in dams treated with 1500 ppm test substance on days 7 and

14 of lactation. No treatment

- related changes in body weight occurred in the second generation,

although the body weights of males and females of the 1500 ppm group were lower during the

complete treatment period. Females in the P generation showed decreased absolute spleen

weight and increased relative adrenal weight at 1500 ppm. No organ weight changes were noted

for the second generation. At the histopathological examinat ion at 1500 ppm , minimal to

moderate diffuse hyperplasia/hyperkeratosis of the forestomach was observed in nine males and

ten females of the first generation and in eight males and six females of the second generation,

all at the 1500 ppm dose level. The se observations correlated with the macroscopic observations

of irregular surface of the forestomach in four males in the first generation and in four males and

one female in the second generation. The parental systemic LOAEL is 1500 ppm (96

- 111

mg/kg bw/ day in males, 107

- 120 mg/kg bw/day in females for both generations when

corrected for mean value of test article recovery), based on decreased body weight,

hyperplasia/hyperkeratosis of the forestomach, decreased spleen weight, and increased

adrenal weight . The parental systemic NOAEL is 800 ppm (43

- 45 mg/kg bw/day in males,

48

- 51 mg/kg bw/day in females for both generations when corrected for the mean value of

test article recovery).

The offspring of both generations exhibited decreased body weight gain and decreased spleen

weight at the 1500 ppm dose level. The offspring LOAEL is 1500 ppm (96

- 111 mg/kg

bw/day in males, 107

- 120 mg/kg bw/day in females for both generations when corrected for

mean value of test article recovery), based on decreased body w eight gain and decreased

spleen weight. The offspring NOAEL is 800 ppm (43

- 45 mg/kg bw/day in males, 48

- 51

mg/kg bw/day in females for both generations when corrected for the mean value of test

article recovery).

Measured sperm count, motility, and morp hology and estrous cycle regularity were unaffected

by treatment in both generations. Reproduction parameters (mating performance, duration of

gestation, fertility, number of implantation sites, number of live/dead pups at first litter check)Page 49 of 73

and breeding parameters (postnatal loss, living pups on day 4 post partum, breeding loss, living

pups on day 21 post partum, viability index, weaning index) were unaffected by treatment in the

first and second generations. Therefore, the reproductive NOAEL is 1500 pp m (96

- 111

mg/kg bw/day in males, 107

- 120 mg/kg bw/day in females for both generations when

corrected for the mean value of test article recovery).

This study is ACCEPTABLE

- GUIDELINE and satisfies the guideline requirement for a two

generation reproduc tive study (OPPTS 870.3800; OECD 416) in rat.



## Chronic Toxicity

There is currently no existing chronic toxicity study for OIT. This is a required study (for metal

working and wood preservative uses) and has been identified as a data gap.



## Carcinogenicity

There is currently one unacceptable mouse carcinogenicity study (MRIDs 00139417, 00139419

and 00139484). Two acceptable studies are required for metalworking fluids and wood

preservative uses and the lack of these studies has been identified as a data gap s

.

870.4200 Carcinogenicity (Oral)

– Mouse

In a carcinogenicity study (TRID 470103024 and MRIDs 00139417, 00139419, and 00139484),

RH

- 893 (octhilinone, purity not stated, Lot No. and Batch No. not provided) was ad m i nistered to

125 (C 57BL/6 x C3H/anf) F 1 m i ce/sex/dose in diet at dose levels of 0, 500, or 1000 ppm

(equivalent m g/kg bw/day could not be deter m ined because analytical m easure m ent of the feed

were not perfor m e d and food consu mption was not m easured) for 78 weeks. Twenty

- five

m i ce/sex/dose were sacri f iced at 6 m onths f

or histopathologic exa m ination. Positive control

m i ce were utilized to co mpare two known carcinogens to the test article; 100 (C 57BL/6 x

C3H/anf) F 1 m i ce/sex were fed diets containing 600 ppm 2

- aceta m idofluorene (AAF), 50 (C

57BL/6 x C3H/anf) F 1 m i ce/sex/dose received 4 m g/kg/day diethylnitrosa m ine (DEN), and 25 (C

57BL/6 x C3H/anf) F 1 m i ce/sex/dose received 6 m g/kg/day in the drinking water.

There was no RH

- 893 treat m e nt effect on m ortality, but both positive controls (i.e., DEN a nd

AAF) caused an increase in m ortality. No clinical f i ndings were attributed to chronic f eeding of

octhilinone. High

- dose RH

- 893 m i ce generally had reduced body weights in the beginning of

the study co mpared to the negative control group; however, by W eek 3 in m a les and W eek 10 in

fe m a les the high

- dose RH

- 893 treated m i ce had co m parable or greater body weight and body

weight gain than the control group. Body weight was depressed in the positive controls. There

were no treat m e nt

- related effects on liver wei ght or m i croscopic pathology in RH

- 893 treated

m i ce.

Positive controls did exhibit an increase in lesions. The DEN ani m als were found with an

increased incidence of carcino m a of the hepatocytes in 6

- m g/kg/day m a les and fe m a les at weeks

26 and 30; the 4

- m g /kg/day ani m als were not exa m ined histopathologically. The DEN 6

-

m g/kg/day m a les and fe m a les were found with bronchitis or bronchiectasis. The AAF m i ce had

increased incidence of hyperplasia of the bladder in the m a les, urinary bladder carcino m a in bothPage 50 of 73

s exes and hepatocellular carcino m as in both sexes.

Under the conditions of this 18

- m onth feeding carcinogenicity study, there was no apparent

carcinogenic potential de m onstrated for RH

- 893 in either m a le or fe m a le (C 57BL/6 x C3H/anf)

F 1 m i ce exposed to 50 0 or 1000 pp m

. However, a nu m ber of study deficiencies precluded

selection of a LOAEL or NOAEL for this study.

At the doses tested, there was no treat m e nt

- related increase in tu m or incidence when co m pared

to controls; however, only 48 ani m als at the high dose were exa m ined histologically. Therefore,

any carcinogenic response would be potentially under

- reported. Dosing was not adequate for

this study, based on a lack of toxicity at the highest dose. Even considering the data from the

preli m inary 7

- week stud y used to deter m ine appropriate doses for the carcinogenicity study, a

dose of 1500 ppm or one between 1000 and 1500 ppm m a y have been a m ore appropriate high

dose for this 18

- m onth carcinogenicity study. In the preli m inary 7

- week study a single m a le

ad m i n istered 1500 ppm died, which is why this dose was neglected.

This carcinogenicity study in m i ce is UNACCEPTABLE/NOT UPGRADABLE and does not

satis f y guideline require m e nt for a carcinogenicity study [OPPTS 870.4200; OECD 451] in

rodents. There are several deficiencies, but the lack an adequate top dose, lack of analysis of the

dose for m ulation, and lack of m i croscopic exa m ination of only half of the high

- dose RH

- 893

m i ce m a de this carcinogenicity study unacceptable and not upgradeable.



## Neurotoxicity

There is no neurotoxicity study in the database for OIT. There is a 90 day oral study in rats

(MRID 47315011) that contains a functional observation battery that will undergo review by the

EPA Hazard and Science Policy C ouncil for determination if the study is s ufficient to fulfill the

requirement for a neurotoxicity study.



## Mutagenicity

In the A m es Sal m onella tests (MRIDs 43935708, 48358626), octhilinone was negative for

reverse m utations in the absence or presence of m i croso m al S9 in Sal m onella strains TA98,

TA100, TA102, TA1535, and TA1537. This assay was negative also negative in an

unacceptable

- nonguideline study (MRID 47107012). An in vitro bacterial gene mutation assay

( E.coli ) mammalian activation gene mutation assay (MRID 47107006) was negative. In a

m o use bone m a rrow chro m oso m a l aberration test (MRID 43935710), octhilinone (96% a.i.) was

negative. In an in vivo mammalian cytogenetics erythrocyte micronucleus assay in mouse bone marrow

cells (MRID 47107007), octhilinone (99.39%) was negative. In an in vi vo mammalian chromosomal

aberration assay in rats, (MRID 40647504), the assay was negative. In a m a mm a lian cell in culture

gene m utation assay, L5178Y m ouse ly m pho m a cells cultured in vitro (MRID 43935709), the

test substance (96% a.i.) was not m utagenic in both the activated and non

- activated conditions.

In a mammalian cells in culture gene mutation assay in Chinese hamster ovary CHO cells

(MRID 40647502), octhilinone (46.7%) was negative. In an unscheduled DNA synthesis in

primary rat hepatocytes/mammali an cell cultures (MRID 40647505), the assay was negative for

unscheduled synthesis.Page 51 of 73



## Dermal Absorption/Penetration

There are three dermal absorption/penetration studies, two acceptable (MRID 47181001 and

47198005) and one unacceptable (MRID 47198002).

Rodent in vivo Dermal Penetration Study

– Rat

In an in vivo dermal penetration study (MRID 47181001) 2

- n

- octyl

- 4

- [4,5

- 14 C]isothiazolin

- 3

- one

(99.1

- 99.2% radiochemical purity, Batch No. 1) dissolved in propylene glycol diluted with water

was applied to th e dorsal skin (10 μL/cm 2 ) of male Wistar rats at a nominal concentration of

1000 mg/L (Group 1) or 200 mg/L (Group 2) (4 animals/dose); actual concentrations were 818

mg/L and 172 mg/L, respectively. The actual doses were 0.0095 mg/cm 2 and 0.0019 mg/cm 2 sk in

for Group 1 and Group 2, respectively. Animals were exposed for 10 hours, at which time the

application site was washed. The radioactivity washed off the animals after the 10

- hr exposure

period was low (7.2% and 6.8% of the radioactive administered dose for Groups 1 and 2,

respectively); almost no radioactivity was washed off the O

- ring (average of 0.4% for both

groups). All animals were sacrificed at 96 hours post

- dosing.

The mean total percent recovery was 91.6% for Group 1 and 93.3% for Group 2. The highest

percentage of the administered dose was recovered from the treated skin at the application site

(52.1% for Group 1, and 56.3% for Group 2). The primary route of excretion of the administered

dose was through the urine (23.7% for Group 1 and 20.0% for Group 2). At 96 hours post

application, the mean absorbed dose was approximately 30% for both dose levels (31.9% for

Group 1 and 30.0% for Group 2). The potentially absorbable dose (which includes the skin

residue) was 84% and 86% of the applied dose in Group 1 and Group 2, respectively.

This in vivo study in the rat is ACCEPTABLE

– NON

- GUIDELINE and does not satisfy the

guideline requirement for a dermal penetration study (870.7600) in rats. Only one exposure

duration and two exposure doses were us ed. The study is not upgradable unless the Agency was

to approve the use of only one exposure duration, and two exposure concentrations.

Rodent in vivo Dermal Bioavailability Study

– Guinea Pig

In a dermal bioavailability study (MRID 47198005) a mixture of 14 C

- RH

- 893 (85

- 90% a.i., lot #

555.0502) and nonradiolabeled RH

- 893 (45.5% a.i., lot #7064) was administered to 3 to 4 male

guinea pigs/dose using a number of vehicles. 14 C

- RH

- 893 diluted in 80% ethanol or acetone

(100, 500, or 2000 ppm a.i.) was admini stered onto the shaved backs of animals by occluded

exposure for 6 hours. 14 C

- RH

- 893 diluted in 80% ethanol or acetone (500 ppm a.i.) was

administered onto the shaved backs of animals by unoccluded exposure for 3 hours.

14 C

- RH

- 893 prepared in two water

- b ased paints (AC

- 388 emulsion and Polyco 2161 emulsion,

each at 1000 ppm a.i.) and two solvent

- based formulations (Lazure stain, 5000 ppm a.i.; alkyd

paint, 1000 ppm a.i.) was also administered onto the shaved backs of guinea pigs by unoccluded

exposure for 3 hours.Page 52 of 73

Following the 3

- hour (unoccluded) or 6

- hour (occluded) exposure periods, the animals were

euthanized. Skin sites were wiped with cotton swabs moistened with 2% soap solution or

mineral spirits (solvent

- based formulations only), and the skin si tes were excised. Skin sites,

cotton swabs, dental dams, and patches (for occluded exposures) were analyzed for 14 C

- label.

The total amount of 14 C

- label recovered ranged from 79

- 110% within all groups. The amount of

14 C

- label recovered in the application site skin represented the minimal dermal bioavailability.

The minimal dermal availability of 14 C

- RH

- 893 ranged from 4 to 47% of the administered dose.

Minimal dermal availability was greatest in 80% ethanol and acetone, where 33

- 47% and 29

- 36%, respecti vely, of the administered 14 C

- RH

- 893 dose was recovered in the skin. In both

acetone and 80% ethanol, the type of exposure (occluded vs. unoccluded) did not markedly

affect the dermal bioavailability of RH

- 893. In the water

- based paints and solvent

- based

e mulsions, 5

- 8% and 4

- 5%, respectively, of the administered 14 C

- RH

- 893 dose was recovered in

the skin. Preparation of the water

- based paints one or seven days prior to application had no

effect on the amount of 14 C

– label bioavailable to the skin.

This derm al bioavailability study in the guinea pig is ACCEPTABLE

- NON

- GUIDELINE

. There are no guidelines for this type of study.

In Vitro Dermal Absorption Study in Male Rat Skin

In an in vitro dermal absorption study (MRID 47198002), freshly excised adult male rat skin

sections (Cr1:CD ® BR; approx.1.78 sq cm area) were mounted in Franz diffusion cells (external

skin surface (stratum corneum) facing upward). The receptor baths, containing Tyrode’s bathing

solution and the antibiotic gentamicin (to control bacte ria growth) were maintained at a constant

temperature of 37o C and continuously stirred throughout each experiment. Aqueous solutions of

14 C

- RH

- 893, solutions of 14 C

- RH

- 893 (300 and 1000 ppm) in propylene glycol and solutions of

14 C

- RH

- 893 (1000 ppm) in c ommercial latex emulsions (Amsco 3077, Acronal 290D, AC 64,

UCAR 366, AC 490, and UCAR 516) were applied to the skin sections (35 μL aliquots)

mounted in the diffusion cells. The skin sections were wiped at designated times (using one of

two wiping proced ures) with cotton swabs moistened with an aqueous soap solution. Aliquots of

the bathing solution were obtained at designated time intervals (0

- 96 hours). 14 C

- label

concentrations were measured in the wipes, the bathing solution, the cell cap and cell bo dy

rinses, and the skin sections using liquid scintillation counters (LSC) and radiographic TLC

methods. The amount of 14 C

- RH

- 893 bioavailable to the skin was defined as the sum of 14 C

label in the skin, the 14 C

- label that had penetrated through the skin into the bathing solution, and

the 14 C

- label measured in the lower cell rinse (expressed as a percentage of the total dose

applied).

The dermal bioavailability of 14 C

- RH

- 893 was measured and calculated to be completely

bioavailable (112±19% of applied dos e) 24 hours following dermal application of a 300 ppm

aqueous solution of 14 C

- RH

- 893 to excised male rat skin contained within a Franz diffusion cell.

This value was calculated as the mean of three studies. The calculated bioavailability of aqueous

solut ions of 14 C

- RH

- 893 (300 ppm) at 3 and 6 hours was 87±14% and 86±10% of the appliedPage 53 of 73

dose, respectively. The majority (85%) of the 14 C

- label was detected bound to or in the skin.

Thin layer chromatography analysis of bathing solutions collected 48

- 96 hours following dermal

application of 300 ppm aqueous or 300 ppm propylene glycol solutions of 14 C

- RH

- 893 suggested

that none of the small amount of 14 C

- label detected was parent compound.

14 C

- RH

- 893 prepared in propylene glycol (300 and 1000 ppm) was more rea dily wiped off the

skin at 3, 6, and 24 hours compared with the aqueous solutions at the same time intervals.

Dermal bioavailability measured at 24 hours post

- application for the 14 C

- RH

- 893 propylene

glycol solution (300 ppm) was 48±16% of the applied dose . Dermal bioavailability increased to

87±24% to 97±9% between 48

- 96 hours, with the majority of the 14 C

- label detected bound to or

in the skin. Calculated mean values for the 1000 ppm dosing solution prepared in propylene

glycol had similar dermal bioava ilability values.

The majority of the 14 C

- RH

- 893 (1000 ppm) in the six latex emulsions (Amsco 3077, Acronal

290D, AC 64, UCAR 366, AC 490, and UCAR 516) was removed via wiping within 3

- 6 hours

following application. Amsco 3077 and UCAR 516 had the highe st amount of 14 C

- label bound to

or in the skin (30 ±31% at 24 hours and 38±37% at 3 hours, respectively). Dermal

bioavailability of 14 C

- RH

- 893 in each of the emulsifiers was 3

- 25% of the bioavailability

(normalized) of the aqueous solutions of 14 C

- RH

- 893 (300 ppm in water 3

- 6 hours post

application). The majority of the dermally bioavailable 14 C

- label applied in the latex emulsifier

doses was detected in the skin sections. Thin layer chromatography analysis of bathing solutions

associated with the emulsi fier dosing solutions 48

- 96 hours post application indicated that the

small amounts of the 14 C

- label penetrating the skin into the bathing solutions represented parent

compound.

This in vitro dermal absorption study is classified UN ACCEPTABLE

– NON

- GUIDEL INE

. There are no established EPA guidelines for in vitro dermal absorption studies using rat skin.

There are considerable missing data (including raw data) and data inconsistencies in the text of

the report. These deficiencies could be rectified with ap propriate data, making the study

ACCEPTABLE. The Agency does not use in vitro studies for hazard assessment evaluation and

no guideline exists for this type of study



## Immuntoxicity

There is currently no existing immunotoxicity study for OIT. This is a requ ired study and has

been identified as a data gap.



## Metabolism

There are two metabolism studies available. One in non

- bile cannulated rats (MRID 48175501)

and one in bile canulated rats (MRID 47985502)

.

Metabolism in Rats

I n a r a t m e tabolism stu d y ( M R I D 48 17550 1 )

, six g roups of W is t a r r a ts w e r e tr e a ted w i t h 2

- n

o c t y l

- 4

- [ 4,5

- 14 C ] iso t h ia z ol in

- 3

- one ( o c th i l i non e ; r a dioch e m i ca l puri t y > 99.1 % ) in p r o p y le n e

g l y c ol b y o r a l g a v a ge a t a dose volu m e of 5 m L /k g

. Th re e g roups o f f

o u r r a ts / s e x w e re used f

o r

m a ss bal a n c e stud i e s ( G r o u ps 1, 2, a nd 3 )

, a nd th r e e g roups o f th re e r a ts / s e x w e re used f o rPage 54 of 73

t ox icokin e t i c stud i e s ( G roups 4, 5, a nd 6 )

. The r a ts w e re do s e d with sin g le g a v a g e dos e o f

ra dio l a b e led o c th i l i none a t 15 m g/kg ( G roups 1 a nd 4) o r 1 50 m g /k g ( G r oups 2 a nd 5 )

, or w i t h

mu l t i ple dos e s of 15 m g /k g f o r t e n d a y s with un l a

b e led o c t h i l inone, f

ol l ow e d b y a sin g le 15

m g /kg do s e wi t h r a dio l a

b e led o c th i l i none ( G r oups 3 a nd 6 )

. F o r t he mass b a lan c e g roups, u rin e

, f e ce s, a nd volati l e s w e re c ol l ec ted a t 0

- 8, 8

- 24, 24

- 48, 48

- 7 2, a nd 7 2

- 96 hou r s pos t

- dose. The

a ni m a ls w e re then e uthani z e d a t 9 6 hou r s, and blood and tissues c ol l ec ted. T otal r a dioa c t i vi t y

w a s de t e rmin e d in t he urin e

, f ece s, a nd t i ssues, a nd s e le c ted u rine a nd f ece s s a mp l e s w e re pooled

p e r g roup a nd the m e taboli t e p r o f i l e w a s de t e rmin e d. F or the to x icokin e t i c g roups, blood w a s

sampled f rom e ac h r a t at the f

o l l owing t i me points: 0.5, 1, 2, 4, 8, 24, 48, and 72 hou r s pos t

dosin g

, a n d to t a l r a dioa c t i vi t y a nd e quival e nt con ce n t r a t i ons w e re d e te r m i n e d. The a ni m a ls w e r e

e utha n i z e d a t 72 hours.

F ol l owing o r a l admin i str a t i on, the t e st compound w a s w e ll a bsor b e d, re a di l y dis t ribut e d in t o a ll

o r g a ns, a n d e x tensiv e l y met a bol iz e d. E x c r e t i ons of the a dm i nis t e r e d r a d i o ac t i vi t y via the u rine

a nd f e c e s w a s e qu a l l y i m port a nt. M e tabo lism oc c u rr e d a cc o r di n g to t h r e e p a thw a y s. No

qu a l i tative di f

f e r e n ce s in met a bol i te p r o f i l e w e re o bse4 r v e d b e t w ee n low a n d hi g h dos e s or

b e tw ee n si n g le a nd r e p e a ted dosin g

. I n a ddi t ion no d i f fe r e n ce s in m e tabo l i sm w e re obs e rv e d

b e tw ee n the s e x e s. No p a r e nt compound w a s ob s e rv e d in t he urine or fe ce s, ind i ca t i ng e x tensive

met a bol i sm of the t e st compound.

Tot a l r ec o v e r y w a s 93. 7

- 99.8% of the a dm i nis t e red dose ( A D ) ac ross a ll g r oups. Abso r pt i on,

ca lcul a ted a s the sum of t he rec o v e ri e s f r om urin e

, volati l e s, c a g e w a sh, a n d t i ssues/c a r c a ss, w a s

45.5

- 60.9% A D

. T h e re w e re no s e x

- r e lat e d dif fe r e n ce s in a bsorption. O v e r a ll e x c r e t i on w a s

r a pid; the m a

jori t y o f ra d ioa c t i vi t y w a s e x c r e ted d u r ing the fi r st 24 hours in the 15 m g /k g g roups

a nd du r i n g the f

irst 48 h o u r s in t he 150 m g /k g g r o up. S l i g ht l y more r a dio a c t i vi t y w a s e x c r e ted in

the u r i ne than in the f

e ce s. U r i n a r y e x c r e t i on r a n g e d f r om 41.0

- 55.6% A D

, with m o r e

ra dio a c t i vi t y e x c r e ted in the u r ine o f the r e p ea ted d o s e g roup than in the sin g le dose g r oups. The

majo r i t y o f u r ina r y r a dio a c t i vi t y w a s e x c r e ted du r ing t h e fi r st 24 hours in the sin g l e a nd mu l t i ple

dose 15 m g /k g g roups, a nd d u ri n g the f irst 48 hours in the 150 m g / k g g roup. F e ca l e x c r e t i on

r a n g e d f r o m 36. 8

- 48.4% A D

, with more ra dio a c t i vi t y e x c r e ted in the f e ce s of t he 150 m g /k g

g roup than in t he 15 m g / k g g roups. Fe c a l e x c r e t i on w a s d e l a y e d c om p a r e d to uri n a r y e x c r e t i on,

with t he m a

jori t y of r a dio a c t i vi t y e x c r e ted f r om 8

- 48 hours post

- dosin g

. Min o r a moun t s of

ra dio a c t i vi t y w e re d e te c ted in e x h a led a ir in the f o r m of 1 4 C O 2 (≤2.8% A D ). Minor a moun t s of

ra dio a c t i vi t y w e re a lso r ec o v e r e d in the c a g e w a sh (≤1.2% A D ) a nd in t he t i ssues/c a rc a ss (≤1.9% AD ) a t 96 hours pos t

- dose.

At 96 hou r s pos t

- dosin g

, the re si d u a l co n ce ntr a t i o ns of ra dioa c t i vi t y in t he t i ssues a nd r e sidual

ca rc a ss w e re 0.080

- 1.276 mg e quiv. / k g in t he 15 m g / k g sin g le do s e g roup, 0.82 1

- 13.082 mg

e quiv. / kg in t he 150 m g / kg si n g le dose g r oup, a n d 0.09 9

- 1.400 mg e quiv. / kg in t he 15 m g / k g

r e p ea t e d dose g roup. C o n ce ntr a t i ons in the 15 m g/kg si n g le a nd r e p e a ted d ose g ro ups we r e

si m i l a r, w hi l e c on ce nt r a t i ons in the 150 m g /kg g r o up w e re a ppro x i m a te l y o ne ord e r o f

ma g ni t ude h i g h e r. T he o n l y t i ssues w i t h c on ce n t r a t i ons a t or a bove those f ound in b l ood w e re the

l i v e r a nd kidn e y

. The c o n ce ntr a t i ons of r a dioa c t i v i t y in b l ood w e re 1 1

- 14 t i mes hi g h e r th a n

plasma in t he 15 m g / k g g r oups, a nd 6

- 7 t i mes hi g h e r in the 150 m g /k g g r o u p, ind i ca t i ng the t e st

subs t a n c e w a s a ssoci a ted with t he re d blood c e l l s, a nd that th i s asso c iation w a s possib l y

s a tur a ted a t 150 m g / k g

.Page 55 of 73

I n the 15 m g /k g g r oups, t he ma x i m a l p l a sma c on ce ntr a t i ons w e r e ac h i e v e d a t 0. 5

- 1.0 hour pos t

dosing (e x ce pt 4.0 hours for the re p ea t dose m a le s ), indic a t i ng the t e st compound w a s r a pid l y

a bsorb e d a t l ow do s e s. In the 150 m g /k g g roup, ma x i m a l p l a sma c on ce ntr a t i ons w e re a t t a ined a t

8

- 24 hou r s pos t

- dosin g

, i ndic a t i ng slow e r a bsorpt i on a t h i g h e r dos e s. E x a m i n a t i on of the A U C ∞

r e v ea l e d a n in c r e a s e in A UC f r om 15 t o 150 m g /k g that w a s g re a ter than w ould be e x p ec ted w i t h

the in c r e a s e in dose ( 10

- f old e x p ec ted vs. 1 5

- to 21

- fold ob s e rv e d ). T his w a s co n side re d to b e

sug g e st i ve o f e nte r o h e p a t ic rec i r c ulation of the test c ompound and/or met a b ol i tes.

L C/MS a n a l y sis of u r ine iso l a ted up to 18 met a bol i tes, of whi c h 6 w e re id e nt i fi e d. The

r e maining uni d e nt i fi e d u r ina r y m e taboli t e s ea c h a c c ounted f or < 5% o f the d ose, w i t h the

e x ce pt i on of Met a bol i te 13, w hich a c c ounted f or 2. 7

- 8.0% of the dos e

. A to t a l of 27. 3

- 35.2% of

the dose w a s identifi e d in urin e

. An a l y sis of fe ca l e x tr ac ts i solat e d a nd ide n t i fi e d fo u r

met a bol i tes, w hich tog e ther a c c ou nted f o r 17. 0

- 2 3.9% of the dos e

. Cons i d e ring u rine a nd f e c e s,

a to t a l of 46.3

- 52.2% of t he dose w a s identifi e d in e x c r e ta f rom both se x e s a nd eac h dose g r oup.

P a r e nt compound w a s n o t found in e i t h e r u r ine or f e ce s.

The met a bol i sm of o c th i l i none in r a ts pr i m a ri l y f o l l ow e d one of th r e e p a t h w a y s: (i) h y d r o l y t i c

c le a v a ge of the S

- N bond of the iso t hia z ol i none r in g ; (ii) o x idation at the isothia z ol i none r ing a t

e i t h e r the S

- a tom or a t t h e double bond; or ( i i i) o x idation of the o c t y l c h a i n

. P h a se II met a bol i sm

w a s on l y ob s e rv e d a s g lucu r onidation.

This m e tabolism s t u d y in the ra t i s cl a ss i fi e d A cc ep tabl e / G u i d e l in e a nd s a t i sfi e s the g uideline

r e quir e ment f

o r a met a b o l i sm s tu d y [ OP P TS 8 70. 7 485, O E CD 417] in r a ts.

Me taboli s m in Ra t s ( B i l e Du c t c a nnulat e d )

I n a r a t m e tabolism stu d y ( M R I D 47985502 )

, two g roups o f th re e bi l e du c t

- ca nnula t e d ma l e

W is t a r ra ts w e r e tr e a ted with 2

- n

- o c t y l

- 4

- [ 4,5

- 1 4 C ] iso t h ia z ol i n

- 3

- one (o c th i l i non e ; r a dioch e m i ca l

puri t y ≥99. 2 % ) in p r op y le n e g l y c ol b y or a l g a v a ge ( 5 m L / k g dose volu m e ) a t dose l e v e ls of 15 or

150 m g / k g

. B i l e

, u r ine, a nd f ece s w e r e c o l le c ted a t 0

- 8, 8

- 24, a nd 24

- 48 hou r s pos t

- do s in g

. The

r a ts w e re th e n e uthani z e d a t 48 hours pos t

- dose. Tot a l r a dioa c t i vi t y w a s de t e rmin e d in urin e

, bi l e

a nd f e c e s, and samples w e re po o l b y mat r ix f or e a c h g roup for a n a l y si s

. U rine a nd bi l e samples

w e re di l uted a nd then a n a l y z e d dir ec t l y usi n g two

L C/MS methods. Fe c e s w e re e x tr ac ted w i t h met h a nol, and the meth a nol i c e x tr ac ts w e re

a n a l y z e d b y L C/M S

.

Tot a l r ec o v e r y w a s 95. 3 % of the a dm i nis t e r e d d o se ( A D ) for the 15 m g /k g g roup a nd 100.2%

AD f or the 150 m g /

k g g r oup. Abso rpt i on, ca lcul a ted a s the sum of the r ec o v e ri e s f r om u r i n e

, bi l e

, c a g e w a sh, a n d c a rc a ss ( w i t hout t he G I tr a c t )

, w a s 65. 7

- 74.9% A D. O v e r a ll e x c r e t i on w a s

r a pid; the m a

jori t y o f ra d ioa c t i vi t y w a s e x c r e ted d u r ing the fi r st 24 hours in the 15 m g /k g g roup

a nd du r i n g the f

irst 48 h o u r s in t he 150 m g /k g g r o up.

The majo r i t y o f the r a dioa c t i vi t y w a s e x c r e ted in t he urine ( 44

. 2

- 51.5% A D ), w i t h the m a jori t yPage 56 of 73

of urin a r y r a dioa c t i vi t y e x c r e ted du r ing t h e f irst 2 4 hou r s in t he 15 m g / k g g roup, a nd du r i n g the

fi r st 48 hours in the 150 m g / k g g roup. B i l ia r y e x c r e t i on a c c o u nted f o r 19

- 2

- 20.2% AD a nd

follow e d a si m i l a r p a t t e r n a s urin a r y e x c r e t i on. F eca l e x c r e t i on a cc ounted for 23. 1

- 29.2% A D,

a nd w a s del a y e d c omp a r e d to urin a r y e x c r e t i on, with t he majo r i t y of r a d i o ac t i vi t y e x c r e t e d f r om

8

- 48 hou r s pos t

- dosing a t 15 m g /k g

, a n d f rom 24

- 48 hou r s at 150 m g /k g

. Minor a moun t s of

r a dioa c t i vi t y w e r e a lso r e c ov e r e d in t he c a ge w a sh ( 0. 9

- 1.2% A D ) a nd in t h e G I tr a c t / ca r ca ss

(1. 8

- 4.2% A D ).

An a l y sis of t h e pooled bile s a mp l e s i s olat e d 9 to 10 pe a ks of r a dioa c t i vi t y

, d e p e ndi n g on L C/MS

s y stem used. A n a l y sis of the pool e d urine samples iso l a ted 8 or 11 p ea ks of ra dioa c t i vi t y

, a nd

a n a l y sis o f the pooled f

e c a l sampl e s y i e lded on o n e ra dio a c t i vi t y r e g ion. A to t a l of f our b i l ia r y

met a bol i tes, e i g ht urin ar y met a bol i tes, a nd t h r e e f eca l m e t a bol i tes w e re id e nt i fi e d b y L C/M S

. The identifi e d bi l ia r y m e taboli t e s a c c ounted for a ppro x i m a te l y 4 % of the t otal AD in t he bi l e ; t he

identifi e d urin a r y met a b o l i tes acc ounted f o r 2 7

- 3 8 % of the to t a l AD in u r i n e ; and the identifi e d

f e ca l m e t a bol i tes acc oun t e d for 9.2% o f the to t a l AD in f e c e s. B i l e a nd u r ine h a d thr e e

met a bol i tes in c om m on, while u r ine a nd f e c e s had one met a bol i te in c om m on. No p a r e nt w a s

found in t he urin e

, bi l e

, o r fe c e s, indic a t i n g e x tensive met a bol i sm.

B a s e d on t h e stru c tur e s o f the i d e nt i fi e d met a bol i tes, the bio t r a nsfo r mation of the t e st compound

a pp ea r s to inclu d e h y d r o l y t ic c l ea v a ge of the iso t h ia z ol i none r in g

, o x idati o n, a nd trun ca t i on.

Cle a v a g e of t h e iso t hia z ol i none r ing prim a ri l y in v olves h y d r o l y sis of the S

- N bond a nd

c onse q u e nt l oss of the S

- a to m

. O x idation oc c u r s on the iso t hia z ol i none r i ng

, e i t h e r a t t he S

- a tom

or a t t he double bond, or on the n

- o c t y l c h a in. Tr u n ca t i on is main l y obs e r v e d on the a l k y l ch a in.

P h a se II met a bol i sm w a s obse r v e d a s g lu t a th i one a nd N

- ace t y lati o n c onj u g a t i on.

W h e n c onsid e r e d in con

j un c t i on with t he sep a

r a t e Tier 1 met a bol i sm s tu d y on o c th i l i none

(M R I D 4817550 1 ), this m e tabolism s t u d y in b i l e

- du c t c a nnulat e d r a ts i s c l a ss i fi e d

A cce p tabl e / G u i d e l in e a nd s a t i sfi e s the g ui d e l i ne r e quir e ment f o r a me t a b o l i sm s tu d y [ OP P TS

870.7485, OECD 417] in ra ts.Page 57 of 73 

# Appendix B En vironmental Fate

Environmental Fate and Transport Properties of Octhilinone and

transformation product(s), degradate(s)

Water and Sediment

Hydrolysis

Under abiotic and buffered medium, it is hydrolytically stable at the three environmentally

relevant pHs: 5, 7, and 9 at 25 o C (MRID 48358618).

Aqueous Photolysis

It photolyses with half

- life of about 16 days. It is not likely to be stable on surface water. The

study was conducted at 25 o C. F our photodegrad a tes were identified: Octhilinone

- sulfoxide., N

- (n

- octyl)acetam ide; 3

- (n

- octyl)

- 4

- thaizolin

- one and N(n

- octyl) malonami c acid + N

- (n

octyl)formic acid (MRID 48358617).

Octanol

- Water Partition Coefficient

Its log K

ow is 3.4 and this value is a high to trigger bioaccumulation in aquatic organisms

Aerobic Aquatic Metabo lism

No review was conducted on the submitted study . Study will be reviewed when the agency

conducts the fate risk assessment.

A na erobic Aquatic Metabolism

No review was conducted on the submitted study . Study will be reviewed when the agency

conducts th e fate risk assessment.

Soil

Soil Leaching/Adsorption/Desorption Batch Equilibrium

It is immobile to slightly mobile from US soil surfaces. Preliminary review also indicate that it

will not run off from soil surfaces. It is not likely to migrate down into ground water and hence is

not likely to contaminate the ground water. It shows the same trend of non

- migration under

aerobic and anaerobic conditions (MRID 47198001)

.Page 58 of 73

Aerobic Soil Metabolism

Octhilinone metabolizes less than 50% is US soils in 120 days. It is therefore not ready

biodegradable. No data have been submitted on the degradates and their characteristics (MRID

471315005)

.

A na erobic Soil Metabolism

Similar results were obtained under anaerobic conditions

Environmental fate of the degradates:

No e nvironmental fate data have been submitted on the following four photodgradates of

Octhilinone (48358617) :

1) Octhilinone

- sulfoxide

2) N

- (n

- octyl)acetamide

3) 3

- (n

- octyl)

- 4

- thaizolin

- one

4) N(n

- octyl) malonamic acid + N

- (n

- octyl)formic acid

The a gen cy has noted that degradates 1, and 3 above have the skeleton of the parent intact. It is

expected that the environmental risks for these two degradates will be sim ilar to the parent.

Therefore, t he a gency is not anticipating requiring for fate studies on these two degradate.

The agency does not have information on the percentages of degradates 2, and 4. The a gency

would request asking the percentages for these tow degradates to determine if any environmental

fate studies would be required for these tow deg radates.

REFERENCES FOR ENVIRONMENTAL FATE ASSESSMENT

1. Hydrolytic Stability Study of Octhilinone ( 14 C)

- Acticie OIT), 1999, by Dr. T. Lucas

MRID#: 447232

- 01. Submitted by: Acti

- Chem Specialties Inc., 56 Quarry Rd.,

Trumbull, CT: 06611

- 4816. Performing L aboratory: Covance Laboratories GmbH,

Kesselfeld 29, D

- 48163 Munster, Germany. Laboratory Report #: 1509

- 1154

- 069

2. Rohm& Haas Technical Reports on Environmental Fate Studies. Reports#s: 23

- 71

- 4

, 23

-

72

- 3, 3923

- 74

- 38, 3923

- 75

- 3, and 3923

- 75

- 11Page 59 of 73 

# Appendix C E pi Suite (Version 3.12)

Ecotoxicity Profile

Toxicity to Terrestrial Receptors

In order to establish the toxicity of octhilinone to avian species, the a gency requires an acute oral

toxicity study and a subacute dietary study using the technical g rade acti ve ingredient (TGAI). The

preferred

- test species is either mallard duck (a waterfowl) or bobwhi te quail (an upland game bird).

The results of five acute oral toxicity studies and five subacute oral studies submitted for

octhilinone, are provided in the tab les Tables C1 & C2.

Table C1. Acute Oral Toxicity of Octhilinone to Birds

Species Chemical,%

Active

Ingredient

Tested Endpoint

(mg/kg) Toxicity

Category Satisfies

Guidelines/

Comments Reference

(MRID No.)

Bobwhite quail

( Colinus

virginianus ) Octhilinone

98.5% LD 50 = 660

NOAEL = ND

(a.i.) Slightly toxic Yes

- 21

- day

test duration

- 19 weeks of

age 416080

- 01

Bobwhite quail

( Colinus

virginianus ) Octhilinone

95.9% LD 50 = 384

NOAEL = 171

(a.i.) Moderately

toxic Yes

- 14

- day

test duration

- 21 weeks of

age 44 8590

- 01

Bobwhite quail

( Colinus

virginianus ) Octhilinone

88.7% LD 50 = 346

(a.i.) Moderately

toxic Yes 00026809

Bobwhite quail

( Colinus

virginianus ) Octhilinone

RH

- 893

(% purity

unknown) LD 50 = 565

(M) and 498

(F) Slightly

toxic No 86

- 870001877

(Ecotox data)

Mallard duck

( Anas

platyrhynchos ) Octhilinone

RH

- 893

(% purity

unknown) LD 50 > 1000 Slightly

toxic No 86

- 870001877

(Ecotox data)Page 60 of 73

Table C2. Subacute Oral Toxicity of Octhilinone to Birds

Species Chemical,

% Active

Ingredient

(a.i.)

Tested Endpoint

(mg/kg) Toxicity

Category Satisfies Guidelines/

Comments Reference

(MRID

No.)

Bobwhite quail

( Colinus

virginianus) Octhilinone

98.5% LC 50 (diet) =

>3267

NOAEC =

1288

(a.i.) Slightly

toxic Yes

- 8

- day test duration

- 11 weeks of age 41608 0

- 02

Bobwhite quail

( Colinus

virginianus) Octhilinone

96% LC 50 (diet) =

2542

NOAEC =

310

(a.i.) Slightly

toxic No

- 12

- day test duration

- 10 days of age

- control mortality

20%

- inadequate housing 439357

- 01

Bobwhite quail

( Colinus

virginia nus) Octhilinone

88.7% LC 50 (diet)

>5620

(a.i.) Relatively

nontoxic Yes

- 8

- day test duration 00026808

Mallard duck

( Anas

platyrhynchos) Octhilinone

98.5% LC 50 (diet) =

1215

NOAEC =

ND

(a.i.) Slightly

toxic Yes

- 8

- day test duration

- 5 days of ag e 416080

- 03

Mallard duck

( Anas

platyrhynchos) Octhilinone

88.7% LC 50 (diet) =

>5620

(a.i.) Relatively

nontoxic Yes 00026807

Three acceptable acute oral toxicity studies on the Bobwhite quail (416080

- 01, 448590

- 01, 00026809) indicate that octhilinone is moderately to

slightly toxic on an acute oral basis. The guideline requirement OPPTS 850.2100 is satisfied.

The results from four acceptable studies (416080

- 02, 00026808, 416080

– 03, and 00026807) indicate that octhilinone is slightly to relatively non

t oxic to avian species through subacute dietary exposure. These studies fulfill guideline requirements OPPTS 850.2100/Bobwhite quail and

Mallard duck).

Mammals : Wild mammal testing is not required by the a gency . In most cases, rat and mice

toxicity valu es obtained from studies conducted to support data requirements for human health

risk assessments are substituted for wild mammal testing. Refer to the human toxicology chapter

of this Reg Review for the mammalian toxicity data summary.

Beneficial Insects : No studies were submitted. Honey bees could be exposed to OIT if the

wood used to construct beehives contains OIT. Therefore , one honeybee stud y, OPPTS

850.3020

, is anticipated to be required for OIT

.

Terrestrial Plants : A seedling emergence study w as submitted testing the effects of OIT on

Wheat, Rape and Lettuce. The results indicated emergence, survival, dry weight and lengthPage 61 of 73

were significantly affected in all three crop species. The most sensitive endpoints are presented

in Table C3 . This st udy fulfills guideline requirements OPPTS 850.4225.

Table C3. Toxicity of Octhilinone to Terrestrial Plants

Species Chemical, %

Active Ingredient

(a.i.) Tested Endpoint (mg/L) Satisfies Guidelines/

Comments Reference

(MRID No.)

Seedling Emergence

and Gr owth Test

Wheat ( Triticum

aestivum ), Lettuce

( Lactuca sativa ), and

Rape ( Brassica

napus ) OIT 100% Wheat (dry weight)

EC 25 =22 mg ai/kg,

NOEC= 22 mg ai/kg

Rape(dry weight)

EC 25 =14 mg ai/kg

NOEC=22 mg ai/kg Yes 483586

- 20

Toxicity to Aquatic Receptors

Fres hwater Fish : In order to establish the acute toxicity of octhilinone to freshwater fish, the

a gency requires freshwater fish toxicity studies using the TGAI. The preferred test species are

rainbow trout (a coldwater fish) and bluegill sunfish (a warmwate r fish). The results of 9

freshwater fish acute studies submitted for octhilinone, 3 coldwater and 6 warmwater, are

presented in Table C4.

Table C4. Acute Toxicity of Octhilinone to Freshwater Fish

Species Chemical,

% Active

Ingredient

(a.i.)

Tested Endpoint

(mg/L) Toxicity

Category Satisfies Guidelines/

Comments Reference

(MRID

No.)

Rainbow Trout

(O ncorhynchus

mykiss ) Octhilinone

96% LC 50 = 0.05

LOEC = 0.05

NOEC = <

0.05

(a.i.) Very highly

toxic No

- 96

- hr test duration

- static renewal test

system

- toxic effects and

death at all

treatment levels

- small aquaria 439357

- 02

Rainbow Trout

(O ncorhynchus

mykiss

, formerly

Salmo

gairdneri ) Octhilinone

90% LC 50 = 0.0655

(a.i.) Very

Highly

toxic No

- 96

- hr test duration

- static test system 00026805

Bluegill

sunfish Octhilinone

98.5% LC50 = 0.18

(a.i.) Highly

toxic Yes 416080

- 04Page 62 of 73

( Lepomis

macrochirus ) - 96

- hr

- flow

- through test

system

Bluegill

sunfish

( Lepomis

macrochirus ) Octhilinone

96% LC 50 = 0.16

NOAEC =

0.07

(a.i.) Hig hly

toxic Yes

- 96

- hr test duration

- static renewal test

system 439357

- 03

Bluegill

( Lepomis

macrochirus ) Octhilinone

90% LC 50 = 0.196

(a.i.) Highly

toxic No

- 96

- hr test duration

- static test system 00026805

Redear

( Lepomis

macrochirus ) Octhilinon e

90% LC 50 = 0.203

(a.i.) Highly

toxic No

- 96

- hr test duration

- static test system 00026805

Fathead

minnow

( Pimephales

promelas ) Octhilinone

90% LC 50 = 0.140

(a.i.) Highly

toxic No

- 96

- hr test duration

- static test system 00026805

Golden shiner

( Notemigonus

crysoleucas ) Octhilinone

90% LC 50 = 0.154

(a.i.) Highly

toxic No

- 96

- hr test duration

- static test system 00026805

Freshwater acute toxicity tests indicate that octhilinone is very highly toxic to the coldwater fish

Rainbow trout and h ighly toxic to the warmwater fish Bluegill sunfish on an acute basis. Study

416080

- 05 fulfills the guideline requirement for the coldwater species and studies 439357

- 03 and

416080

- 04 fulfill the guideline requirement for a warmwater fish species under OPP TS 850.1075

(72

- 1a&b). Because acute toxicity to fish is <1.0 mg/L the environmental hazard section of

octhilinone labels must state: “This pesticide is toxic to fish.”

Freshwater Invertebrates : The a gency requires a freshwater aquatic invertebrate study using

the TGAI to establish the acute toxicity to freshwater invertebrates. The preferred test species is

Daphnia magna . The results of three studies submitted for octhilinone are provided in the

following table (TableC5).Page 63 of 73

Table C5. Acute Toxicity of Octhilinone to Freshwater Invertebrates

Species Chemical,

% Active

Ingredient

(a.i.)

Tested Endpoint

(mg/L) Toxicity

Category Satisfies Guidelines/

Comments Reference

(MRID

No.)

Waterflea

( Daphnia

magna ) Octhilinone

98.5% EC 50 =273

ug/L

NOAEC=193

ug/L Very highly

toxic Yes 483586

- 19

Waterflea

( Daphnia

magna ) Octhilinone

98.5% EC 50 = 0.32

NOAEC =

0.21 (a.i.) Highly

toxic Yes

- 48

- hr test duration

- flow

- through test

system 416080

- 06

Waterflea

( Daphnia

magna ) Octhilinone

96% EC 50 = 0.107

NOAEC =

0.055

(a.i.) Highly

toxic No

- 48

- hr test duration

- static test system

- total hardness

above guideline

- small test aquaria 439357

- 04

Waterflea

( Daphnia

magna ) Octhilinone

88.7% LC 50 = 0.18

(a.i. ) Highly

toxic Yes

- 48

- hr test

duration

- static test system 00026806

(Ecotox

data No.

86

-

870001884

)

The results of two core studies (416080

- 06 and 00026806) indicate that octhilinone is highly

toxic to freshwater invertebrates. These studies fulfill guideline requirement OPPTS 85 0.1010

(72.2a). Because the acute aquatic invertebrate toxicity value is < 1.0 mg/L, the environmental

hazard section of octhilinone labels must state: “This pesticide is toxic to aquatic invertebrates.”Page 64 of 73

Estuarine and Marine Organisms : Acute toxicity tes ting with estuarine and marine organisms

using the TGAI is required when the end

- use product is intended for direct application to the

marine/estuarine environment or effluent containing the active ingredient is expected to reach

this environment. The pre ferred fish test species is the sheepshead minnow. The preferred

invertebrate test species are Mysid shrimp and Eastern oyster. This testing is required for

octhilinone based on the chemical’s potential to reach estuarine and marine environments. The

re sults of toxicity studies submitted for octhilinone are presented in Table C6.

Table C6. Acute Toxicity of Octhilinone to Estuarine and Marine Organisms

Species Chemical,

% Active

Ingredient

(a.i.)

Tested Endpoint

(mg/L) Toxicity

Category Sat isfies Guidelines/

Comments Reference

(MRID

No.)

Sheepshead

minnow

( Cyprinodon

variegatus ) Octhilinone

98.5% LC 50 = 0.16

NOAEC =

0.0.054

(a.i.) Highly

toxic Yes

- 96

- hr test duration

- flow

- through test

system 416080

- 07

Mysid shrimp

( Mysidopsis

bahia ) Octhilinone

98.5% LC 50 = 0.071

NOAEC =

<0.034

(a.i.) Very highly

toxic Yes

- 96

- hr test duration

- flow

- through test

system 416080

- 08

Eastern oyster

( Crassostrea

virginica ) Octhilinone

98.5% LC 50 >0.057

EC 50 <0.013

NOAEC <

0.003 Very highly

to xic Yes

- 96

- hr test duration

- flow

- through test

system 417007

- 01

The results of the three acceptable studies indicate that octhilinone is highly toxic to

estuarine/marine fish and very highly toxic to the estuarine/marine invertebrates shrimp and

oys ters on an acute basis. The sheepshead minnow study (416080

- 07) fulfills the guideline

requirement OPPTS 850.1075/(72

- 3a) for an acute estuarine/marine fish study. The Mysid

shrimp study (416080

- 08) fulfills the guideline requirement OPPTS 850.1035/(72

- 3 c) for an

estuarine/marine shrimp study. The Eastern oyster study (417007

- 01) fulfills the guideline

requirement OPPTS 850.1025/(72

- 3b) for an acute estuarine/marine mollusk study. Because

estuarine/marine aquatic fish, mollusk, and shrimp acute toxicity values are < 1.0 mg/L, the

environmental hazard section of octhilinone labels must state: “This pesticide is toxic to oysters

and shrimp.”Page 65 of 73

Chronic Toxicity of Aquatic Organisms : C hronic toxicity testing (fish early life stage and

aquatic invertebrate lif

e cycle) is required for pesticides when certain conditions of use and

environmental fate apply. The preferred freshwater fish test species is the fathead minnow. The

preferred freshwater invertebrate is Daphnia magna . This testing is required for octhil inone. The

results of two toxicity studies submitted for octhilinone are presented in Table C7.

Table C7. Chronic Toxicity of Octhilinone to Freshwater Organisms

Species Chemical, %

Active

Ingredient

(a.i.) Tested Endpoint

(mg/L) Toxicity Category Satisfies

Guidelines/

Comments Reference

(MRID No.)

Fathead

Minnow

( Pimephales

promelas ) Octhilinone

98.5% LOAEC = ND

NOAEC = ND

MATC >8.5

and < 0 .018;

0.012 geo.

Mean

(a.i.) No

- 35

- day test duration

- early

- life stage

- flow

- through test system

- relative S.D. for fish weight in

one control replicate

unacceptable (53%)

Waterflea

( Daphnia

magna ) Octhilinone

98.5% NOAEC =

0.074

(a.i.) No

- 21

- day test duration

- life

- cycle

- flow

- through test system

- MATC could not be

determine

- raw data missing

The fathead minnow study (419093

- 01) does not fulfill the guideline requirement for a fish early

life stage toxicity test (72

- 4a/OPPTS 850.1400) due to missing raw data. The study on the

waterflea (41909 4

- 01) also does not fulfill the guideline requirement for a chronic aquatic

invertebrate because the maximum allowable toxicant concentration (MATC) could not be

determined (>0.074 mg/L).

Aquatic Plants : Non

- target plant phytotoxicity testing is require d for pesticides when certain

conditions of use and environmental fate apply. Octhilinone use as an antisapstain wood

treatment may result in chemical leachate from treated wood into the aquatic environment.

Aquatic plant toxicity data are necessary for a non

- target plant risk assessment. Testing is

conducted with one species of aquatic vascular plant ( Lemna gibba ) and four species of algae:

(1) freshwater green alga, Selenastrum capricornutum, (2) marine diatom, Skeletonema

costatum, (3) freshwater dia tom, Navicula pelliculosa, and (4) bluegreen cyanobacteria,

Anabaena flos

- aquae.

Freshwater aquatic plant growth studies, that evaluated the toxicity of octhilinone to freshwater

green algae, freshwater diatom, marine algae, marine diatom, bluegreen cyan obacteria, and an

aquatic vascular plant, were reviewed. Results of this studies are presented in Table 7.Page 66 of 73

Table C8. Toxicity of Octhilinone to Aquatic Plants

Species Chemical,

% Active

Ingredient

(a.i.) Tested Endpoint (mg/L) Satisfies

Guidelines/

Com ments Reference

(MRID

No.)

Aquatic vascular

plant ( Lemna

gibba G3) OIT

100.0% EC 50 =280 ug/L

(dry weight biomass)

NOAEC=<62 ug/L (dry

weight biomass) Yes 485574

- 04

Marine Diatom

( Skeletonema

costatum ) OIT 99.9% IC 50 =1.6 ug/L (growth

rate)

NOAEC=1.5 ug/L ( growth

rate) Yes 483588

- 22

Freshwater

Diatom

( Navicula

pelliculosa ) OIT

100.0% IC 50 =0.61 ug/L (biomass)

NOAEC=<0.143 ug/L

(biomass) Yes 485574

- 05

Freshwater

Green Algae

( Pseudokirchner

iella

subcapitata ) OIT 98.5% IC 50 =58 ug/L (cell density)

NOAEC=1.42 ug/L (cell

density) Yes 483586

- 21

Bluegreen

cyanobacteria

( Anabaena

aquae ) OIT 97.8% IC 50 =69 ug/L (cell density)

NOAEC=35.1 ug/L (cell

density) Yes 485574

- 06

Green alga

( Selenastrum

capricornutum) Octhilinone

99.2% EC 50 (120

- hour, cell

density) = 0.015)

NOEC (120

- hour cell

density) = <0.011 Yes

- growth

inhibition

- 120

- hr test

duration

- static test system 440710

- 01

All of the aquatic plant studies were classified as acceptable and fulfills the guideline requirements

for non

- target plant studies (850.4 400 & 850.5400). Plants are the most sensitive species to

octhilinone.Page 67 of 73

V. REFERENCES

00026805. 1979. Bioassay Report: Acute Toxicity of RH

- 893 Technical to Five Species of

Freshwater Fishes. Unpublished data. Conducted by Bionomics, Inc. for Rohm and Haas

Company.

00026806. 1979. Acute Toxicity of RH

- 893 Technical to the Water Flea (Daphnia magna). Lab

Report No. BW

- 79

- 7

- 503. Unpublished data. Conducted by Bionomics, Inc. for Rohm and Haas

Company.

00026807. 1979. Eight

- day Dietary LC 50

– Mallard Duck RH

- 893 Technical (79P

- 251) Final

Report. Unpublished data. Conducted by Wildlife International. Ltd. for Rohm and Haas

Company.

00026808. 1979. Eight

- day Dietary LC 50

– Bobwhite Quail RH

- 893 Technical (79P

- 253) Final

Report. Unpublished data. Conducted by Wildlife International. Ltd. for Rohm and Haas

Company.

00026809. 1979. Acute Oral LD 50

– Bobwhite Quail RH

- 893 Technical (79P

- 252) Final Report.

Unpublished data. Conducted by Wildlife International. Ltd. for Rohm and Haas Company.

86

- 870001877 . Gough, B.J. and T.E. Shellenberger. 1971. Acute Toxicological Evaluation of

Fungicide with Wildlife. Final Report. Unpublished Data. Conducted by Gulf South Research

Institute for Rohm and Haas Company.

MRID 416080

- 01. Pedersen, C.A.. 1990. Octhilinone

– 21

- Day Acute Oral LD50 Study in

Bobwhite Quail. Rohm and Haas Report No. 90RC

- 0020. Unpublished data. Conducted by Bio

Life Associates, Ltd. for Rohm and Haas Company.

MRID 416080

- 02. Pedersen, C.A.. 1990. Octhilinone

– 8

- Day Acut e Dietary LC50 Study in

Bobwhite Quail. Rohm and Haas Report No. 90RC

- 0021. Unpublished data. Conducted by Bio

Life Associates, Ltd. for Rohm and Haas Company.

MRID 416080

- 03. Pedersen, C.A.. 1990. Octhilinone

– 8

- Day Acute Dietary LC50 Study in

Mallar d Ducklings. Rohm and Haas Report No. 90RC

- 0022. Unpublished data. Conducted by

Bio

- Life Associates, Ltd. for Rohm and Haas Company.

MRID 416080

- 04. Sousa, J.V. 1990. Octhilinone

– Acute Toxicity to Bluegill ( Lepomis

macrochirus ) Under Flow

- Through Con ditions. Lab Report No. 90

- 7

- 3375. Unpublished data.

Conducted by Springborn Laboratories for Rohm and Haas Company.

MRID 416080

- 05. Sousa, J.V. 1990. Octhilinone

– Acute Toxicity to Rainbow Trout

( Oncorhynchus mykiss ) Under Flow

- Through Conditions. La b Report No. 90

- 7

- 3367.

Unpublished data. Conducted by Springborn Laboratories for Rohm and Haas Company.Page 68 of 73

MRID 416080

- 06. McNamara, P.C. 1990. Octhilinone

– Acute Toxicity to Daphnids ( Daphnia

magna ) During a 48

- Hour Flow

- Through Exposure. Lab Report N o. 90

- 6

- 3350. Unpublished

data. Conducted by Springborn Laboratories for Rohm and Haas Company.

MRID 416080

- 07. Sousa, J.V. 1990. Octhilinone

– Acute Toxicity to Sheepshead Minnow

( Cypridon variegatus ) Under Flow

- Through Conditions. Lab Report No. 90

- 7

- 3375.

Unpublished data. Conducted by Springborn Laboratories for Rohm and Haas Company.

MRID 416080

- 08. Sousa, J.V. 1990. Octhilinone

– Acute Toxicity to Mysid Shrimp

( Mysidopsis bahia ) Under Flow

- Through Conditions. Lab Report No. 90

- 7

- 3383. Unpubli shed

data. Conducted by Springborn Laboratories for Rohm and Haas Company.

MRID 417007

- 01. Dionne, E. 1990. Mollusc 96

- Hour Flow

- Through Shell Deposition

Study.Unpublished data. Conducted by Springborn Laboratories, Inc. for Rohm and Haas

Company.

MRID 419093

- 01. Sousa, J.V. 1991. Octhilinone

– Toxicity Test with Fathead Minnow

(Pimephales promelas) Embryos and Larvae. Lab. Report No. 90

- 10

- 3525. Unpublished data.

Prepared by Springborn Laboratories, Inc. for Rohm and Haas Company.

MRID 419094

- 01. McNamara, P.C. 1991. Octhilinone

– The Chronic Toxicity to Daphnia

magna Under Flow

- Through Conditions. Lab Report No. 90

- 09

- 3473. Unpublished data.

Prepared by Springborn Laboratories for Rohm and Haas Company.

MRID 439357

- 01. Wyness, L.E. 1995. N

- Oc tylisothiazolone (OIT): Subacute Dietary Toxicity

LC50 to Bobwhite Quail. Lab Project No. 1154/45. Unpublished data. Conducted by Corning

Hazleton (Europe) for Thor Americas, Inc.

MRID 439357

- 02. Wyness, L.E. 1995. N

- Octylisothiazolone (OIT): Acute Tox icity to

(Oncorhynchus mykiss). Lab Project No. 1154/47. Unpublished data. Conducted by Corning

Hazleton (Europe) for Thor Chemicals Ltd. (UK).

MRID 439357

- 03. Wyness, L.E. 1995. N

- Octylisothiazolone (OIT): Acute Toxicity to

(Lepomis macrochirus). La b Project No. 1154/46. Unpublished data. Conducted by Corning

Hazleton (Europe) for Thor Chemicals Ltd. (UK).

MRID 439357

- 04. Wyness, L.E. 1995. N

- Octylisothiazolone (OIT): Acute Toxicity to

(Daphnia magna). Lab Project No. 1154/48. Unpublished data. Conducted by Corning Hazleton

(Europe) for Thor Chemicals Ltd. (UK).

MRID 439357

- 04. Wyness, L.E. 1995. N

- Octylisothiazolone (OIT): Reproduction Test with

(Daphnia magna). Lab Project No. 1154/48. Unpublished data. Conducted by Corning Hazleton

(Euro pe) for Thor Chemicals Ltd. (UK).Page 69 of 73

MRID 440710

- 01. Hoberg, J.R. 1996. Octhilinone

– Acute Toxicity to the Freshwater Green

Alga, Selenastrum capricornutum. Lab Report No. 95

- 12

- 6255. Unpublished data. Conducted

by Springborn Laboratories, Inc.

MRID 44 8590

- 01. Rodgers, M. 1999. Acticide OIT: Acute Oral Toxicity (LD 50 ) to Bobwhite

Quail. Lab Project No. THR 053. Unpublished data. Conducted by Huntingdon Life Sciences,

Ltd. For Thor Chemie GmbH/Acti

- Chem Specialties, Inc.

MRID#: 447232

- 01. Hydrolytic Stability Study of Octhilinone ( 14 C)

- Acticie OIT), 1999, by Dr.

T. Lucas Submitted by: Acti

- Chem Specialties Inc., 56 Quarry Rd., Trumbull, CT: 06611

- 4816.

Performing Laboratory: Covance Laboratories GmbH, Kesselfeld 29, D

- 48163 Munster,

Germany. Labora tory Report #: 1509

- 1154

- 069

MRID# 48557

- 04. Porch, J.R., Kendell, T.Z., Krueg Rohm& Haas Technical Reports on

Environmental Fate Studies. Reports#s: 23

- 71

- 4

, 23

- 72

- 3, 3923

- 74

- 38, 3923

- 75

- 3, and 3923

- 75

-

11

EPI SUITE (Version 3.12)

MRID# 485574

- 04. Porch, J,R, Kendall, T.Z., Krueger, H.O . 2011. Kathon 893 Biocide: A 7 Day

Static

- Renewal Toxicity Test with Duckweed ( Lemna gibba G3). An unpublished study

performed by Wildlife International, Ltd, Easton, Maryland. Project number 103A

- 151. Study

sponsored by Th e Dow Chemical Company, Midland, Michigan. Sponsor study number

100202. Study initiated 10 February 2011 and completed 21 June 2011.

MRID# 485574

- 05. Porch, J.R., Kendall, T.Z., Krueger, H.O. 2011. Kathon 893T Biocide: A 96

- Hour Toxicity Test with the Fres hwater Diatom ( Navicula pelliculosa ). An unpublished study

performed by Wildlife International, Ltd., Easton, Maryland. Laboratory study number 103A

150. Study sponsored by the Dow Chemical Company, Midland, Michigan. Sponsor study

number 100201. Study ini tiated 02 March 2011 and completed 21 June 2011.

MRID# 485574

- 06. Porch, J.R., Kendall, T.Z., Krueger, H.O. 2011. Kathon 893T Biocide: A 96

- Hour Toxicity Test with the Freshwater Alga ( Anabaena flos

- aquae ). An unpublished study

performed by Wildlife Inter national, Ltd., Eason, Maryland. Laboratory study number 103A

149A. Study sponsored by The Dow Chemical Company, Midland, Michigan. Sponsor study

number 100200. Study initiated 15 November 2010 and completed 21 June 2011.

MRID# 483586

- 19. Marino, T.A., Naj ar, J.R., Carr, M.S. 2008. OIT 100: An Acute Toxicity Study

with the Daphnid, Daphnia magna. An unpublished study performed by Toxicology &

Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan.

Laboratory project study ID: 071 114. Study sponsored by The Dow Chemical Company, Dow

Biocides, Midland, Michigan, and Chemipol, S.A., Barcelona, Spain. Study completed 17

December 2008.

MRID# 483586

- 20. Buche, C. 2005. Terrestrial (non

- target) plant test with 2

- N

- octyl

- 4

-

isothiazolin

- 3

- one (OIT): Seedling Emergence and Seedling Growth Test. Unpublished study

performed by RCC Ltd., Itingen, Switzerland. RCC Study Number: 857453. Study sponsored

by Thor GmbH, Speyer, Germany. Study completed November 30, 2005.Page 70 of 73

MRID# 483586

- 21. Hancock , G.A., Carr, M.S., Najar, J.R. 2008. OIT 100: Growth Inhibition test

with the Freshwater Green Alga, Pseudokirchneriella subcapitata . Study performed by

Toxicology & Environmental Research and Consulting, The Dow Chemical Company,

Midland, Michigan. Labo ratory Project Study ID: 071113. Study sponsored by The Dow

Chemical Company, Dow Biocides, Midland, Michigan, and Chemipol S.A., Barcelona,

Spain. Study completed 13 March 2008.

MRID# 483586

- 22. Seyfried, B. 2007. 2

- n

- Octyl

- 4

- isothiazolin

- 3

- one (OIT): Tox icity to

Skeletonema costatum (Marine Algae) in a 96

- Hour Algal Growth Inhibition Test. Study

performed by RRC Ltd, Environmental Chemistry and Pharamanalytics, Switzerland. Study

number 857450. Study sponsored by THOR GmbH, Germany. Study completed 22 Ja nuary

2007.Page 71 of 73



# Appendix D S creening Level

Down

- the

- Drain Analysis

The Down

- the

- Drain (DtD) module of E

- FAST (Exposure and Fate Assessment Screening Tool),

[version 2] was used to screen for the potential for aquatic organisms downstream of domestic

waste water treatment plants to be exposed to Octhilinone (OIT) and its degradates. The Down

the

- Drain module uses daily per capita release of household wastewaters, stream dilution factors,

and wastewater treatment plant removal efficiency to provide both high

- end and median

(average) time

- averaged surface water concentrations of chemicals discharged by domestic

wastewater treatment plants. The high

- end scenario uses surface water concentrations

downstream of domestic wastewater treatment plants based on the 10 th percentile stream dilution

factor (SDF); the average scenario uses surface water concentrations based on the 50th percentile

SDF. SDF is defined as the ratio of the stream flow downstream of a wastewater treatment plant

to the wastewater treatment plan t flow. Inputs used to run the DtD module included

concentrations of concern (COCs) for aquatic organisms, percent removal during wastewater

treatment, and hypothetical wastewater treatment plant influent volumes. The results of the DtD

module are express ed as number of days of exceedance of COCs for aquatic organisms. COCs

are grouped into 3 categories: acute, endangered/listed, and chronic. Acute COCs for freshwater

fish and invertebrates were derived by dividing LC50 values for freshwater organisms by 2.

Endangered/listed COCs for freshwater fish and invertebrates were derived by dividing LC50

values by 20. EC50 values for plants were used to establish acute COCs for plants. NOAEC

values for plants were used to establish endangered/listed COCs for pl ants. Chronic COCs for

freshwater fish and invertebrates are based on NOAEC values. For acute and endangered listed

COCs, there may be potential concern for freshwater organisms if the COC is exceeded for 1 day

or more. For chronic COCs, there may be po tential concern for freshwater organisms if the COC

is exceeded 20 days or more.

The Down

- the

- Drain module was first run using a high

- end scenario assuming a percentage of

production volume and 0% removal sorption or degradation to determine whether the mo del

predicted exceedances of concentrations of concern.Page 72 of 73 

# Appendix E P roduct Chemistry

Octhilinone product chemistry information is summarized in Table E1 (source: MRID No.

41687801).

Table E1

– Product Chemistry of Octhilinone

Guideline

No. Physical and Chemical

Properties Octhilinone

830.1800 Enforcement analytical

method High Pressu re Liquid Chromatography (HPLC)

Capillary Gas Chromatography

830.6302 Color Light golden yellow; Yellow to light brown.

830.6303 Physical State Clear liquid at 25 o C.

830.6304 Odor Very weak, sharp smell; Characteristic of aromatic compounds.

830.6313 Stability to normal and

elevated temperature,

metals/metal ions Stable at room temperature (25 o C). No degradation observed for 14 days at

54 o C. Stable to sunl ight, metal (mild steel) and metal ion (ferric chloride)

.

830.6314 Oxidation/Reduction Not required. Does not contain an oxidizing or reducing agents

.

830.6315 Flammability Not flammable

Flash point (closed cup) >175 o F

830.6316 Explodability Not explosi ve

830.6320 Corrosion Characteristic Corrosive to metals (aluminum, tin and steel); non

- corrosive to polyethylene

containers

.

830.7000 pH <0.1% soluble in water. Test is not applicable. The test material is <0.1%

soluble in water and the test material does not dissociate into Bronsted Acid

Base ions (no measurable pH). Because of these reasons, this test is not

applicable to the test material.

830.7050 UV/Visible Absorption Absorption max. at 280 nm

830.7100 Viscosity 56 cps at 25°C; 61.255 (20 ° C)

830.7200 Melting point Not applicable. The test material is a liquid at room temperature.

830.7220 Boiling point 133 ° C at 2.3 x 10

- 2 mm Hg r; No degradation

. 116°C/0.005 mm Hg; 128

- 130°C /0.4 mm Hg

830.7300 Density 1.036 g/ml

830.7370 Dissociat ion Constant This test is not applicable since the test substance does not dissociate into

ions.

830.7550 Partition coefficient ( n

octanol/water) 4.4 (PAI)

830.7840 Solubility in water at 25oC 481 mg/L ( 481 ppm ) at 25 o C

830.7860 Solubility in organic

solvents at 25oC Most organics

- 50% (aromatics, alcohols, ethers, etc.)

Ethyl acetate

- 940g/L

Methanol

- 840 g/L

Toluene

- 800 g/L

Hexane

- 640 g/L

830.7950 Vapor p ressure at 25 ° C 3.68 x 10

- 5 to 4 x 10

- 6 mm HG at 25 ° C (PAI)

PAI = Pure Active IngredientPage 7 3 of 73 

# Appendix F P ublic Comments

A letter from the Physician s Committee for Responsible Medicine (PCRM) was submitted to the

docket with the following requests or com ments:

1) For GLN 870.1300 Acute Inhalation Toxicity study, the PCRM refers the agency to a

study entitled “Acute Inhalation Exposure in Rats (final report)” conducted by Hazleton

Laboratories. Also, two additional studies are referenced in the California DP R database.

Agency Response: The acute inhalation toxicity study data requirement remains and it is up

to the company to point out or re

- submit acute inhalation studies if conducted by them.

2) For GLN 870.4100 Chronic Oral Toxicity and 870.4200 Carcinogenic ity Studies , the

PCRM would like to ensure that both the chronic oral toxicity and carcinogenicity data

requirements are fulfilled with GLN 870.4300 Combined Chronic

Toxicity/Carcinogenicity Study instead of the two individual guideline requirements.

Agenc y Response: A footnote was added to Table 6

- Studies Anticipated as Needed for the

Registration Review of OIT noting that s tudies which are designed to simultaneously fulfill

the requirements of both the chronic oral and carcinogenicity studies ( i.e. , a combined study)

may be conducted

.

3) For GLN 870.3200 21/28 Day Dermal Toxicity study , the PCRM requests that this study

be removed because there is an existing study in the Octhilinone database that satisfies

the requirements for a 90

- day dermal toxicity st udy in rats (870.3250 90

- day Dermal

Toxicity in Rats ).

Agency Response: GLN 870.3200 21/28 Day D ermal Toxicity study wi ll be removed and

the lower dermal irritation LOAEL will be added along with an uncertainty factor.