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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 General Counsel

Philip Ross
Docket Number EPA-HQ-OPP-2014-0160

www.regulations.gov

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TERMS, ABBREVIATIONS AND SYMBOLS

AD Antimicrobials Division

A.I. or a.i. active ingredient

aPAD acute population adjusted dose 

ASRI activated sludge respiration inhibition

atm-m

3

/mole atmospheric pressure-cubic meter per mole

BCF bioconcentration factor 

°C degrees Celsius

CAS Chemical Abstracts Service 

CFR Code of Federal Regulations 

CHO Chinese hamster ovary

CMA Chemical Manufacturers Association

CO2 carbon dioxide

COC concentration-of-concern

cPAD chronic population adjusted dose 

CS2 carbon disulfide

DCI data call-in

EC50 median (or 50 percent) effect concentration

EC05 5 percent effect concentration

ECOTOX ECOTOXicology

EDI estimated daily intake

EDSP Endocrine Disruptor Screening Program 

E-FAST Exposure and Fate Assessment Screening Tool

EPI Suite Estimation Program Interface Suite

EPA Environmental Protection Agency

FDA Food and Drug Administration 

FFDCA Federal Food, Drug, and Cosmetic Act

FGD flue-gas desulfurization

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act 

FWP Final Work Plan

g/mol grams per mole

GLN guideline number

HPV high production volume

IDS Incident Data System 

Koc organic carbon normalized soil-water partition coefficient

Kd soil-water partition coefficient

Kow octanol-water partition coefficient

LC50 median (or 50 percent) lethal concentration

LD50 median (or 50 percent) lethal dose

LOAEC lowest-observed-adverse-effect-concentration 

LOEC lowest-observed-effect-concentration

LOAEL lowest-observed-adverse-effect-level

Log Kow logarithm of the octanol-water partition coefficient

μg microgram

ml/g milliliter per gram

mg/kg milligram per kilogram

mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury
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MOE margin of exposure 

MRID Master Record Identification Number

MRL maximum residue limit 

N/A not applicable

nm nanometers

NOAEC no-observed-adverse-effect-concentration

NOAEL no-observed-adverse-effect-level

OCSPP Office of Chemical Safety and Pollution Prevention

OECD Organization for Economic Co-operation and Development

OPP Office of Pesticide Programs

PAD population adjusted dose

PAI pure active ingredient

PDM Probabilistic Dilution Model

% percent

PC Code Pesticide Chemical Code

PCF pounds per cubic foot

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

PHED Pesticide Handler’s Exposure Data

PIS primary irritation score

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

dissociation constant of a solution

ppb parts per billion 

ppm parts per million

PWP Preliminary Work Plan

QSAR quantitative structure-activity relationship

RED Reregistration Eligibility Decision

SAR structure activity relationship

SF safety factor

SSTS Section Seven Tracking System

TEP typical end-use product

TGAI technical grade active ingredient

TMDL total maximum daily loads

UF uncertainty factor

UV/VIS ultraviolet/visible light absorption

% w/w percent weight per weight.

WP wettable powder

WWTPs wastewater treatment plants
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Table of Contents

1 Introduction............................................................................................................................. 8

1.1 Statutory and Regulatory 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 History ......................................................................................................... 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 Environmental Fate Assessment .................................................................................... 25

4.1.1 Leaching Wood/Paint/Antifoulant Paint/Plastic/Textiles/e.g., treated article ........ 25

4.1.2 Water 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............................................................................................................................. 29
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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 Endpoints for Assessing for OIT ORE Exposures (2007 RED)............ 19

Table 8 – Occupational Handler Exposure Scenarios to be assessed in Registration Review ..... 22
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1 Introduction

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

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

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

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

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

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

Work Plan (PWP) 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 unreasonable 

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

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

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

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

http://www2.epa.gov/pesticide-reevaluation.

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

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

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

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

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

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

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

and data or information it believes are needed to make a registration review decision. 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 letter 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 associated 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 below 

summarize the issues relevant to this registration review case and the anticipated registration 

review schedule. 
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Table 1 – Summary of Anticipated Risk Assessments and Data Needs: 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 details)

Dietary (food) Yes N/A New

Chronic Oral Toxicity

Carcinogenicity – 2 species

Acute neurotoxicity

Immunotoxicity

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

Immunotoxicity

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 - Incidental 

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 Respiration Inhibition or 

one of the three biodegradation 

in activated sludge simulation 

tests

N/A = Not applicable
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Table 2 – Anticipated Registration Review Schedule

Anticipated Activity Target Date* Completion Date

Phase 1: Opening the Docket 

Open Docket and 60-Day Comment Period for Preliminary Work Plan 2014-06 2014-06-25

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 Proposed Decision 2020-12

Close Public Comment Period 2021-02

Issue Final Decision 2021-06

Begin Post-Decision Follow-up 2021

Total (years) 7

*The anticipated schedule will be revised as necessary (e.g., need arising under the Endocrine Disruptor Screening Program with 

respect to the active ingredients in this case).

1.2 Updates to the Final Work Plan

 Updated Table 2 – Anticipated Registration Review Schedule to reflect completion date.

 Clarified in Table 6 that studies 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 residues study (OPPTS 850.3030) 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 “Studies Anticipated To Be Required Through The 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

OPPTS 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.
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1.4 Chemical Identification and Properties

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

Table 3 – Chemical Identification of OIT

Chemical Name 3(2H)-Isothiazolone, 2-Octyl

Other names

2-Octyl (2H)-Isothiazolone (OIT)

2-Octyl-3 2(H)-isothiazolone (OIT)

2-Octyl-2H-isothiazol-3-one (OIT)

Octhilinone

KathonTM 893T

Chemical Classification Isothiazolone

PC Code 099901

CAS Number 26530-20-1

Molecular Formula C11H19NOS

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 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.

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

830.7220 Boiling point (oC) 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 substance does not 

dissociate into ions.

830.7550 Octanol-water partition 

coefficient at 25oC (Log Kow)

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/L
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Guideline # Parameter Octhilinone

Hexane - 640 g/L

830.7950 Vapor pressure (mmHg) 3.68 x 10-5to 4 x 10-6 mm HG at 25°C( PAI)

Environmental Fate Properties

Octanol-air partition coefficient at 25 oC (Log

KOA)

Not Available

Air-water partition coefficient (Log KAW) Not Available

Mobility

Organic Carbon Partitioning Coefficient (Koc)

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 

silt clay loam (tech report)

Persistence in Water (half-life)

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

Aqueous photolysis at 25 oC (days) Half-life of 16.3 days

Aerobic aquatic metabolism (days) The submitted data will 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 not required.

Aerobic soil metabolism at 25 oC (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.

Persistence in WWTP (% removed)

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

is conducted.

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

millimeters of mercury.

Several metabolism studies have been submitted to the agency 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 contain 

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 presents 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 the following 

application methods: spray, open pour, meter pump, padding and dip. In addition, materials 
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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 Uses

Use Application Method Application Rate

(ppm a.i. by weight)

Agricultural Premises and Equipment

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

solution)

Commercial, Industrial, Institutional, Premises and Equipment

Mildew control 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

Coatings, 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, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump 

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump 

Open Pour, Meter Pump

Open Pour, Meter Pump 

Open Pour, Meter Pump

Open Pour, Meter Pump

Open Pour, Meter Pump

Pad, Dip or Spray

250 – 2700 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

75 -1400 ppm

9.9 – 2000 ppm

Medical Premises and Equipment

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

solution)

Residential and Public Access Premises and Equipment

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

solution)
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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 included 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 are 

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

1.6 Regulatory History

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-Octyl3(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 occupational/residential exposure assessment was conducted 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 antimicrobial 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 experienced. 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 

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

blisters and burns on the exposed area. 

One incident 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 reports only contain basic information such as the date, 

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

symptoms experienced are not included. 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 to 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 agency’s Ecological Incident Information 

System (EIIS) for the time period spanning 2005 to 2013.

2 Anticipated Data Needs

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

review.
Docket Number EPA-HQ-OPP-2014-0160

www.regulations.gov

Page 16 of 73

Table 6 – Studies Anticipated as Needed for the Registration Review of OIT

GLN Study Name Test 

Substance

Time Frame 

(Measured in 

months from DCI 

Receipt)

Risk Assessment(s) Data 

Will Support

Use Site(s) Triggering 

Anticipated Data 

Requirement

Applicable Exposure 

Scenario

Studies Anticipated to be Required through the Registration Review DCI

870.1300 Acute Inhalation TGAI 12 Occupational and 

Residential All All potential inhalation exposures

870.41005 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

870.42005 Carcinogenicity – 2 

species 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

870.6200 Acute neurotoxicity TGAI 12 Occupational and 

Residential All All potential exposures

870.7800 Immunotoxicity TGAI 24 Occupational and 

Residential All All potential exposures

875.1200

875.1400

Dermal and Inhalation 

Exposure – Indoor

TGAI or 

surrogate

24 Occupational and 

Residential

Mold Preventative Spray and 

household cleaners

Low pressure 

handwand application 

of mold preventative 

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

850.1300 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 

discharges into water 

bodies

850.3020 Honeybee acute 

contact

TGAI 12 Ecological Effects Wood preservative Wooden structures
Page 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 

Scenario

850.33004

Activated Sludge 

Respiration Inhibition 

test TGAI 12

Fate and persistence in 

WWTP, down-the-drain 

assessment

Paints, Material 

Preservatives, Drilling Muds 

and Flooding Fluids, 

Textiles

Toxicity to WWTP 

organisms

835.31103 Ready biodegradability TGAI 12

Fate and persistence in 

WWTPs Down the drain 

assessment

Paints, Material 

Preservatives, Drilling Muds 

and Flooding Fluids, 

Textiles

Toxicity to WWTP 

organisms

835.32203 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

835.32403

Simulation test –

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

835.32803

Simulation test –

Biodegradation TGAI 12

Fate and persistence 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 Textiles 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 –

Outdoor 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 2
Page 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 

Scenario

875.1700 Product Use 

Information

TGAI 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 24 All All All

1The exposure scenarios include: Open pour for material preservation and leather processing, sapstain treatment, machinist exposure 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 the 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 mg/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 Ready 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 – Aerobic Sewage Treatment: A. Activated Sludge Units, or c) the Porous Pot 

study would likely be required.

4 Data have been submitted to the agency for review.

5 Studies which are designed to simultaneously fulfill the requirements of both the chronic oral and carcinogenicity studies (i.e., a combined study) may be conducted.
Page 19 of 73

3 Human Health Risk Assessment

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

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

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

3.1 Existing Toxicological Endpoints

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

review. Table 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 data 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 endpoints to be used in the registration review risk assessment. A 

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

Table 7 – Toxicological Endpoints for Assessing for OIT ORE Exposures (2007 RED)

Exposure

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 days6 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 

endpoint) 

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/cm2) 

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 Exposure, 

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 HGB, 

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 HEC: 0.29 mg/m3

4 hr HEC: 0.15 mg/m3

6 hr HEC: 0.10 mg/m3

8 hr HEC: 0.073 

mg/m3

MOE = 30b

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 nasal 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 toxicity 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 (6hr (rats 

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

3.2 Dietary Exposure

The agency will need to conduct dietary exposure (food and drinking water) assessments to 

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

Uses of OIT that may result in dietary exposure (food) include paper products/wrappings as well 

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

material preservative may result in OIT being discharged in waste water or leached from 

preserved 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 agency (3/2011) and FCNs for latex emulsions to be used in paper/paper products 

have been issued by FDA. Since these can contribute to dietary (food) exposure, the agency 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 additional 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 as well as relied on high-end assumptions to be 

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

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

will have been 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 

dishwashing 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 chemistry data may be required.

3.2.2 Drinking Water

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

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

water cooling systems) the agency 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 agency anticipates needing certain environmental 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 agency anticipates using these data and/or other 

sources of information during the risk assessment stage of this registration review 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 agency anticipates the need to revise the previous Occupational Residential Exposure (ORE) 

assessments. 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 submitted 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 preservation, wood preservation sapstain treatment, leather processing and use of 

preserved products such as metal working fluids and paint. Both dermal and inhalation exposures 
Page 22 of 73

were assessed. The short-term dermal irritation concerns for workers were mitigated 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 preserved 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 rate 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 AlgicidPlus for Treating Walls and Exterior Surfaces (US EPA, 2013) for brush/roller and low pressure 

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

and both 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 worn 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 assessed during Registration Review

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 scenarios that are anticipated to 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 application for material preservation and leather 

processing. Dermal, Inhalation Short and IntermediateTerm 

Sapstain treatment Dermal, Inhalation Short and Intermediate 

Term 

Brush/roller 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 Term 

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 inhalation MOEs for 

brush/roller application ranged from 60 to 180 and were not of concern because they exceeded 
Page 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 AlgicidPlus for Treating Walls and Exterior Surfaces (US EPA, 2013) for brush/roller and low pressure 

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

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

brush roller and low pressure sprayer, 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.

Residential Handler Exposures to be assessed 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 scenarios 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

Scenario Exposure Route(s) Duration

Brush/Roller and Airless Spray application of preserved paints 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 conducted in 

support of the 2007 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 carpets remained above the 

agency’s LOC, even when using 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 residential 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 be 
Page 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

Scenario Exposure Route(s) Duration

Treated carpet - child Dermal and Incidental Oral Short and Intermediate Term 

Vinyl flooring – 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 2007

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

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

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

water) exposures and residential exposures. 

3.4.2 Cumulative Exposures 

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

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

common mechanism of toxicity finding as to OIT and any other substances and OIT does 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 efforts to determine which 

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

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

4 Environmental Risk Assessment

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

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

review will allow the agency to determine potential acute and chronic 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 agency 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 species 
Page 25 of 73

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

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

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-(noctyl)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 textiles as a materials preservative and as an 

antisapstain 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 the 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 

agency’s National Pesticides Cause of Impairment of Waters website (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 agency’s National Pesticide TMDL web site (searched 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

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

group_name=PESTICIDES
Page 26 of 73

4.2 Conceptual Models for Environmental Exposure Pathways

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

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

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

from surface 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 roughly 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 agency, but these studies have not yet been 

reviewed. 

4.3 Ecological Effects Assessment

OIT has use patterns that could lead to exposure to non-target organisms. The wood preservative 

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

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

required. The industrial processes and water systems use and material preservative use could 

lead to the exposure of non-target aquatic organisms from wastewater release 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 potential water exposures. 

4.3.1 Mode 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 measures of effects to aquatic and terrestrial 

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

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

literature are tabulated 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 Rainbow Trout

Acute 96-h LC50 = 0.047 mg/L 41608051

Chronic None

Freshwater 

invertebrates

Acute 48-h EC50 = 273 ug/L 48358616

Chronic None

Estuarine/marine fish Sheepshead Minnow Acute LC50=0.16 mg/L 41608007 

Estuarine/marine 

invertebrates

Mollusk Acute LC50=>0.057 mg/L 41700701

Shrimp Acute LC50=0.071 mg/L 41608008

Algae Nonlisted IC50 = 0.61ug/L 48557405

Listed NOAEC = <0.143 48557405

Aquatic vascular 

plants Duckweed

Nonlisted IC50 = 280 ug/L 48557404

Listed NOAEC = <62 ug/L 48557404

Seedling Emergence

Nonlisted IC25 = 14 mg a.i./kg 48358620

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

Birds

Bobwhite Quail Acute LD50 = 384 mg/kg 44859001

Mallard duck Subacute 

dietary LC50 > 3267 mg/L 41608002

Mammals Acute LD50 = 794 mg/kg 00070456

Chronic NOAEL = 5 mg/kg/day 41482500

Nontarget insects Honey bee Acute Required --

4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

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

(EECs) in the aquatic environment. 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 to 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 wastewater 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 predicted Exceedences 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 uses, 

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 production 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 agency 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 toxicity 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 ECOTOXicology (ECOTOX) 

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

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

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

more sensitive than those currently in 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 Research and Development, and the National Health and Environmental 

Effects Research Laboratory's Mid-Continent Ecology Division.

5 Endocrine Disruptor Screening Program (EDSP)

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

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

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

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

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

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

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

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

taxonomic groups. As part of its 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 developed the EDSP to determine whether certain substances (including pesticide 

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

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

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

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

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

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

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

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

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

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

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

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

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

identified for EDSP screening was published on June 14, 20133and includes some pesticides 

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

construed as a list of known or likely endocrine disruptors.

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

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

website.

3

6 Optional Label Changes

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

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

and/or improve label clarity, 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-OPP2014-0160, 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 (Tox ID No.): Copley, M. (1994) Octhilinone, Waiver Request for a Dermal 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: Project 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 [for Octhininone]: Acute Oral - Rats;

Draize Eye Irritation - Rabbits; Primary 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, received Jul 18, 1978 under 707-127; prepared by

Hazleton Laboratories, Inc., Philadelphia, Pa.; CDL: 234400-C).

00070456 (MRID) Powers, M.B. (1970) Final Report [for Octhininone]: Acute Oral - Rats; Acute

Dermal - 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 TRW, Inc. submitted by Rohm & Haas Co., 

Philadelphia, Pa; CDL:233428-B).

00136524 (MRID) Powers, M.; Kundzin, M.; Ferrell, J. (1970) Three-month Dietary Administration-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; prepared 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 received 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. 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-K).
Page 31 of 73

00136528 (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 & 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 RH893 Is Being Added to the Diet of Mice: Monthly Reports. (Unpublished study received 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) Piccirillo, 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 Laboratories, 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 Number: 83R143. Unpublished study prepared 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 

Number: 83R-025. Unpublished study prepared by Rohm 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 & Haas Co., Philadelphia, PA; CDL: 004372-

L).

41482509 (MRID) Solomon, H.; Lutz, M. (1987) Skane M-8 HQ Industrial Mildewcide: Oral 
Page 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 prepared 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. (1995) 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-Octylisothiazolone (OIT) 96%: 14-Day Oral (Gavage) 

Dose Range-Finding Study in the Female Rat: Final Report: Lab Project Number: 1248-1154-

050: 1154-050. Unpublished study prepared by Hazleton Deutschland GmbH. 108 p.

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

43935710 (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) Fuchs, 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. (1993) 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-isothiazolin-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-isothiazolin-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). SkaneTM M-8: Microbial mutagen test. Rohm and Haas, 

Toxicology 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 M8 HQ: (Kathon 893T). Project Number: WIL/91002, 86RC/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-(carbon14)]Isothiazolin-3-One in the Wistar Rat: Acticide OIT. Project Number: 397856. Unpublished 

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 Rohm & 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 & Haas Co. 58 p.

47315011 (MRID) Otterdijk, F. (2007) 90-Day Dietary Toxicity Study with Acticide OIT (2-NOctyl-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-NOctyl-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 Reproduction 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 Excretion 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 Excretion 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 

Primary 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

Acute 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 toxicity 

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 unacceptable.

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 dermal

toxicity, the database includes four studies: an acceptable 14-day dermal toxicity study in rats

(MRID 43935705); an unacceptable 21-day dermal toxicity study in rabbits (MRID 00136526);

and two 90-day dermal toxicity studies in rats (MRID’s 42007301 and 43935706) that are

classified as acceptable and supplemental, 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-Guideline 14-Day Oral Toxicity (Rat)

In a repeated dose oral toxicity study (MRID 43935707), N-octylisothiazolone (OIT 96%, Batch 

No. K1217) was administered by intragastric intubation to eight female Sprague Dawley

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

was for selection of doses for a developmental toxicity study in the rat.

Clinical observations and gross pathology findings indicated dose-related signs of toxicity in all 

treatment groups. Observations of salivation and abnormal position increased in incidence and 

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

urination were also noted in the 120-mg/kg/day animals. Treatment-related gross pathology 

findings included a prominent lobular pattern in the liver (≥10 mg/kg/day), and whitish-colored 

and thickened fundus of the stomach (≥60 mg/kg/day). Gastric hemorrhages of the fundus were 

also noted in one 120-mg/kg/day rat. Body weight gain and food consumption were reduced at

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

large standard deviations, and food consumption was only significantly reduced at the Day 1-3 

treatment interval. This study had numerous deficiencies in meeting criteria for a repeat dose 

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

for a rat developmental toxicity study and not for fulfillment of a specific guideline, the 

information contained in this study may be scientifically useful for examining toxic effects from 

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

suggested for the rat developmental toxicity study.

The LOAEL for N-octylisothiazolone (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 NONGUIDELINE and does not satisfy the Guideline requirements (OPPTS 870.3050; OECD 407) 

for a 28-day oral toxicity study in rodents. Although there are major deficiencies in the 

guideline requirements, the study is scientifically acceptable for the dose range-finding purpose 

for which it was intended.

870.3100 90-Day Oral Toxicity (Rat)

In a 90-day oral toxicity study (MRID 136524), RH-893 (octhilinone, % a.i. not reported, lot no. 

SW 70/0293) was administered 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 mg/kg bw/day, respectively). There was

no effect on survival, feed efficiency, urinalysis, or gross and microscopic pathology.

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

treatment for high-dose males and females, but were comparable to the respective control groups 

for the remainder of the study. The results for hematology, clinical chemistry, and organ weight 

were equivocal because of the high variability, low number (5 rats/sex/treatment group for 

clinical chemistry and hematology), inconsistency between the sexes, and lack of a dose

response. The results, however, suggest a possible decrease in hemoglobin and RBCs in all

female treatment groups, which was accompanied by an increase in serum carbon dioxide levels.

Similar results were not observed in the males. There was a decrease in total WBC in the highdose group at 13 weeks for both sexes and at 4 weeks in females. There also were some changes
Page 37 of 73

in the differential leukocyte counts with an increase in the percent of segmented neutrophils 

accompanied by a decrease in the percent of lymphocytes in all male (4 weeks only) and female 

(13 weeks only) treatment groups. All treated males and females also had increases in absolute 

and relative thyroid weight.

The deficiencies in this study were numerous with several being sufficiently severe enough to 

compromise the overall integrity of the study. These deficiencies are mainly due to the age of 

the study, having been performed prior to the implementation of Good Laboratory Practices 

(GLP). These deficiencies 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 formulation to indicate that homogeneity, stability, or adequate concentrations were 

achieved and maintained throughout the study; an inadequate number of animals (only 5 

animals/sex/treatment) used for hematology, clinical chemistry, and histopathology 

examinations; and the lack of numerous measured parameters (e.g., neurological exams). The 

deficiencies in this study are such that neither 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 requirement for a 90-day oral toxicity study (OPPTS 870.3100; 

OECD 408) in rodents. There were no analyses performed on the dose formulation to determine

homogeneity, stability, or concentration of the test compound. In addition, only 5 of the 10 rats

per sex and dose group were examined for hematology, clinical chemistry, and histopathology

endpoints.

870.3150 90-Day Oral Toxicity (Dog)

In a 90-day oral toxicity study (MRID 136525), RH-893 (octhilinone, Lot no. SW70/0293; 

purity assumed to be 100%) was administered 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 mg/kg bw/day, 

respectively, based on the assumption that the dose formulation was homogeneous, stable,

and at the correct concentration).

Data were highly variable, even at the initial measurement, making it difficult to determine 

treatment-related effects. The results indicate the following as possibly related to the 

administration of RH-893: reduced body weight gain in 500-ppm males and 2000-ppm males 

and females, with reduced food efficiency in these groups; slightly reduced hematocrit and 

hemoglobin and increased alkaline phosphatase in the high-dose groups; decreased total

protein in high-dose males and all females, accompanied by some disruption in the protein 

electrophoresis; increased relative liver weight (high-dose males only); increased relative

kidney weight (high-dose females only); and decreased relative testis weight with an increase

in slight to moderate epididymitis in high-dose males. The major deficiency in this study was

the complete lack of analyses on the dose formulation. Because there was high variability in

the results, coupled with very little apparent affects, this becomes a great deficiency. The

animals had such variability initially in their body weights and the majority of the other

measured parameters that it cannot be determined if there is an inadequate homogeneity,

stability, or concentration in the dose formulation or if there were just great variability in the
Page 38 of 73

animals. Given the great variability, the slight differences between the groups, and the lack

of information on the dose formulations, it cannot be determined what effects are actually

related to the treatment. Although it is possible that higher doses may have yielded more

definitive results, this would again largely depend on the homogeneity, stability, and accuracy

of the dose formulations. The deficiencies in this study are so great that neither a LOAEL

nor NOAEL can be assigned.

This 90-day oral toxicity study in the dog is UNACCEPTABLE/NOT UPGRADABLE and

does not satisfy the guideline requirement for a 90-day oral toxicity study (OPPTS 870.3150;

OECD 409). This study is unacceptable because homogeneity, stability, and concentration of the

dose formulations were not measured. Additionally, the animals were not randomized and were 

possibly of different ages or older than 9 months prior to dosing. These and other numerous 

deficiencies discussed in this review make the study not upgradable.

Non-Guideline 14-Day Dermal Toxicity (Rat)

In a 14-day dermal 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 mg/kg bw/day for 6 hours/day during a 14-day period.

There were no treatment-related effects in mortality, clinical signs, and food consumption. 

Dermal irritation was observed at ≥100 mg/kg/day in both males and females at Weeks 1 and 2. 

Slight to moderate erythema, edema, atonia, and desquamation were observed in 100-mg/kg/day 

treated rats. The severity of dermal irritation increased to moderate to severe in the 1000-

mg/kg/day treated rats. Some 1000 mg/kg/day females also exhibited slight to moderate fissures 

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

≥100 mg/kg/day at Weeks 1 and 2, and scabbing with exfoliation was observed at 1000 

mg/kg/day in males and females at Week 2. There were no statistically-significantfindings for 

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

mg/kg/day males and females at Week 2 and in overall weight gain. The lowered weight gain 

was greater in males than in females. Food consumption data did not provide an explanation for 

the reductions observed in body weight gain. There were no statistically-significant effects in 

mean food consumption in treated rats throughout the study. Macroscopic findings reported at 

necropsy were generally insignificant. A dermal-related finding of subcutaneous redness in the 

neck and indurated skin in the treated area was observed in one 1000 mg/kg/day male. The

lowest-observable-adverse-effect level (LOAEL) for N-octylisothiazolone (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 dermal toxicity study is ACCEPTABLE-NONGUIDELINE. Although

a number of deficiencies were noted for meeting the guideline requirements for a 28-day dermal 

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 dermal toxicity study (MRID 136526), RH-893-50% (purity assumed to be 100.0% 

a.i. by study authors; however, the test article’s name is RH-893-50%, lot and/or batch # not 

provided) was applied to the shaved skin of 10 New Zealand White 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 volume of

1.0 mL/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, subgroups were 3 males with abraded skin and 2 males with intact shaved skin 2 females with 

abraded skin and 3 females with intact shaved skin. Dose volume for vehicle treated animals 

was 2.0 mL/kg body weight/day for the first 4 days of treatment, propylene glycol for the fifth 

day and 1.0 mL/kg body weight/day of 1% Tween 80/distilled water solution for the rest of the 

study duration. Undiluted compound at a dosing volume of 0.25 mL/kg body weight/day was 

applied for the first four days of Week 1; these animals were then given a 10% dilution of RH893-50% in a 1% Tween 80/distilled water solution for the rest of the study duration. The 

control and 1% animals’ vehicle was 1% Tween 80/distilled water solution except on the fifth 

day of treatment when propylene glycol was applied to the rabbits; all subsequent doses were in 

the 1% Tween 80/distilled water solution vehicle.

There were no treatment-related effects on mortality, appearance, and behavior. The 10% 

treatment effected dermal clinical findings, body weight, body weight gain, hematological 

parameters (leukocytes, segmented neutrophils, and lymphocytes) and histological findings of 

the skin (acanthosis, hyperkeratosis, dermatitis, pseudoepithelial hyperplasia, pustular 

epidermitis [males], ulcerations, folliculitis [males]) with the abraded animals displaying a 

slightly more severe skin lesions but with the small number of intact skin animals examined at

necropsy comparisons were difficult. The 1% animals, displayed clinical signs of dermal effects, 

decreases in body weight gains (males with a greater effect noticed in males with abraded skin), 

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

dermatitis, and pustular epidermitis) with the abraded animals displaying a slightly more severe 

skin lesions but with the small number of intact skin animals examined at necropsy comparisons 

were difficult.

In addition, a 10% dose-male, had severe hepatic necrosis and inflammation and suppurative 

hepatitis; these changes cannot be fully attributed to dosage due to the low number of control 

animals for comparison but cannot be ruled at as incidental.

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 weight gain) and 1% in males (body weight 

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

This 21-day dermal toxicity study in the New Zealand White albino rabbits is

UNACCEPTABLE-NONGUIDELINE and does not satisfy the guideline requirement for a

21/28-day dermal toxicity study (OPPTS 870.3200; OECD 410) in rodents. The experimental 

design of this study appears to be one of range-finding, where dose volumes, vehicles, and area
Page 40 of 73

of application were altered during the course of the study. Determining if a change was treatment

related was difficult due to low sample size, variability of the blood chemistry and hematology

data, and variation in experimental design during the study. Several hematological parameters,

clinical chemistry, and several organs were not examined. These and other numerous 

deficiencies make the study not upgradable.

870.3250 90-Day Dermal Toxicity (Rat)

In a dermal subchronic toxicity study (MRID 42007301), doses of 1 mL/kg of RH-893 HQ 

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

rats/sex/dose at dose levels of 0, 2.97, 5.95, or 14.87 mg/kg/day for 6 hours/day for 5 days/week 

for 13 weeks. Skin irritation occurred in all treatment groups in a dose-related manner. The

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

No mortality or treatment-related signs of clinical toxicity were observed during the study. 

Treatment-related microscopic changes observed in the treated area of the skin of male and 

female rats in Groups 3, 4, and 5 and in male rats in Group 2 (vehicle control) include 

hyperkeratosis, acanthosis, foci of necrosis, and eschar formations in the epidermis and chronic 

inflammation and sebaceous gland hyperplasia in the dermis. No statistically significant effects 

on food consumption or food efficiency were observed in Groups 2, 3, or 4 of either sec. In 

Group 5 males, food consumption and decreased body weights were observed. No changes in 

absolute organ weights or organ/body weight ratios for males or females were considered to be 

treatment-related. The only treatment –related changes in hematology parameters observed in the 

high-dose females, a slight but statistically-significant decrease in red blood cell count, 

hematocrit, and hemoglobin were observed; the biological significance of this effect is

questioned because of the low magnitude of the effect and because the effect was only observed

in females. Likewise, statistically-significant treatment-related changes in clinical chemistry

patterns were observed in the high dose animals, including decreases in albumin, glucose, and

total protein in females and an increase in alkaline phosphatase and a decrease in triglycerides in 

males; the biological significance of these effects is also questioned because of the low 

magnitude of the effects and because 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/day, 

based on decreases in HGB, HCT, RBC, albumin, glucose, and total protein in females and a 

decrease in body weight and body weight gain in males.

This dermal subchronic toxicity study is classified as Acceptable because it satisfies the 

requirements for a repeated dose dermal toxicity study (§82-3). Minor deficiencies noted in the 

study report include: the test site was not occluded after dose administration, and data for the 

differential leukocyte counts were not provided.

870.3250 90-Day Dermal Toxicity (Rat)

In a dermal subchronic toxicity study (MRID 43935706), N-octylisothiazolone (94 ± 3% ai, Lot# 

K1217) was applied to the shaved skin of ten young adult Sprague-Dawley CD rats/sex/dose at 

dose levels of 0, 5, 25, or 125 mg/kg/day for 6 hours/day for 90 days.
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Male and female rats in the 125 mg/kg treatment groups exhibited slight to moderate (mean

score ≤ 2.l on a scale of 0 to 3) erythema, edema, atonia, desquamation, and fissures, and lesions 

described as squamous cell hyperplasia, sebaceous cell hyperplasia, folliculitis, dermatitis, and 

hemorrhages at the site of treatment. Body weight gains of male rats in the 125 mg/kg treatment 

group were 21% less than rats in the control group after 90 days of treatment; the depressed 

weights were first noted at 22 days. The body weight and body weight gains of female rats in

the 125 mg/kg treatment group were unaffected. Male and female rats in the 25 mg/kg treatment 

groups were found to have minimal (mean scores ≤1) erythema, edema, and atonia; no lesions 

were observed. No dermal irritation was observed in the 5 mg/kg treatment group during the 

study. Body weights of rats in the 5 and 25 mg/kg treatment groups were similar to the controls. 

For all treatment groups, food consumption was similar to the controls. There were no

treatment-related differences in ophthalmology, hematology parameters, clinical blood

chemistry, urine chemistry and appearance, organ weights, or macroscopic or microscopic organ 

morphology (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 failed to 

microscopically examine samples of tissue from the treatment sites in the mid- and low-dose 

groups. Damage to the treatment sites was not assessed. Therefore, the NOEL/LOEL cannot 

be determined.

This dermal subchronic toxicity study is classified unacceptable/upgradable and does not 

satisfy the guideline requirement for a repeated dose dermal toxicity study (§82-3). The study

may be upgraded once microscopic examination of the treatment sites in the lower dose groups is 

conducted.

Non-Guideline 10-Day Inhalation (Rat)

In a 10-day inhalation toxicity study (MRID136527), RH-893-50% (octhilinone, Lot and Batch 

no. not provided; purity assumed to be 50%), was administered to 10 Sprague-Dawley albino 

rat/sex/dose, in an aerosol under dynamic conditions at nominal concentrations of 0, 1%, or

10% with a target chamber concentrations of 2.0 mg/L for 1 hour per day, for a total of 10 days. 

The vehicle was propylene glycol; the control animals received the vehicle control as an aerosol. 

All exposures were whole 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 animals were sacrificed and necropsied on Day 26, after a 14

th day recovery period.

Animals in the 10% exposure group were found dead or sacrificed due to moribundity 9/10

males and 7/10 females died as early as Day 3. Clinical signs of toxicity related to treatment

were nose shuffling (1% and 10%), dried red material around the eyes (10%), gasping (10%),

lacrimation (10%), red nasal exudate (10%), and coughing (10%); preening, hypoactivity, wet

hair, excessive water consumption, and wheezing were exhibited in control and treated animals.

Data were highly variable, making it difficult to determine treatment-related effects. Weight loss

was observed in the 10%-RH-893-50% males and females; however, only 1 male rat and 3

female rats survived to Day 8 so the body weights on Days 8, 12, and 26 could not be 

statistically compared to controls. By the end of the recovery period the 10%-RH-893-50% 

group had gained weight; however, the surviving 10%-treated male displayed a weight gain of 

69% of control, the 1% males a weight gain of 26% of control, 10%-treated female displayed a 
Page 42 of 73

weight gain of 86% of control; the 1% females a weight gain of 91% of control. Blood was only 

taken on Day 26 from the surviving animals and not on Day 12, after exposure termination, it is 

difficult to determine treatment-related effects. Analysis of hematological data demonstrated a 

decrease in total white blood cells (10% males and females; 1% females), an increase in 

segmented neutrophils (1 and 10% males and females), and a decrease in lymphocytes (10% 

males and females; 1% males), which may indicate an irritation response. However, without 

data from Day 12 this is speculation. A significant decrease in glucose was observed in the highdose male. Clinical pathology data does not correlate to this change; therefore, it could be an 

incidental change. Without data from Day 12 when the treatment was terminated it is impossible 

to make a conclusion as to the relevance of this finding. An increase in aspartate 

aminotransferase levels was observed in the 10% animals; however due to data variability and 

the fact that only 1 male and 3 females remained after treatment, these values were not 

statistically-significant. These changes may have corresponded with gross pathology findings of 

mottled liver; however, without clinical chemistry data from Day 12 when the treatment was 

terminated it is impossible to make 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 treatment was

terminated, this becomes a great deficiency.

Microscopic treatment related effects were limited to the respiratory tract and included mild to 

moderate bronchiolitis in multiple 10% RH-893-50% rats. Additionally, four male rats from the

1%-RH-893-50% group exhibited severe lung lesions, which were consistent with chronic 

murine pneumonia that may have been exacerbated by inhalation treatment.

Based on the data in this study, neither a NOAEL nor LOAEL can be determined. 

Analytical concentrations of test material in the breathing zone of the rats were 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 requirement for a subchronic inhalation study OPPTS 

870.3465; OECD 413 in the rats. This study is unacceptable 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 animals were only exposed for 1 hour/day for 5 days a week for a total of 10 

exposures where the guideline states exposure for 6 hours/day, 5 days a week. Homogeneity, 

stability, and concentration of the dose formulations were not measured; test article concentrations

and analytical determination of the test article in the exposure chamber were not provided. 

Several toxicity testing parameters were not measured. These and other numerous deficiencies

discussed in section III.C make the study not upgradable.

870.3465 90-day inhalation (Rat)

In a subchronic aerosol inhalation (nose-only) toxicity study (MRID 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 (ambient air), 0 (propylene glycol, 123 mg/m3), 0.05,

0.64 and 6.39 mg of octhilinone/m

3

. An additional eleven rats/sex/exposure group were 
Page 43 of 73

assigned to a fourteen-week recovery period.

The mean mass diameter (MMD) and geometric mean (GM) were 2.5 μm and 9.2, respectively, 

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 mg/m3groups. 

Clinical signs in the 6.39 mg/m

3

exposure group included: rales [males and females 5-22/22; 

weeks 1-13]; dyspnea [females: 3/22: week 4; 3-9/22: weeks 7-10]; thriftless [(males: 3/22:

weeks 8 and 10) and (females: 9-22/22: weeks 7-10)]; and red staining of the dropping sheet

[(males: 11/22: week 2) and (females: 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 male and female rats in the 6.39 mg/m3group. No

clinical chemistry and organ weight changes and deaths were related to the exposures. There 

were no gross pathological findings in exposed males and females. Histopathological findings in 

the male and/or females from the 6.39 mg/m

3

group consisted of secretory cell hyperplasia, 

squamous metaplasia, inflammation, and eosinophilic droplets in the nasal cavity at the 13-week 

sacrifice.

During the recovery period, rales were present in the males and females from the 6.39 mg/m

3

group. Based upon the clinical signs, the decreased body weights, fluid in the uterus, and the

pulmonary histopathological findings at the terminal sacrifice for males and females in the 6.39

mg/m

3

group, the LOAEL for 13-week inhalation exposure is 6.39 mg/m

3

. The NOAEL is

0.64 mg/m3. The study is classified as Acceptable, satisfying the requirements for a subchronic

inhalation toxicity study in the rats (§82-4).

Developmental Toxicity 

The database includes four developmental toxicity studies in rats and two in rabbits. The 

developmental toxicity studies in rats include three acceptable studies (MRIDs 41482508,

43944401 and 47107014) and one unacceptable study (MRID 00046403). For

developmental toxicity in rabbits, 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 developmental toxicity study (MRID 41482508), SkaneTM M-8 HQ (43% a.i., lot SW 86

6155) was administered to 25 Crl:CD

® BR rats/dose by gavage at dose levels of 0, 1, 5, or 30 mg 

active ingredient/kg bw/day from days 6 through 15 of gestation. Because SkaneTM M-8 HQ 

contains about 50% propylene glycol; an additional control group comprised of 25 rats was 

administered propylene glycol at 30 mg/kg/day, a volume equal to that of the highest does group.

Maternal toxicity was observed at 30 mg/kg/day. Signs of toxicity at 30 mg/kg/day include: one 

death; salivation and decreased defecation; decreased body weight and body weight gain; 

decreased corrected body weight and body weight gain; and decreased food consumption. The 
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investigator also concluded that there was a slight, treatment-related increase in resorptions/dam 

and post-implantation loss at 30 mg/kg/day. Upon further inspection, however, the values 

appear comparable to control values, as well as other treatment groups. Additionally, these 

changes did not reach statistical significance. Although the investigator concluded that maternal 

toxicity also was observed at 5 mg/kg/day, this determination does not seem reasonable.

Changes in body weight, corrected body weight and body weight gain, and food consumption 

observed at the mid-dose and deemed treatment-related by the investigator were slight, and the 

values were not statistically different in comparison to the control values. The values actually 

appear to be comparable to control values, especially when standard deviations are taken into 

consideration. The findings at the mid-dose do not warrant being called a treatment-related 

effect. Consequently, the maternal LOAEL is 30 mg/kg bw/day, based on death,

salivation and decreased defecation, decreased body weight and body weight gain,

decreased corrected body weight and body weight gain, and decreased food

consumption. The maternal NOAEL is 5 mg/kg bw/day.

Developmental toxicity was not observed at any dose level. The investigator concluded that 

developmental toxicity was observed at 30 mg/kg/day due to an increased percentage of litters 

and fetuses with any type of malformation (external, visceral, or skeletal). Malformations 

occurred in only three fetuses from three litters at 30 mg/kg bw/day in comparison to one control 

fetus from one control litter. The difference was not statistically significant, and the apparently 

high percentage values (1.2% of fetuses and 17.6% of litters at 30 mg/kg/day; 0.4% of fetuses

and 5.3% of litters in the control; and 0.3% of fetuses and 4.3% of litters in the historical control) 

are most likely an artifact of the very small number of fetuses and litters available for evaluation. 

In addition, the malformations observed are known to occur spontaneously in this strain of rats

as demonstrated by the historical data. Consequently, the developmental NOAEL is 30 mg/kg 

bw/day.

This developmental toxicity study is classified ACCEPTABLE-GUIDELINE and satisfies the 

guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700a Prenatal Developmental Toxicity (Gavage) Study – Rat

In a developmental toxicity study (MRID 43944401), N-octylisothiazolone (octhilinone, 94% ai, 

Lot# K1217) was administered to 25 female Sprague Dawley rats/dose in corn oil by gavage at 

dose levels, of 0, 5, 30, or 60 mg/kg/day from days 6 through 15 of gestation.

Maternal toxicity was demonstrated by reduced mean body weight gains on days 6-9 of gestation 

(14%, compared to controls). No other treatment-related effects in mortality, clinical signs of 

toxicity, body weight, food consumption, or cesarean parameters were noted at any dose level. 

The maternal LOEL is 60 mg/kg/day, based on reduced body weight gains. The maternal 

NOEL is 30 mg/kg/day.

There were no treatment-related effects noted in the developmental parameters. A 

developmental LOEL was not observed. The developmental NOEL is 60 mg/kg/day.

This developmental toxicity study is classified ACCEPTABLE-GUIDELINE and satisfies the 
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guideline requirement for a developmental 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/day4from 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/day, a dose equal to of the amount of propylene glycol in the highest SkaneTM 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 included 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: dried 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 consumption 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 early 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 submucosal 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 treatmentrelated 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 level 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 guideline 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 developmental toxicity study (MRID 00046403), RH-893 (octhilinone, lot no. SW 70/0293; 

purity assumed to be 100% active ingredient) was administered to up to 18 female Charles River 

Caesarean-derived rats/dose in the diet at dose levels of 0, 200, or 1000 ppm from days 6-15 of 

gestation. All dams were sacrificed at gestation day (gd) 19.

There was no maternal toxicity observed at any dose level. It should be noted, however, that 

there may be treatment-related changes in maternal body weight. Mean maternal body weight 

values show 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 

number of animals. The maternal NOAEL is 1000 ppm.

There were no developmental effects attributed to oral exposure to RH-893 in the diet; therefore, 

the developmental NOAEL is 1000 ppm.

This developmental toxicity study in the rat is UNACCEPTABLE/NOT UPGRADABLE and 

does not satisfy the guideline requirement for a developmental toxicity study (OPPTS 870.3700; 

OECD 414) in rats. Several major study reporting deficiencies including a lack of animal data 

would not allow this study to be upgraded.

870.3700b Prenatal Developmental Toxicity (Gavage) Study – Rabbit

In a developmental toxicity study (MRID 41482509), SkaneTM M-8 HQ Industrial Mildewcide 

(46.3% a.i., lot SW86-6155) was administered to 19 New Zealand White rabbits via gavage at 

dose levels of 0, 5, 20, or 80 mg active ingredient/kg bw/day from days 7 through 19 of 

gestation. Because SkaneTM M-8 HQ Industrial Mildewcide contains about 50% propylene 

glycol, an additional control group of 19 rabbits was administered propylene glycol at 92.8 

mg/kg/day, a volume equal to that of the highest does group.

Maternal toxicity was observed at 80 mg/kg/day and included clinical signs of toxicity (anorexia 

and scant, soft, or no feces), decreased body weight and body weight gains, and increased

number of abortions. The maternal LOAEL is 80 mg/kg bw/day, based on clinical signs of

toxicity, decreased body weight and body weight gains, and increased number of abortions. 

The maternal NOAEL is 20 mg/kg bw/day.
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There was a significant treatment-related decrease in male fetal body weight and total (male and 

female) fetal body weight at 80 mg/kg/day. There were no other treatment-related signs of 

developmental toxicity. The developmental LOAEL is 80 mg/kg bw/day, based on

decreased male fetal body weight and total (male and female) fetal body weight. The

developmental NOAEL is 20 mg/kg bw/day.

The developmental toxicity study in the rabbit is classified Acceptable (Guideline) and satisfies 

the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in 

rabbits.

870.3700b Prenatal Developmental Toxicity (Gavage) Study – Rabbit

In a developmental toxicity study (MRIDs 00058029 and 00136528), RH-893 (100% a.i., lot SW

70/0293) was administered to 15 New Zealand White rabbits/dose by gavage at dose levels of 0,

6, or 60 mg/kg bw/day. Of the 15 rabbits/group, 8/group were designated for Caesarean section 

and 7/group were designated for normal hutching. Doses were administered on gestation days 

(gd) 6 through 18 (for females designated for Caesarean section) or gd 6 through 16 (for females 

designated for normal hutching). Treatment was terminated two days earlier in dams designated 

for normal hutching due to high mortality.

The test material was toxic at both dose levels and resulted in high maternal mortality rates. 

Death occurred in 6 low-dose dams (3 designated for Caesarean section and 3 designated for 

normal hutching) and 10 high-dose dams (6 designated for Caesarean section and 4 designated 

for normal hutching). Changes in body weight and food consumption appear treatment-related 

with those animals dying prior to scheduled sacrifice exhibiting body weight losses and 

decreased food consumption. Animals that died prior to study termination also showed gross 

pathology findings, with the predominate findings being dark, red lungs or chest cavity 

anomalies. There were no apparent treatment-related changes in the number of implantation 

sites compared to the number corpora lutea. Additionally, there were no apparent treatmentrelated changes in the number and placement of implantation and resorption sites or in the 

number of live and dead fetuses/pups. The lack of a treatment-related response could be the 

result of too few animals available for comparison. Additional data are needed to fully assess

these endpoints. The maternal LOAEL is 6 mg/kg/day based on mortality, body weight

loss, decreased food consumption, and gross pathology findings. A Maternal NOAEL was

not achieved.

There were no apparent developmental effects. Fetal and pup body weight and length in treated 

groups appeared to be comparable with the control groups. Skeletal changes occurred more 

frequently in high-dose fetuses; however, these effects predominately occurred in one litter

where one out of five fetuses died. There were only two high-dose litters to examine. Therefore, 

it is difficult to draw any meaningful conclusions from these data. A developmental NOAEL/ 

LOAEL could not be determined.

This developmental toxicity study is classified UNACCEPTABLE/NOT UPGRADABLE and 

does not satisfy the guideline requirement for a developmental toxicity study (OPPTS 870.3700; 
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OECD 414) due to major study deficiencies. These include an inadequate number of dams per 

group, high maternal mortality and abortion, and a lack of individual animal data.

Reproductive Toxicity

There is one reproduction and fertility effect study 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 F1 generations, no treatment-related clinical signs were observed. No 

mortalities occurred in the P generation, but in the F1 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 significantly 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 examination 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. These 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 weight 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 morphology 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 ppm (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 twogeneration reproductive 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 gaps.

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 administered to 

125 (C 57BL/6 x C3H/anf) F1 mice/sex/dose in diet at dose levels of 0, 500, or 1000 ppm 

(equivalent mg/kg bw/day could not be determined because analytical measurement of the feed 

were not performed and food consumption was not measured) for 78 weeks. Twenty-five 

mice/sex/dose were sacrificed at 6 months for histopathologic examination. Positive control 

mice were utilized to compare two known carcinogens to the test article; 100 (C 57BL/6 x 

C3H/anf) F1 mice/sex were fed diets containing 600 ppm 2-acetamidofluorene (AAF), 50 (C

57BL/6 x C3H/anf) F1 mice/sex/dose received 4 mg/kg/day diethylnitrosamine (DEN), and 25 (C

57BL/6 x C3H/anf) F1 mice/sex/dose received 6 mg/kg/day in the drinking water.

There was no RH-893 treatment effect on mortality, but both positive controls (i.e., DEN and 

AAF) caused an increase in mortality. No clinical findings were attributed to chronic feeding of 

octhilinone. High-dose RH-893 mice generally had reduced body weights in the beginning of

the study compared to the negative control group; however, by Week 3 in males and Week 10 in 

females the high-dose RH-893 treated mice had comparable or greater body weight and body 

weight gain than the control group. Body weight was depressed in the positive controls. There 

were no treatment-related effects on liver weight or microscopic pathology in RH-893 treated 

mice.

Positive controls did exhibit an increase in lesions. The DEN animals were found with an 

increased incidence of carcinoma of the hepatocytes in 6-mg/kg/day males and females at weeks 

26 and 30; the 4-mg/kg/day animals were not examined histopathologically. The DEN 6-

mg/kg/day males and females were found with bronchitis or bronchiectasis. The AAF mice had 

increased incidence of hyperplasia of the bladder in the males, urinary bladder carcinoma in both 
Page 50 of 73

sexes and hepatocellular carcinomas in both sexes.

Under the conditions of this 18-month feeding carcinogenicity study, there was no apparent 

carcinogenic potential demonstrated for RH-893 in either male or female (C 57BL/6 x C3H/anf) 

F1 mice exposed to 500 or 1000 ppm. However, a number of study deficiencies precluded 

selection of a LOAEL or NOAEL for this study.

At the doses tested, there was no treatment-related increase in tumor incidence when compared

to controls; however, only 48 animals at the high dose were examined 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 

preliminary 7-week study used to determine appropriate doses for the carcinogenicity study, a 

dose of 1500 ppm or one between 1000 and 1500 ppm may have been a more appropriate high 

dose for this 18-month carcinogenicity study. In the preliminary 7-week study a single male 

administered 1500 ppm died, which is why this dose was neglected.

This carcinogenicity study in mice is UNACCEPTABLE/NOT UPGRADABLE and does not 

satisfy guideline requirement 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 formulation, and lack of microscopic examination of only half of the high-dose RH-893 

mice made 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 Council for determination if the study is sufficient to fulfill the 

requirement for a neurotoxicity study. 

Mutagenicity 

In the Ames Salmonella tests (MRIDs 43935708, 48358626), octhilinone was negative for

reverse mutations in the absence or presence of microsomal S9 in Salmonella 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

mouse bone marrow chromosomal 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 vivo mammalian chromosomal 

aberration assay in rats, (MRID 40647504), the assay was negative. In a mammalian cell in culture

gene mutation assay, L5178Y mouse lymphoma cells cultured in vitro (MRID 43935709), the

test substance (96% a.i.) was not mutagenic 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/mammalian 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-

14C]isothiazolin-3-one 

(99.1-99.2% radiochemical purity, Batch No. 1) dissolved in propylene glycol diluted with water 

was applied to the dorsal skin (10 μL/cm2) 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/cm2 and 0.0019 mg/cm2 skin 

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 postapplication, 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 used. 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 14C-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. 14C-RH-893 diluted in 80% ethanol or acetone 

(100, 500, or 2000 ppm a.i.) was administered onto the shaved backs of animals by occluded 

exposure for 6 hours. 14C-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.

14C-RH-893 prepared in two water-based 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 sites were excised. Skin sites, 

cotton swabs, dental dams, and patches (for occluded exposures) were analyzed for 14C-label. 

The total amount of 14C-label recovered ranged from 79-110% within all groups. The amount of 

14C-label recovered in the application site skin represented the minimal dermal bioavailability. 

The minimal dermal availability of 14C-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%, respectively, of the administered 14C-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 

emulsions, 5-8% and 4-5%, respectively, of the administered 14C-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 14C–label bioavailable to the skin.

This dermal 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 bacteria growth) were maintained at a constant 

temperature of 37o C and continuously stirred throughout each experiment. Aqueous solutions of 

14C-RH-893, solutions of 14C-RH-893 (300 and 1000 ppm) in propylene glycol and solutions of 

14C-RH-893 (1000 ppm) in commercial 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 procedures) with cotton swabs moistened with an aqueous soap solution. Aliquots of 

the bathing solution were obtained at designated time intervals (0-96 hours). 14C-label 

concentrations were measured in the wipes, the bathing solution, the cell cap and cell body 

rinses, and the skin sections using liquid scintillation counters (LSC) and radiographic TLC 

methods. The amount of 14C-RH-893 bioavailable to the skin was defined as the sum of 14Clabel in the skin, the 14C-label that had penetrated through the skin into the bathing solution, and 

the 14C-label measured in the lower cell rinse (expressed as a percentage of the total dose 

applied).

The dermal bioavailability of 14C-RH-893 was measured and calculated to be completely 

bioavailable (112±19% of applied dose) 24 hours following dermal application of a 300 ppm 

aqueous solution of 14C-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 

solutions of 14C-RH-893 (300 ppm) at 3 and 6 hours was 87±14% and 86±10% of the applied 
Page 53 of 73

dose, respectively. The majority (85%) of the 14C-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 14C-RH-893 suggested 

that none of the small amount of 14C-label detected was parent compound.

14C-RH-893 prepared in propylene glycol (300 and 1000 ppm) was more readily 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 14C-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 14C-label detected bound to or 

in the skin. Calculated mean values for the 1000 ppm dosing solution prepared in propylene 

glycol had similar dermal bioavailability values. 

The majority of the 14C-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 highest amount of 14C-label bound to 

or in the skin (30 ±31% at 24 hours and 38±37% at 3 hours, respectively). Dermal 

bioavailability of 14C-RH-893 in each of the emulsifiers was 3-25% of the bioavailability 

(normalized) of the aqueous solutions of 14C-RH-893 (300 ppm in water 3-6 hours postapplication). The majority of the dermally bioavailable 14C-label applied in the latex emulsifier 

doses was detected in the skin sections. Thin layer chromatography analysis of bathing solutions 

associated with the emulsifier dosing solutions 48-96 hours post application indicated that the 

small amounts of the 14C-label penetrating the skin into the bathing solutions represented parent 

compound.

This in vitro dermal absorption study is classified UNACCEPTABLE – NON-GUIDELINE. 

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 appropriate 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 required 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

In a rat metabolism study (MRID 48175501), six groups of Wistar rats were treated with 2-noctyl-4-[4,5-

14C]isothiazolin-3-one (octhilinone; radiochemical purity >99.1%) in propylene

glycol by oral gavage at a dose volume of 5 mL/kg. Three groups of four rats/sex were used for

mass balance studies (Groups 1, 2, and 3), and three groups of three rats/sex were used for
Page 54 of 73

toxicokinetic studies (Groups 4, 5, and 6). The rats were dosed with single gavage dose of

radiolabeled octhilinone at 15 mg/kg (Groups 1 and 4) or 150 mg/kg (Groups 2 and 5), or with

multiple doses of 15 mg/kg for ten days with unlabeled octhilinone, followed by a single 15 

mg/kg dose with radiolabeled octhilinone (Groups 3 and 6). For the mass balance groups, urine,

feces, and volatiles were collected at 0-8, 8-24, 24-48, 48-72, and 72-96 hours post-dose. The

animals were then euthanized at 96 hours, and blood and tissues collected. Total radioactivity

was determined in the urine, feces, and tissues, and selected urine and feces samples were pooled

per group and the metabolite profile was determined. For the toxicokinetic groups, blood was

sampled from each rat at the following time points: 0.5, 1, 2, 4, 8, 24, 48, and 72 hours postdosing, and total radioactivity and equivalent concentrations were determined. The animals were

euthanized at 72 hours.

Following oral administration, the test compound was well absorbed, readily distributed into all 

organs, and extensively metabolized. Excretions of the administered radioactivity via the urine 

and feces was equally important. Metabolism occurred according to three pathways. No 

qualitative differences in metabolite profile were obse4rved between low and high doses or 

between single and repeated dosing. In addition no differences in metabolism were observed 

between the sexes. No parent compound was observed in the urine or feces, indicating extensive 

metabolism of the test compound.

Total recovery was 93.7-99.8% of the administered dose (AD) across all groups. Absorption, 

calculated as the sum of the recoveries from urine, volatiles, cage wash, and tissues/carcass, was

45.5-60.9% AD. There were no sex-related differences in absorption. Overall excretion was 

rapid; the majority of radioactivity was excreted during the first 24 hours in the 15 mg/kg groups 

and during the first 48 hours in the 150 mg/kg group. Slightly more radioactivity was excreted in

the urine than in the feces. Urinary excretion ranged from 41.0-55.6% AD, with more

radioactivity excreted in the urine of the repeated dose group than in the single dose groups. The

majority of urinary radioactivity was excreted during the first 24 hours in the single and multiple

dose 15 mg/kg groups, and during the first 48 hours in the 150 mg/kg group. Fecal excretion

ranged from 36.8-48.4% AD, with more radioactivity excreted in the feces of the 150 mg/kg

group than in the 15 mg/kg groups. Fecal excretion was delayed compared to urinary excretion,

with the majority of radioactivity excreted from 8-48 hours post-dosing. Minor amounts of

radioactivity were detected in exhaled air in the form of 14CO2 (≤2.8% AD). Minor amounts of

radioactivity were also recovered in the cage wash (≤1.2% AD) and in the tissues/carcass

(≤1.9% AD) at 96 hours post-dose.

At 96 hours post-dosing, the residual concentrations of radioactivity in the tissues and residual 

carcass were 0.080-1.276 mg equiv./kg in the 15 mg/kg single dose group, 0.821-13.082 mg 

equiv./kg in the 150 mg/kg single dose group, and 0.099-1.400 mg equiv./kg in the 15 mg/kg 

repeated dose group. Concentrationsin the 15 mg/kg single and repeated dose groups were 

similar, while concentrationsin the 150 mg/kg group were approximately one order of

magnitude higher. The only tissues with concentrations at or above those found in blood were the 

liver and kidney. The concentrations of radioactivity in blood were 11-14 times higher than 

plasma in the 15 mg/kg groups, and 6-7 times higher in the 150 mg/kg group, indicating the test 

substance was associated with the red blood cells, and that this association was possibly

saturated at 150 mg/kg.
Page 55 of 73

In the 15 mg/kg groups, the maximal plasma concentrations were achieved at 0.5-1.0 hour postdosing (except 4.0 hours for the repeat dose males), indicating the test compound was rapidly 

absorbed at low doses. In the 150 mg/kg group, maximal plasma concentrations were attained at

8-24 hours post-dosing, indicating slower absorption at higher doses. Examination of the AUC∞ 

revealed an increase in AUC from 15 to 150 mg/kg that was greater than would be expected with 

the increase in dose (10-fold expected vs. 15- to 21-fold observed). This was considered to be 

suggestive of enterohepatic recirculation of the test compound and/or metabolites.

LC/MS analysis of urine isolated up to 18 metabolites, of which 6 were identified. The 

remaining unidentified urinary metabolites each accounted for <5% of the dose, with the 

exception of Metabolite 13, which accounted for 2.7-8.0% of the dose. A total of 27.3-35.2% of 

the dose was identified in urine. Analysis of fecal extracts isolated and identified four 

metabolites, which together accounted for 17.0-23.9% of the dose. Considering urine and feces, 

a total of 46.3-52.2% of the dose was identified in excreta from both sexes and each dose group. 

Parent compound was not found in either urine or feces.

The metabolism of octhilinone in rats primarily followed one of three pathways: (i) hydrolytic 

cleavage of the S-N bond of the isothiazolinone ring; (ii) oxidation at the isothiazolinone ring at 

either the S-atom or at the double bond; or (iii) oxidation of the octyl chain. Phase II metabolism 

was only observed as glucuronidation.

This metabolism study in the rat is classified Acceptable/Guideline and satisfies the guideline 

requirement for a metabolism study [OPPTS 870.7485, OECD 417] in rats.

Metabolism in Rats (Bile Duct cannulated)

In a rat metabolism study (MRID 47985502), two groups of three bile duct-cannulated male

Wistar rats were treated with 2-n-octyl-4-[4,5-

14C]isothiazolin-3-one (octhilinone; radiochemical

purity ≥99.2%) in propylene glycol by oral gavage (5 mL/kg dose volume) at dose levels of 15 or

150 mg/kg. Bile, urine, and feces were collected at 0-8, 8-24, and 24-48 hours post-dosing. The

rats were then euthanized at 48 hours post-dose. Total radioactivity was determined in urine, bile

and feces, and samples were pool by matrix for each group for analysis. Urine and bile samples

were diluted and then analyzed directly using two

LC/MS methods. Feces were extracted with methanol, and the methanolic extracts were

analyzed by LC/MS.

Total recovery was 95.3% of the administered dose (AD) for the 15 mg/kg group and 100.2% 

AD for the 150 mg/kg group. Absorption, calculated as the sum of the recoveries from urine, 

bile, cage wash, and carcass (without the GI tract), was 65.7-74.9% AD. Overall excretion was 

rapid; the majority of radioactivity was excreted during the first 24 hours in the 15 mg/kg group 

and during the first 48 hours in the 150 mg/kg group.

The majority of the radioactivity was excreted in the urine (44.2-51.5% AD), with the majority 
Page 56 of 73

of urinary radioactivity excreted during the first 24 hours in the 15 mg/kg group, and during the 

first 48 hours in the 150 mg/kg group. Biliary excretion accounted for 19-2-20.2% AD and 

followed a similar pattern as urinary excretion. Fecal excretion accounted for 23.1-29.2% AD, 

and was delayed compared to urinary excretion, with the majority of radioactivity excreted from

8-48 hours post-dosing at 15 mg/kg, and from 24-48 hours at 150 mg/kg. Minor amounts of 

radioactivity were also recovered in the cage wash (0.9-1.2% AD) and in the GI tract/carcass 

(1.8-4.2% AD).

Analysis of the pooled bile samples isolated 9 to 10 peaks of radioactivity, depending on LC/MS 

system used. Analysis of the pooled urine samples isolated 8 or 11 peaks of radioactivity, and 

analysis of the pooled fecal samples yielded on one radioactivity region. A total of four biliary 

metabolites, eight urinary metabolites, and three fecal metabolites were identified by LC/MS.

The identified biliary metabolites accounted for approximately 4% of the total AD in the bile; the 

identified urinary metabolites accounted for 27-38% of the total AD in urine; and the identified 

fecal metabolites accounted for 9.2% of the total AD in feces. Bile and urine had three 

metabolites in common, while urine and feces had one metabolite in common. No parent was 

found in the urine, bile, or feces, indicating extensive metabolism.

Based on the structures of the identified metabolites, the biotransformation of the test compound 

appears to include hydrolytic cleavage of the isothiazolinone ring, oxidation, and truncation. 

Cleavage of the isothiazolinone ring primarily involves hydrolysis of the S-N bond and 

consequent loss of the S-atom. Oxidation occurs on the isothiazolinone ring, either at the S-atom 

or at the double bond, or on the n-octyl chain. Truncation is mainly observed on the alkyl chain. 

Phase II metabolism was observed as glutathione and N-acetylation conjugation.

When considered in conjunction with the separate Tier 1 metabolism study on octhilinone 

(MRID 48175501), this metabolism study in bile-duct cannulated rats is classified 

Acceptable/Guideline and satisfies the guideline requirement for a metabolism study [OPPTS

870.7485, OECD 417] in rats.
Page 57 of 73

Appendix B Environmental 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 oC (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 oC. Four photodegradates were identified: Octhilinone-sulfoxide., N-

(n-octyl)acetamide; 3-(n-octyl)-4-thaizolin-one and N(n-octyl) malonamic acid + N-(noctyl)formic acid (MRID 48358617).

Octanol-Water Partition Coefficient

Its log Kow is 3.4 and this value is a high to trigger bioaccumulation in aquatic organisms

Aerobic Aquatic Metabolism

No review was conducted on the submitted study. Study will be reviewed when the agency 

conducts the fate risk assessment.

Anaerobic Aquatic Metabolism

No review was conducted on the submitted study. Study will be reviewed when the agency 

conducts the 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).

Anaerobic Soil Metabolism

Similar results were obtained under anaerobic conditions

Environmental fate of the degradates:

No environmental 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 agency 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 similar to the parent. 

Therefore, the agency 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 agency

would request asking the percentages for these tow degradates to determine if any environmental

fate studies would be required for these tow degradates.

REFERENCES FOR ENVIRONMENTAL FATE ASSESSMENT

1. Hydrolytic Stability Study of Octhilinone ( 14C)-Acticie OIT), 1999, by Dr. T. Lucas 

MRID#: 447232-01. Submitted by: Acti-Chem Specialties Inc., 56 Quarry Rd., 

Trumbull, CT: 06611-4816. Performing Laboratory: 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 3923-75-11
Page 59 of 73

Appendix C Epi Suite (Version 3.12) 

Ecotoxicity Profile

Toxicity to Terrestrial Receptors

In order to establish the toxicity of octhilinone to avian species, the agency requires an acute oral 

toxicity study and a subacute dietary study using the technical grade active ingredient (TGAI). The 

preferred-test species is either mallard duck (a waterfowl) or bobwhite 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 tables 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%

LD50 = 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%

LD50 = 384

NOAEL = 171 

(a.i.)

Moderately 

toxic

Yes- 14-day 

test duration

- 21 weeks of 

age

448590-01

Bobwhite quail

(Colinus 

virginianus)

Octhilinone

88.7%

LD50 = 346

(a.i.)

Moderately 

toxic

Yes 00026809

Bobwhite quail

(Colinus 

virginianus)

Octhilinone

RH-893

(% purity 

unknown)

LD50 = 565 

(M) and 498 

(F) 

Slightly

toxic

No 86-870001877

(Ecotox data)

Mallard duck

(Anas 

platyrhynchos)

Octhilinone

RH-893

(% purity 

unknown)

LD50 > 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%

LC50 (diet) = 

>3267

NOAEC = 

1288

(a.i.)

Slightly 

toxic

Yes

- 8-day test duration

- 11 weeks of age

416080-02

Bobwhite quail

(Colinus 

virginianus)

Octhilinone 

96%

LC50 (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 

virginianus)

Octhilinone 

88.7%

LC50 (diet) 

>5620 

(a.i.)

Relatively 

nontoxic

Yes

- 8-day test duration

00026808

Mallard duck

(Anas 

platyrhynchos)

Octhilinone 

98.5%

LC50 (diet) = 

1215

NOAEC = 

ND

(a.i.)

Slightly 

toxic

Yes

- 8-day test duration

- 5 days of age

416080-03

Mallard duck

(Anas 

platyrhynchos)

Octhilinone 

88.7%

LC50 (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 nontoxic 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 agency. In most cases, rat and mice 

toxicity values 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 study, OPPTS 

850.3020, is anticipated to be required for OIT.

Terrestrial Plants: A seedling emergence study was submitted testing the effects of OIT on 

Wheat, Rape and Lettuce. The results indicated emergence, survival, dry weight and length 
Page 61 of 73

were significantly affected in all three crop species. The most sensitive endpoints are presented 

in Table C3 . This study 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 Growth Test 

Wheat (Triticum 

aestivum), Lettuce 

(Lactuca sativa), and 

Rape (Brassica 

napus)

OIT 100% Wheat (dry weight) 

EC25=22 mg ai/kg, 

NOEC= 22 mg ai/kg

Rape(dry weight)

EC25=14 mg ai/kg

NOEC=22 mg ai/kg 

Yes 483586-20

Toxicity to Aquatic Receptors

Freshwater Fish: In order to establish the acute toxicity of octhilinone to freshwater fish, the 

agency requires freshwater fish toxicity studies using the TGAI. The preferred test species are 

rainbow trout (a coldwater fish) and bluegill sunfish (a warmwater 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 

(Oncorhynchus 

mykiss)

Octhilinone

96%

LC50 = 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 

(Oncorhynchus 

mykiss 

,formerly 

Salmo 

gairdneri)

Octhilinone

90%

LC50 = 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 416080-04
Page 62 of 73

(Lepomis 

macrochirus)

- 96-hr

- flow-through test 

system

Bluegill 

sunfish 

(Lepomis 

macrochirus)

Octhilinone 

96%

LC50 = 0.16

NOAEC = 

0.07 

(a.i.)

Highly 

toxic

Yes

- 96-hr test duration

- static renewal test 

system

439357-03

Bluegill

(Lepomis 

macrochirus)

Octhilinone

90%

LC50 = 0.196

(a.i.)

Highly 

toxic

No

- 96-hr test duration

- static test system

00026805

Redear

(Lepomis 

macrochirus)

Octhilinone

90%

LC50 = 0.203

(a.i.)

Highly 

toxic

No

- 96-hr test duration

- static test system

00026805

Fathead 

minnow

(Pimephales 

promelas)

Octhilinone

90%

LC50 = 0.140

(a.i.)

Highly 

toxic

No

- 96-hr test duration

- static test system

00026805

Golden shiner

(Notemigonus 

crysoleucas)

Octhilinone

90%

LC50 = 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 highly 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 OPPTS 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 agency 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%

EC50=273 

ug/L

NOAEC=193

ug/L

Very highly 

toxic

Yes 483586-19

Waterflea 

(Daphnia 

magna)

Octhilinone

98.5%

EC50 = 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%

EC50 = 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%

LC50 = 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 850.1010 

(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 testing 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 preferred 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 

results 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

Satisfies Guidelines/

Comments

Reference

(MRID 

No.)

Sheepshead 

minnow 

(Cyprinodon 

variegatus)

Octhilinone

98.5%

LC50 = 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%

LC50 = 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% 

LC50 >0.057

EC50 <0.013

NOAEC< 

0.003

Very highly 

toxic

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 

oysters 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/(72-3c) 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: Chronic toxicity testing (fish early life stage and 

aquatic invertebrate life 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 octhilinone. 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 (419094-01) 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 required 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 diatom, 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 cyanobacteria, 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/

Comments

Reference

(MRID 

No.)

Aquatic vascular 

plant (Lemna 

gibba G3)

OIT 

100.0%

EC50=280 ug/L

(dry weight biomass)

NOAEC=<62 ug/L (dry 

weight biomass)

Yes 485574-04

Marine Diatom 

(Skeletonema 

costatum)

OIT 99.9% IC50=1.6 ug/L (growth 

rate)

NOAEC=1.5 ug/L (growth 

rate) 

Yes 483588-22

Freshwater 

Diatom 

(Navicula 

pelliculosa)

OIT 

100.0%

IC50=0.61 ug/L (biomass) 

NOAEC=<0.143 ug/L 

(biomass)

Yes 485574-05

Freshwater 

Green Algae 

(Pseudokirchner

iella 

subcapitata)

OIT 98.5% IC50=58 ug/L (cell density)

NOAEC=1.42 ug/L (cell 

density)

Yes 483586-21

Bluegreen 

cyanobacteria 

(Anabaenaaquae)

OIT 97.8% IC50=69 ug/L (cell density)

NOAEC=35.1 ug/L (cell 

density)

Yes 485574-06

Green alga 

(Selenastrum 

capricornutum)

Octhilinone

99.2%

EC50 (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 (850.4400 & 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 LC50 – 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 LC50 – 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 LD50 – 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 BioLife Associates, Ltd. for Rohm and Haas Company.

MRID 416080-02. Pedersen, C.A.. 1990. Octhilinone – 8-Day Acute Dietary LC50 Study in 

Bobwhite Quail. Rohm and Haas Report No. 90RC-0021. Unpublished data. Conducted by BioLife Associates, Ltd. for Rohm and Haas Company.

MRID 416080-03. Pedersen, C.A.. 1990. Octhilinone – 8-Day Acute Dietary LC50 Study in 

Mallard 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 Conditions. 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. Lab 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 No. 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. Unpublished 

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-Octylisothiazolone (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 Toxicity 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). Lab 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 

(Europe) 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 448590-01. Rodgers, M. 1999. Acticide OIT: Acute Oral Toxicity (LD50) 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 ( 14C)-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. Laboratory 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 The 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 Freshwater Diatom (Navicula pelliculosa). An unpublished study 

performed by Wildlife International, Ltd., Easton, Maryland. Laboratory study number 103A150. Study sponsored by the Dow Chemical Company, Midland, Michigan. Sponsor study 

number 100201. Study initiated 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 International, Ltd., Eason, Maryland. Laboratory study number 103A149A. 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., Najar, 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: 071114. 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. Laboratory 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): Toxicity 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 January 

2007.
Page 71 of 73

Appendix D Screening 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 

wastewater treatment plants to be exposed to Octhilinone (OIT) and its degradates. The Downthe-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 10th 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 plant 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 expressed 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 plants. 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 potential 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 model 

predicted exceedances of concentrations of concern. 
Page 72 of 73

Appendix E Product 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 Pressure Liquid Chromatography (HPLC)

Capillary Gas Chromatography

830.6302 Color Light golden yellow; Yellow to light brown.

830.6303 Physical State Clear liquid at 25oC.

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 (25oC). No degradation observed for 14 days at 

54 oC. Stable to sunlight, 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) >175oF

830.6316 Explodability Not explosive

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 AcidBase 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 Hgr; 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 This test is not applicable since the test substance does not dissociate into 

ions.

830.7550 Partition coefficient (noctanol/water) 4.4 (PAI)

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

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 pressure at 25°C 3.68 x 10-5 to 4 x 10-6 mm HG at 25°C (PAI)

PAI = Pure Active Ingredient
Page 73 of 73

Appendix F Public Comments

A letter from the Physicians Committee for Responsible Medicine (PCRM) was submitted to the 

docket with the following requests or comments:

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 DPR 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 Carcinogenicity 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.

Agency Response: A footnote was added to Table 6 - Studies Anticipated as Needed for the 

Registration Review of OIT noting that studies 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 study in rats (870.3250 90-day Dermal 

Toxicity in Rats).

Agency Response: GLN 870.3200 21/28 Day Dermal Toxicity study will be removed and 

the lower dermal irritation LOAEL will be added along with an uncertainty factor.