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DIMTS Registration Review Team

Human Health & Environmental Effects

Jenny Tao

Nate Mottl

Kristin Rury

Siroos Mostaghimi

Daniel Cherry

Jim Breithaupt

Risk Management

Lorena Rivas/Jacqueline Hardy

SanYvette Williams

Rose Kyprianou
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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-m3

/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 

DCI data call-in

DOC Dissolved organic carbon

EC50 median (or 50 percent) effect concentration

EC05 5 percent effect concentration

ECOTOX ECOTOXicology

EDI estimated daily intake

EDSP Endocrine Disruptor Screening Program 

E-FAST Exposure and Fate Assessment Screening Tool

EPI Suite Estimation Program Interface Suite

EPA Environmental Protection Agency

FDA Food and Drug Administration 

FFDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act 

FWP Final Work Plan

g/mol grams per mole

GLN guideline number

HPV high production volume

IDS Incident Data System 

Koc organic carbon normalized soil-water partition coefficient

Kd soil-water partition coefficient

Kow octanol-water partition coefficient

LC50 median (or 50 percent) lethal concentration

LD50 median (or 50 percent) lethal dose

LOAEC lowest-observed-adverse-effect-concentration 

LOEC lowest-observed-effect-concentration

LOAEL lowest-observed-adverse-effect-level

Log Kow logarithm of the octanol-water partition coefficient

μg microgram

ml/g milliliter per gram

mg/kg milligram per kilogram

mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury
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MOE margin of exposure 

MRID Master Record Identification Number

MRL maximum residue limit 

N/A not applicable 

nm nanometers

NOAEC no-observed-adverse-effect-concentration

NOAEL no-observed-adverse-effect-level

OCSPP Office of Chemical Safety and Pollution Prevention

OECD Organization for Economic Co-operation and Development

OPP Office of Pesticide Programs

PAD population adjusted dose

PAI pure active ingredient

PDM Probabilistic Dilution Model

% percent

PC Code Pesticide Chemical Code

PCF pounds per cubic foot

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

PHED Pesticide Handler’s Exposure Data

PIS primary irritation score

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

dissociation constant of a solution

ppb parts per billion 

ppm parts per million

PWP Preliminary Work Plan

QSAR quantitative structure-activity relationship

RED Reregistration Eligibility Decision

SAR structure activity relationship

SF safety factor

SSTS Section Seven Tracking System

TEP typical end-use product

TGAI technical grade active ingredient

TMDL total maximum daily loads

UF uncertainty factor

UV/VIS ultraviolet/visible light absorption

% w/w percent weight per weight.

WP wettable powder

WWTPs wastewater treatment plants
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Table of Contents

1 Introduction............................................................................................................................. 7

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

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

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

1.4 Use/Usage Description................................................................................................... 11

1.4.1 Registrations ........................................................................................................... 11

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

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

1.5.1 Recent/Pending Regulatory Actions....................................................................... 12

1.5.2 Tolerance Information ............................................................................................ 12

1.6 Incidents......................................................................................................................... 13

1.6.1 Human Health ......................................................................................................... 13

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

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

3 Human Health Risk Assessment........................................................................................... 16

3.1 Existing Toxicological Endpoints.................................................................................. 16

3.2 Dietary Exposure............................................................................................................ 18

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

3.2.2 Drinking Water ....................................................................................................... 21

3.3 Occupational and Residential Exposures....................................................................... 21

3.3.1 Occupational Handler Exposure ............................................................................. 22

3.3.2 Occupational Post-application Exposure ................................................................ 22

3.3.3 Residential Handler Exposures............................................................................... 23

3.3.4 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 Waste Water Treatment Plants (WWTP)................................................................ 26

4.1.2 Water Quality.......................................................................................................... 26

4.2 Conceptual Models for Environmental Exposure Pathways.......................................... 26

4.3 Ecological Effects Assessment....................................................................................... 27

4.3.1 Mechanism of Action.............................................................................................. 27

4.3.2 Measures of Effect (Ecotoxicology Endpoints)...................................................... 27

4.4 Exposure Analysis Plan.................................................................................................. 28

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates ............................................ 28

4.4.2 Screening Level Down-the-Drain Analysis............................................................ 28

4.5 Effects Analysis Plan ..................................................................................................... 30

5 Endocrine Disruptor Screening Program (EDSP)................................................................. 30

6 Optional Label Changes........................................................................................................ 31

7 Guidance for Commenters.................................................................................................... 31

7.1 Preliminary Work Plan................................................................................................... 31

7.1.1 Trade Irritants.......................................................................................................... 31

7.1.2 Water Quality.......................................................................................................... 31
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7.1.3 Environmental Justice............................................................................................. 32

7.1.4 Structure Activity Relationships............................................................................. 32

7.1.5 Additional Information ........................................................................................... 33

8 Next Steps............................................................................................................................. 33

9 References............................................................................................................................. 34

Appendix A Toxicology Profile............................................................................................... 35

Appendix B Environmental Fate ............................................................................................. 64

Appendix C Ecotoxicology Profile.......................................................................................... 71

Appendix D Screening Level Down-the-Drain Analysis ........................................................ 76

Appendix E Product Chemistry............................................................................................... 77

List of Tables

Table 1 – Summary of Anticipated Risk Assessments and Data Needs for Registration Review: 

DIMTS ............................................................................................................................................ 8

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

Table 3 – Chemical Identification of DIMTS................................................................................. 9

Table 4 – Physical-Chemical and Environmental Fate Properties for Parent DIMTS ................... 9

Table 5 – Physical-Chemical and Environmental Fate Properties for Monoiodo-pmethyltolylsulfone (MIMPTS), methyl-p- tolylsulfone (MPTS), and p-toluene sulfonic acid 

(PTSOA) Degradates.................................................................................................................... 10

Table 6 – Summary of Diiodomethyl p-tolyl sulfone (DIMTS) Registered Uses........................ 11

Table 7 – Studies Anticipated as Needed for the Registration Review of DIMTS ...................... 14

Table 8 – Data Needs Required by the February 24, 2010 Data Call-In for the DIMTS RED.... 15

Table 9 – Existing Toxicological Endpoints for DIMTS.............................................................. 16

Table 10 – Occupational Handler Exposure Scenarios for DIMTS ............................................. 22

Table 11 – Residential Handler Exposure Scenarios for DIMTS................................................. 23

Table 12 – Residential Post-Application Exposure Scenarios for DIMTS................................... 23

Table 13 – Selected Ecological Effects Endpoints for Risk Assessment of DIMTS.................... 27

Table 14 – Summary of Screening Level Down-the-Drain Analysis Results for Aquatic 

Organisms..................................................................................................................................... 29
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1 Introduction

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

agency”) Preliminary Work Plan (PWP) for Diiodomethyl p-tolyl sulfone (DIMTS), formerly

referred to as Amical 48. The PWP document explains what EPA's Office of Pesticide Programs 

(OPP) knows about DIMTS, 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 the DIMTS review.

The registration review process was designed to include a public participation component to 

solicit input from interested stakeholders. The agency intends, by sharing this information in the 

docket, to inform the public of what it knows about DIMTS and what types of new data or other 

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

The agency encourages all interested stakeholders to review the PWP and to provide comments 

and additional information that will help the agency’s decision-making process for this chemical.

1.1 Statutory and Regulatory Authority

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

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

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

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

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

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

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

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

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

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

http://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. After 

reviewing and responding to comments and data received in the docket during this initial 

comment period, the agency will develop and commit to a Final Work Plan (FWP) and 

anticipated schedule for the DIMTS case. 

1.2 Case Overview

The docket for DIMTS (case 4009) has been established at http://www.regulations.gov in docket 

number EPA-HQ-OPP-2015-0264. Documents associated with this registration review can be 
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viewed in this docket. Tables 1-2 below summarize the issues relevant to this registration review 

case and the anticipated registration review schedule.

Table 1 – Summary of Anticipated Risk Assessments and Data Needs for Registration 

Review: DIMTS

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 7 for details)

Dietary (food) Yes 3/28/2008

(RED) Updated Toxicology and Residue Data (Table 7)

Dietary (drinking water) Yes N/A New Environmental Fate Data (Table 7)

Occupational Handler Yes 3/28/2008 Updated (Table 7)

Occupational PostApplication Exposure No 3/28/2008 None None

Residential Handler Yes 3/28/2008 Updated (Table 7)

Residential Post 

Application - Incidental 

Oral and Dermal 

Yes 3/28/2008 Updated (Table 7)

Residential Post 

Application - Inhalation No 3/28/2008 None None

Aggregate Yes 3/28/2008 Updated (Table 7)

Cumulative No 3/28/2008 None None

Tolerance Review No N/A None None

Ecological Yes 11/1/2007 Updated Leaching-adsorption-desorption and 

Ecotoxicity data

N/A = Not applicable

* Table 1 is a summary of the anticipated risk assessments and data needs for Registration Review. For data called in through the postReregistration Eligibility Decision (RED) Data Call-In (DCI), see Table 8 of this PWP.

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 2015-09 2015-09

Close Public Comment Period 2015-11 2015-11

Phase 2: Case Development 

Issue Final Work Plan 2016-03

Issue Data Call-In (DCI) 2017-03

Receive Data to be Considered in Risk Assessment 2019-03

Open 30-Day Public Comment Period for Preliminary Risk Assessment(s) 2020-09

Close Public Comment Period 2020-10
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Phase 3: Registration Review Decision and Implementation 

Open 60-Day Public Comment Period for Proposed Decision 2021-03

Close Public Comment Period 2021-05

Issue Final Decision 2021-09

Begin Post-Decision Follow-up 2021

Total (years) 6

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

respect to the active ingredients in this case).

1.3 Chemical Identification and Properties

Table 3 presents the active ingredient to be assessed in case 4009: DIMTS (PC Code 101002).

Table 3 – Chemical Identification of DIMTS

Chemical Name DIMTS Reference/Comments

PC Code 101002 N/A

CAS Number 20018-09-1 EPI-WEB 4.11

Smiles code O=S(=O)(c(ccc(c1)C)c1)C(I)I EPI-WEB 4.11

Molecular Formula C8H8I2O2S EPI-WEB 4.11

Molecular Weight 

(grams/mole) 422.02 EPI-WEB 4.11

Molecular Structure

N/A

The physical chemistry information for parent DIMTS relevant to risk assessment is summarized 

in Table 4, while the physical chemistry information for the degradates monoiodo-pmethyltolylsulfone (MIMPTS, parent compound minus one iodo group), methyl-p- tolylsulfone 

(MPTS, parent compound minus both iodo groups) and p-toluene sulfonic acid (PTSOA, parent 

compound minus both iodo groups and a methyl group with added hydroxyl group) are 

summarized in Table 5. Further information on physical chemistry is located in Appendix E. 

Table 4 – Physical-Chemical and Environmental Fate Properties for Parent DIMTS

Guideline No. Parameter DIMTS Reference (MRID unless specified)

Comments

830.7050 UV/Visible Absorption Max sorption at 288 nm, 

some tailing through 409 nm 47234003

830.7370 Dissociation constant (pKa) Not applicable 48511201
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Guideline No. Parameter DIMTS Reference (MRID unless specified)

Comments

830.7550 Octanol-water partition coefficient 

at 25 oC (Log Kow) 2.66 42177202

830.7840 Solubility in water (mg/L) <2 47373801

830.7950 Vapor pressure (mmHg) 4.9 x 10-7 47373801

None Henry's law constant at 25 oC 

(atm-m3/mol) 1.4 x 10-7 Calculated

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

millimeters of mercury.

Table 5 – Physical-Chemical and Environmental Fate Properties for Monoiodo-pmethyltolylsulfone (MIMPTS), methyl-p- tolylsulfone (MPTS), and p-toluene sulfonic acid 

(PTSOA) Degradates

Guideline 

No. Parameter

Monoiodo-pmethyltolylsulfone 

(MIMPTS)

Methyl-p-tolyl 

sulfone

(MPTS)

P-toluene sulfonic 

acid (PTSOA)

Reference (MRID 

unless specified)

Comments

None Structure None

None Description Parent minus 1 iodine Parent minus two 

iodines

Hydroxylated, 

once-demethylated 

MPTS None

None PC Code None None None Not applicable

None CAS No. 37891-96-6 59203-01-9 104-15-4

Dow MSDS 

(MIMPTS)

Chemical Book 

(MPTS)

None Smiles code O=S(=O)(c(ccc(c1)C)

c1)C(I)

O=S(=O)(c(ccc(c1)C)

c1)C

O=S(O)(=O)(c(ccc(

c1)C)c1) EPI-WEB 4.11

None Molecular 

formula C8H9IO2S C8H10O2S C7H8O3S EPI-Web 4.11

None Molecular 

weight 296.12 170.23 172.20 EPI-WEB 4.11

830.7050 UV/Visible 

Absorption No data No data No data Similar to parent

830.7370 Dissociation 

constant (pKa) Not applicable Not applicable Not applicable Similar to parent 

830.7550

Octanol-water 

partition 

coefficient at 

25 o

C (Log 

Kow)

2.3 1.94 -0.62

47338402 (MIMPTS 

and MPTS)

EPI-WEB 4.11 

(PTSOA)

830.7840 Solubility in 

water (mg/L) 140.4 1,352 6.2 x 105

47338402 (MIMPTS 

and MPTS)

EPI-WEB 4.11 

(PTSOA)

O

S

O

H3C

I O

H3C S O

CH3
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Guideline 

No. Parameter

Monoiodo-pmethyltolylsulfone 

(MIMPTS)

Methyl-p-tolyl 

sulfone

(MPTS)

P-toluene sulfonic 

acid (PTSOA)

Reference (MRID 

unless specified)

Comments

830.7950 Vapor pressure 

(mmHg) 2.3 x 10-5 2 x 10-3 2.9 x 10-6 EPI-WEB 4.11

None Henry's law 

constant at 25 

o

C (atmm3

/mol)

6.4 x 10-8 3.3 x 10-7 1.1 x 10-12 Calculated

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

millimeters of mercury.

1.4 Use/Usage Description

1.4.1 Registrations

There are seven EPA-registered products that contain diiodomethyl p-tolyl sulfone as an active 

ingredient (a.i.). The percent a.i. ranges from 0.95 to 95 percent, and the formulations include 

flowable and soluble concentrates, liquids, and wettable powder. Some of these registered 

products also contain other active ingredients such as propiconazole, 3-iodo-propyl butyl 

carbamate (IDPC), and chlorothalonil.

1.4.2 Summary of Registered Uses

A summary of the registered uses of DIMTS that will be assessed in this registration review is 

shown in Table 6. DIMTS can be applied by the following application methods: roll coating, 

liquid pour, liquid pump, solid pour, solid place, sapstain spray and dip, airless sprayer (paints 

and stains), paint brush/roller (paints and stains) and high pressure sprayer (treated wood). 

Table 6 – Summary of Diiodomethyl p-tolyl sulfone (DIMTS) Registered Uses

Uses Application Method Application Rate

Material Preservatives

Paints Liquid Pour

Liquid Pump 5700 ppm

Roll Coating

Paintbrush/Roller

2850 ppm Airless Sprayer

Solid Pour

Solid Place

Adhesives, caulks, dispersions, and 

sealants

Solid Pour

2358 ppm Solid Place

Liquid Pour 1650 ppm Liquid Pump

Pigment Dispersions, Inks and Extender 

Slurries

Liquid Pour 1425 ppm Liquid Pump
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Uses Application Method Application Rate

Rubber, Plastics and Vinyl Products Liquid Pour 7600 ppm

Liquid Pump 7600 ppm

Paper Production

Liquid Pour 3156 ppm

Liquid Pump 3156 ppm

Solid Pour 3156 ppm

Solid Place 3156 ppm

Hides and Leather

Liquid Pour 2650 ppm

Liquid Pump 2650 ppm

Solid Pour 3000 ppm

Solid Place 3000 ppm

Textiles

Liquid Pour 5000 ppm

Liquid Pump 5000 ppm

Solid Pour 4750 ppm

Solid Place 4750 ppm

Wood Preservatives

Forest Products Pressure Treatment 0.0065 lb ai/cu. ft

Forest Products High Pressure Spray 400 ppm

Forest Products Spray Sapstain

40 ppm

Forest Products Dip

1.5 Regulatory History

DIMTS was first registered as an active ingredient on September 17, 1980. A Reregistration 

Eligibility Decision (RED) was done in 2008. Currently, there are seven active registrations

(EPA Reg. Nos. 464-670, 464-672, 464-673, 60061-112, 60061-126, 60061-127, and 74075-1)

for products containing DIMTS as an algaecide, bactericide, and fungicide. It is used as a 

materials preservative in paints, air duct coatings, fire-retardant coatings, pigment dispersions, 

inks, emulsions, extender slurries, adhesives, caulks, sealants, rubbers, plastic, textiles, leather, 

paper production to protect pulp and slurries, paper/paperboard, and wetlap. It is also used as a 

wood preservative.

1.5.1 Recent/Pending Regulatory Actions

There are no recent or pending regulatory actions for DIMTS.

1.5.2 Tolerance Information

For DIMTS, there are no EPA registered direct food contact uses. However there are multiple 

registered labeled uses that could result in indirect food contact including under 21 CFR parts 

175, 176 and 177: (1) use in caulks and sealants (adhesives), (2) use in rubber and plastic 

products (polymers), and (3) use as a mold preventer during paper production and paper storage
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(paper slimicides). There is a Food and Drug Administration (FDA) food additive regulation 

under CFR 176.300, which allows 0.2 lb DIMTS per ton of dry weight fiber for paper and paper 

board. This food additive regulation in relation to currently registered uses for DIMTS is 

discussed further in Section 3.2.1 of this document.

EPA has not established tolerances or exemptions for tolerances in/on any raw agricultural 

commodities or processed food and feed products under the Federal Food, Drug and Cosmetic 

Act (FFDCA) Section 408.

1.6 Incidents

1.6.1 Human Health 

No DIMTS human poisoning incidents have been reported in OPP’s Incident Data System (IDS) 

since 1992 based on the search conducted on June 25, 2015.

1.6.2 Ecological

No DIMTS ecological incidents have been reported in IDS since 1992 based on the search 

conducted on June 23, 2015. 

2 Anticipated Data Needs

Several studies were already required from the assessment of DIMTS in the 2008 RED. In 

addition to the already-required RED DCI data, the following studies as listed in Table 7 are 

anticipated to be needed for the registration review of DIMTS. Table 8 outlines the data 

requirements required by the post-RED DCI issued on February 24, 2010. The agency

anticipates reviewing any data received in response to the post-RED DCI as well as data 

requested for this registration review prior to conducting the registration review risk assessments 

for DIMTS. 
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Table 7 – Studies Anticipated as Needed for the Registration Review of DIMTS

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

835.1230 Leaching-adsorptiondesorption

TGAI, 

MIMPTS, 

MPTS

12 Ecological All Ecological exposure and 

drinking water

850.1075 Acute estuarine/marine 

fish toxicity TGAI 12 Ecological All Ecological exposure

850.1035 Mysid acute toxicity test TGAI 12 Ecological All Ecological exposure

850.1025 Oyster acute toxicity test TGAI 12 Ecological All Ecological exposure

850.1300 Aquatic invertebrate life 

cycle MIMPTS 12 Ecological All Ecological exposure

850.1400 Fish early-life stage MIMPTS 12 Ecological All Ecological exposure

850.3020 Honeybee acute contact TGAI 12 Ecological All Ecological exposure

850.4400 Aquatic vascular plant 

growth TEP 12 Ecological All Ecological exposure

850.4500 Aquatic plant growth 

(algal) 1 TEP 12 Ecological All Ecological exposure

850.4550 Cyanobacteria toxicity 1 TEP 12 Ecological All Ecological exposure

860.1340 Residue analytical method TGAI 12 Human Health All Human health exposure

860.1380 Storage stability data TGAI 12 Human Health All Human health exposure

870.4300 Combined Chronic 

Toxicity/Carcinogenicity TGAI 24 Human Health All Human health exposure

870.6200 Neurotoxicity screening 

battery 2 TGAI 24 Human Health All Human health exposure

870.7800 Immunotoxicity 3 TGAI 12 Human Health All Human health exposure

None Migration Study 4 EP 12 Human Health

Paper production, 

plastics, adhesives 

and sealants 

Human health exposure

1In a Federal Register Notice dated June 27, 2012, EPA split the Public Draft OPPTS 850.5400 test guideline into two test guidelines: OCSPP 850.4500 and 

OCSPP 850.4550. See “Final Test Guidelines; OCSPP 850 Series; Notice of Availability” 77 FR 38282, June 27, 2012. 

http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0154-0028. 2

Acute (study due 12 months after receipt of DCI) and subchronic (study due 24 months after receipt of DCI) neurotoxicity studies are anticipated to be required. 

A protocol should be submitted to the agency for review prior to conducting the neurotoxicity studies. 3 All 90-day subchronic studies in the rodent can be designed to simultaneously fulfill the requirements of the 90-day immunotoxicity studies by adding separate 

groups of animals for testing of immunotoxicity parameters.
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4 Based on the results of the screening-level dietary (food) analysis for paper mold inhibition, paper plant storage and preservation, and food-contact polymers 

using label-provided inputs resulting in risks above the agency’s level of concern for some population subgroups, the migration study is expected to be required

and protocols must be approved by the agency prior to the initiation of the study.

Table 8 – Data Needs Required by the February 24, 2010 Data Call-In for the DIMTS RED

GLN Study Name Status

875.1100 Dermal exposure--outdoor

Study not received

875.1300 Inhalation exposure- outdoor

875.1600 Application exposure monitoring data reporting Waived

875.2300 Indoor Surface Residue Dissipation Study not received

875.1700 Product Use

Acceptable

875.2700 Product Use

875.2800 Description of Product Use
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3 Human Health Risk Assessment

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

agency will evaluate the additional data required by the post-RED DCI. Additionally, the agency 

anticipates the need to require additional data for the registration review of DIMTS, based on the 

currently registered uses. These additional studies include mammalian toxicity data from a

combined chronic toxicity/carcinogenicity study, an immunotoxicity study and neurotoxicity 

screening battery, and all applicable exposure studies. A detailed description of the available 

toxicity studies is provided in Appendix A.

3.1 Existing Toxicological Endpoints

The agency anticipates the need to revise the existing toxicological endpoints from the 2008 

RED, shown in Table 9, as part of registration review. All available information, including 

existing toxicology studies and valid scientific literature, will be considered in establishing the 

toxicology endpoints to be used in the registration review risk assessment.

Table 9 – Existing Toxicological Endpoints for DIMTS

Exposure 

Scenario

Dose Used in

Risk Assessment

(mg/kg/day)

Target MOE, UF, Special 

FQPA SF, for Risk 

Assessment

Study and

Toxicological Effects

Dietary Risk Assessments

Acute Dietary

(All populations)

No appropriate endpoint can be selected for acute RfD.

Chronic Dietary

(All populations)

NOAEL = 2 UF = 1000 (10x for interspecies extrapolation, 10x for 

intra-species variation, and 

10x for lack of chronic and 

cancer data)

90-Day Oral Toxicity Study in Dogs 

(MRIDs 42054403 & 43246402) 

LOAEL = 2 mg/kg/day, based on 

histopathologic changes in the 

thyroid glands (degeneration 

[mineralization within colloid 

clumping of sloughed follicular cells 

and colloid depletion]) in the midand high-dose males and females, 

salivary gland (sialadenitis [ducted 

and periductal inflammation]) and 

gastrointestinal (GI) tract 

(hemorrhagic gastritis, necrosis).

cRfD = 0.002 mg/kg/day

Non-Dietary Risk Assessments

Incidental Oral

Short-Term 

(1-30days) 

NOAELmaternal = 4 UF = 100 (10x for interspecies extrapolation, 10x for 

intra-species variation)

Developmental Toxicity in Rabbits

(MRIDs 42243801/43246404)

LOAEL = 15 mg/kg/day, based on 

clinical signs, reduced body weight 

gain and food consumption.
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Exposure 

Scenario

Dose Used in

Risk Assessment

(mg/kg/day)

Target MOE, UF, Special 

FQPA SF, for Risk 

Assessment

Study and

Toxicological Effects

Incidental Oral

IntermediateTerm

(1-6 months) 

NOAEL = 2 UF = 100 (10x for interspecies extrapolation, 10x for 

intra-species variation)

90-Day Oral Toxicity Study in Dogs 

(MRIDs 42054403/43246402) 

LOAEL = 10 mg/kg/day, based on 

histopathological changes observed 

in the thyroid glands (degeneration 

of the thyroid gland [mineralization 

within colloid clumping of sloughed 

follicular cells and colloid 

depletion]), salivary gland 

(Sialadenitis [ductal and periductal 

inflammation of the salivary gland]) 

and gastrointestinal (GI) tract

(hemorrhagic gastritis, necrosis of 

the small intestine and keratitis).

Dermal 

Absorption 

Factor

12% (based on a pharmacokinetics and metabolism study in rats (MRID 47076641)

Dermal

Short-Term 

(1-30 days)

NOAELmaternal = 4 UF = 100 (10x for interspecies extrapolation, 10x for 

intra-species variation)

Developmental Toxicity in Rabbits

(MRIDs 42243801/43246404)

LOAEL = 15 mg/kg/day, based on 

clinical signs, reduced body weight 

gain and food consumption.

Dermal

IntermediateTerm

(1-6 months)

NOAEL = 2 MOE = 100 (10x for interspecies extrapolation, 10x for 

intra-species variation)

90-Day Oral Toxicity Study in Dogs 

(MRIDs 42054403/43246402) 

LOAEL = 10 mg/kg/day, based on 

histopathological changes observed 

in the thyroid glands (degeneration 

of the thyroid gland [mineralization 

within colloid clumping of sloughed 

follicular cells and colloid 

depletion]), salivary gland 

(Sialadenitis [ductal and periductal 

inflammation of the salivary gland]) 

and gastrointestinal (GI) tract

(hemorrhagic gastritis, necrosis of 

the small intestine and keratitis).
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Exposure 

Scenario

Dose Used in

Risk Assessment

(mg/kg/day)

Target MOE, UF, Special 

FQPA SF, for Risk 

Assessment

Study and

Toxicological Effects

Dermal

Long-Term

(> 6 months)

NOAEL = 2 MOE = 1000 (10x for interspecies extrapolation, 10x for 

intra-species variation, 10x 

for lack of chronic and 

cancer and reproductive 

data)

90-Day Oral Toxicity Study in Dogs 

(MRIDs 42054403/43246402) 

LOAEL = 10 mg/kg/day, based on 

histopathological changes observed 

in the thyroid glands (degeneration 

of the thyroid gland [mineralization 

within colloid clumping of sloughed 

follicular cells and colloid 

depletion]), salivary gland 

(Sialadenitis [ductal and periductal 

inflammation of the salivary gland]) 

and gastrointestinal (GI) tract

(hemorrhagic gastritis, necrosis of 

the small intestine and keratitis).

Inhalation

(All Durations)

NOAEL = 2 MOE = 1000 (10x for interspecies extrapolation, 10x for

intra-species variation, 10x 

for route-to-route 

extrapolation)

 

90-Day Oral Toxicity Study in Dogs 

(MRIDs 42054403 & 43246402) 

LOAEL = 10 mg/kg/day, based on 

histopathological changes observed 

in the thyroid glands (degeneration 

of the thyroid gland [mineralization 

within colloid clumping of sloughed 

follicular cells and colloid 

depletion]), salivary gland 

(Sialadenitis [ductal and periductal 

inflammation of the salivary gland]) 

and gastrointestinal (GI) tract

(hemorrhagic gastritis, necrosis of 

the small intestine and keratitis).

Cancer

(oral, dermal, 

inhalation)

No carcinogenicity data available for DIMTS. This study is anticipated to be required.

3.2 Dietary Exposure

The agency anticipates the need to conduct a dietary exposure (food and drinking water) 

assessment to support registration review of DIMTS since there are multiple labeled uses that 

could result in indirect food contact and the potential for entering surface water and, therefore, 

dietary exposure (food and drinking water) to DIMTS. 

3.2.1 Food

The agency anticipates the need to conduct dietary (food) exposure assessments as part of the 

registration review process to update the previously conducted dietary (food) exposure 

assessments in the 2008 RED. There are multiple labeled uses that could result in indirect food 

contact, and, therefore, dietary exposure to DIMTS. The registered uses of DIMTS (EPA Reg. 

Nos. 464-670, 464-672, and 464-673) that may result in dietary exposure include: (1) use in 
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caulks and sealants, (2) use in rubber and plastic products, and (3) use as a mold preventer during 

paper production and paper storage. 

Currently, the label statement on EPA Reg. No. 464-670 reads “This product is not cleared for 

use in the manufacture of paper and paperboard products that come in contact with food.” 

However, this registrant indicated they plan to submit a label change amendment and other 

information in order to allow food contact use.

A screening-level (food only) analysis was conducted using established toxicological points of 

departure (PODs). Each end-use product results in different screening-level inputs and analysis 

results. There are no effects attributable to a single dose for DIMTS; therefore an acute 

population adjust dose was not established, and an acute dietary exposure assessment was not 

conducted. However, the chronic population adjusted dose (cPAD) is 0.002 mg/kg/day for 

DIMTS. Additional toxicity and residue chemistry data are anticipated to be required based on 

the result of the screening-level analyses.

Dietary Exposure Assessment – Paper Production

Three end-use product labels could result in indirect food contact to DIMTS: EPA Reg. Nos. 

464-670, 464-672, and 464-673. The results have been presented here for the three products for 

both mold inhibition during paper production and for use in paper plant storage. 

Paper Mold Inhibition During Production 

For the use of DIMTS to prevent mold during paper production, the screening-level dietary risk 

assessment indicates that chronic dietary (food only) exposure and risk estimates exceed the 

level of concern (LOC) [i.e., >100% of the PAD] for some sub-populations for all the registered 

end-use products. 

For the use of DIMTS to prevent mold during paper production, and assuming a food contact 

surface area of 2000 cm2

, the screening-level model for paper production results in a total 

estimated daily dietary intake of DIMTS less than 200 ppb for all three EPA Reg. Nos. 464-673, 

464-672 and 464-670. 

Mold Inhibition During Paper Plant Storage

DIMTS is approved for use in preserving finished paper or paper plant pulp, alum, broke, 

polymers, defoamers, emulsions, adhesives, paper mill coatings, pigments, and slurries. For 

these uses of DIMTS, the screening level dietary exposure analysis indicates that the chronic 

dietary (food only) exposure and risk estimates exceed the level of concern (LOC) [i.e., >100% 

of the PAD] for all population subgroups and all EPA registered end-use products. 

For the use of DIMTS to prevent mold during paper plant preservation, and assuming a food 

contact surface area of 2000 cm2

, the screening-level model for paper production results in a total 

estimated daily dietary intake of DIMTS greater than 200 ppb for all population subgroups and 

registered labels; EPA Reg. Nos. 464-673, 464-672 and 464-670. 
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Dietary Exposure Assessment – Paper Production Using FDA Food Additive Regulation Level

The concentrations listed on EPA Reg. Nos. 464-673, 464-672 and 464-670 are greater than the 

currently established FDA food additive regulation under CFR 176.300, which only allows 0.2 lb 

DIMTS per ton of dry weight fiber. Using the assumption of 0.2 lb DIMTS per ton of dry 

weight fiber, the screening-level dietary exposure analysis for paper production indicates that the 

chronic dietary (food only) risk estimates do not exceed the level of concern (LOC) [i.e., < 100% 

of the PAD] for all population subgroups. Furthermore, using the FDA Food Additive 

Regulation Level for DIMTS and assuming a food contact surface area of 2000 cm2

, the 

screening-level model for paper production results in a total estimated daily dietary intake (EDI) 

of DIMTS less than 200 ppb for all population subgroups. If the registered DIMTS labels intend 

to treat paper that may contact food, the labels should be revised to comply with the FDA food 

additive regulation level of 0.2 lb a.i. per ton of dry weight fiber. If labels are not changed before 

the risk assessment for this registration review, the dietary assessment will be done using 395 

ppm listed on the EPA labels.

Dietary Exposure Assessment – Adhesives 

Two products containing DIMTS allow for use in adhesives and sealants; EPA Reg. Nos. 464-

670 and 464-673. Use of DIMTS in sealants used in food packaging may result in DIMTS

migrating into food indirectly. Therefore, a screening-level analysis was completed for DIMTS. 

The screening-level assessment was based on the FDA guidance and assumed that a maximum of 

seven ppb DIMTS may migrate from the food packaging adhesive into the food; which is a 

conservative estimate. Using these assumptions, the screening-level dietary exposure analysis for 

DIMTS in food-contact adhesives indicates that the chronic dietary (food only) risk estimates do 

not exceed the level of concern (LOC) [i.e., < 100% of the PAD] for all population subgroups. 

Furthermore, the use of DIMTS in food contact adhesives and assuming a food contact surface 

area of 2000 cm2

, the screening-level model for adhesives results in a total estimated daily 

dietary intake (EDI) of DIMTS less than 200 ppb for all population subgroups and registered 

labels. 

Dietary Exposure Assessment – Polymers 

EPA Reg. No. 464-670 allows for use of DIMTS in plastic products that may contact food. 

Therefore, a screening-level analysis was completed for DIMTS in polymers. The assessment 

was conducted using the screening-level FDA model for food contact (hard surfaces) in 

commercial areas since no chemical-specific information on density was available. Additionally, 

the screening-level assessment assumed that 100% of the DIMTS residues in the plastics will 

migrate to food and a food contact surface of 4000 cm2, which are conservative assumptions. 

The assessment was based on the registered product concentration of 0.8% DIMTS. Using these 

assumptions, the screening-level dietary exposure analysis for DIMTS in food-contact plastics

indicates that the chronic dietary (food only) risk estimates exceed the level of concern (LOC) 

[i.e., > 100% of the PAD] for all population subgroups. 
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Furthermore, the use of DIMTS in food contact polymers and assuming a food contact surface 

area of 4000 cm2

, the screening-level model for plastics results in a total estimated daily dietary 

intake (EDI) of DIMTS greater than 200 ppb.

Conclusions & Data Requirements

The results of the screening-level analysis for paper mold inhibition, paper plant storage and 

preservation, and food-contact polymers using label-provided inputs result in risks above the 

agency’s level of concern for some population subgroups. Additional residue data, including 

migration studies, residue analytical method for data collection (Guideline 860.1340), and 

storage stability studies (860.1380), are required because the level of concern is exceeded, per 40

CFR§158.2290. The labeled uses may need to be removed or revised during Registration Review 

if additional refinement data are not available for the risk assessment. 

Additionally, the total daily dietary intake for chronic exposures for paper plant preservation and 

polymers is > 200 ppb for the US population and/or some population subgroups. Therefore, 

under 40CFR§158.2230, a total daily dietary intake greater than 200 ppb triggers toxicity data 

that should be submitted to the agency.

3.2.2 Drinking Water

DIMTS is also registered for use as a fungicide to control mold and sapstain fungi that cause 

discoloration and staining of freshly sawn lumber. It can also be applied to dimensional lumber, 

logs, plywood, Oriented Strand Board (OSB) and particle board to prevent surface mold growth. 

There are uncertainties with respect to DIMTS as well as its degradates entering drinking water 

based on the use patterns, the potential for exposure to surface water during manufacturing for 

the use as a materials preservative, and leaching of DIMTS from treated wood demonstrated in 

the available data.

The agency has not previously conducted a drinking water assessment for DIMTS and its 

degradates. Based on the registered uses, however, the agency cannot rule out the potential for 

exposure of humans to the parent DIMTS and/or its degradates in drinking water. Leaching of 

DIMTS from treated wood was demonstrated (MRID 47375907), and there is the potential for 

exposure to surface water during manufacturing for the use as a materials preservative. In 

addition, based on the water solubility values of parent DIMTS in Table 4 and the degradation 

products in Table 5 and observations in the anaerobic aquatic metabolism study (MRID 

42177201), most environmental residues of DIMTS are expected to partition to water in the 

presence of soil and sediment. Moreover, the agency does not have adequate fate data on 

sorption of parent compound and its degradation products to determine the potential for 

contamination of drinking water. These fate data are anticipated to be required during 

registration review, as noted in Table 7 of this PWP. These data will be used to determine 

whether and to what extent DIMTS and its degradates pass through the WWTP that may result in 

human dietary exposure through drinking water which may trigger a drinking water assessment.

3.3 Occupational and Residential Exposures
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The agency anticipates the need to update the occupational and residential exposure (ORE) 

assessment which was originally performed for the 2008 RED. The earlier ORE assessment from 

the RED will need to be revised to incorporate any revised toxicology endpoint selections and to 

utilize the exposure data anticipated to be received from the post-RED DCI.

3.3.1 Occupational Handler Exposure

EPA anticipates the need to revise the occupational handler assessment conducted in support of 

the 2008 RED. The ORE was conducted on March, 2008 (D344853). Occupational handler 

dermal and inhalation exposures to DIMTS were assessed in the RED for the following 

applications: liquid pour, liquid pump, solid pour, solid place, paintbrush/roller, pressure 

treatment, non-pressure treatment (dip and spray) and airless sprayer. The agency expects to 

conduct new assessments for liquid pour, solid pour, paintbrush/roller, pressure treatment and 

airless sprayer scenarios in registration review upon receipt of the anticipated exposure data 

expected from the RED DCI. These exposures were originally assessed using unit exposure data 

from the Pesticide Handler Exposure Database (PHED) and Chemical Manufacturer’s 

Association (CMA) data in the RED. 

Table 10 – Occupational Handler Exposure Scenarios for DIMTS

Scenario Exposure 

Route(s) Duration

Occupational Exposures

Open Pour of Liquids for Material Preservatives* Dermal 

Inhalation 

Short and Intermediate 

Term 

Solid Pour of Wettable Powders for Material Preservatives* Dermal 

Inhalation 

Short and Intermediate 

Term 

Application of Paints and Stains (Brush/Roller and Airless Sprayer) Dermal

Inhalation

Short and Intermediate 

Term

Sapstain Dip for Wood Preservatives Dermal 

Inhalation

Short, Intermediate and 

Long-term

Sapstain Spray for Wood Preservatives Dermal 

Inhalation

Short, Intermediate, and 

Long-term

Pressure Treatment for Wood Preservatives Dermal 

Inhalation

Short, Intermediate and 

Long-term

* material preservatives will include uses such as paints, adhesives and caulks, slurries, emulsions, plastics and vinyl 

products, leather tanning, and paper and paper board.

3.3.2 Occupational Post-application Exposure

Based on the low vapor pressure (~1E-6 mm Hg) of the active ingredient, EPA does not expect 

that DIMTS will volatilize in dry paint. Therefore, EPA will not conduct a post-application 

inhalation assessment for treated paint. Workers can be exposed to DIMTS while working at 

wood pressure plants and non-pressure treatment plants (sapstain dip and spray scenarios). The 

typical workers at pressure treatment facilities include tram setters, stacker operators, loader 

operators, QA/AC test borers, and tallymen. The typical workers at non-pressure treatment 

facilities includes chemical operators, loader operator, graders, millwrights, trim saw operators, 

and clean-up crews. Although worker exposure at pressure and non-pressure treatment plants 
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could be considered post-application, EPA will include these exposures collectively as 

occupational handler scenarios in registration review and will conduct an updated assessment in 

registration review for both the pressure treatment and non-pressure treatment scenarios upon 

receipt of the required data from the RED DCI.

3.3.3 Residential Handler Exposures

EPA anticipates the need to revise the residential handler assessment conducted in support of the 

2008 RED. Residential handler dermal and inhalation exposures to DIMTS were assessed in the 

RED for paint brush/roller and airless spray application of paints and stains and finger painting 

(dermal). The quantitative exposure/risk assessment to be developed for residential handlers will 

be based on the following scenarios presented in Table 11. 

Table 11 – Residential Handler Exposure Scenarios for DIMTS

Scenario Exposure Route(s) Duration

Residential Exposures

Applications of paints and stains from brush/roller Dermal Inhalation Short Term 

Applying of paints and stains from airless sprayer Dermal

Inhalation Short Term 

3.3.4 Residential Post-Application Exposures

EPA anticipates the need to revise the residential post-application assessment conducted in 

support of the 2008 RED. Residential post-application exposures result when adults and children 

come in contact with diiodomethyl p-tolyl sulfone in areas where pesticide end-use products 

have recently been applied (e.g., treated wood), or when children incidentally ingest the pesticide 

residues through mouthing the treated end-products/treated articles (i.e., hand-to-mouth of finger 

paints). The quantitative exposure/risk assessment to be developed for residential postapplication exposure will be based on the following scenarios presented in Table 12. The agency 

required post-application data (indoor surface residue data, product use and description of 

product use) during the RED data call-in to support these uses. A residential post-application 

assessment for textiles and plastics will not be conducted because textile use is restricted to nonclothing use only and to carpet backing and plastics not to be manufactured into toys.

Table 12 – Residential Post-Application Exposure Scenarios for DIMTS

Scenario Exposure Route(s) Duration

Residential Exposures

Post application exposure to toddlers from finger paints with preserved inks. Dermal Incidental 

oral 

Short 

Term 

Post application exposure to toddlers from pressure treated wood used on decks 

and play sets

Dermal

Incidental oral

Short 

Term 
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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 2005 

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 likely need to be assessed. This assessment is anticipated to include indirect 

chronic dietary (food and drinking water) (e.g., adhesives, paper/paper products and polymers) 

exposures and residential exposures (e.g., residential handler in paint and post-application 

exposures for wood treatment).

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 DIMTS and any other substances, and DIMTS 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 DIMTS 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 anticipates the need to conduct an environmental risk assessment for DIMTS during 

registration review. Additionally, the agency anticipates the need to require additional ecological 

toxicity data for the registration review of DIMTS, based on the currently registered uses. There 

was an ecological hazard and environmental risk assessment conducted on November 1, 2007 in 

support of the RED.

1

 

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

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

review will allow the agency to determine potential acute and chronic risks to aquatic organisms 

exposed to DIMTS and its degradates that are transported from treatment sites into the aquatic 

environment. Such sites include antisapstain uses, leather tanning, paint preservation, adhesives, 

caulks, and sealants, rubber and plastics, paper production, and paper preservation during 

storage. All uses are assumed to have the potential to result in Down-the-Drain (DtD) exposure. 

In addition, the wood preservation and paper production use and the paint preservation use have 

the potential to result in runoff into the aquatic environment. Sorption and bioconcentration of 

all residues are expected to be limited. The risk assessment will also allow the agency to 

determine whether each use of the DIMTS 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 or its designated critical 

 1 Mostaghimi and Erickson.
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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

The environmental fate assessment will address the persistence and mobility of parent DIMTS

and the degradates MIMPTS, MPTS, and PTSOA. 

DIMTS is stable to hydrolysis at pH 5, but degrades with half-lives of 2.1 days at pH 7 and 3.4 

days at pH 9 (MRID 43008701). It degraded rapidly in irradiated water with a half-life of 1.4 

hour (MRID 47343001)); however, photodegradation is expected to be limited because of the 

lack of light penetration caused by suspended sediment and shading. Photodegradation on soil 

occurred with a half-life of 5.3 days (MRID 47323601). In soil, DIMTS is rapidly degraded with 

half-lives of 1.5 day under aerobic conditions (MRID 41765405) and 4.2 days under anaerobic 

conditions (MRID 41765406). Under anaerobic aquatic conditions representing bottom 

sediment, DIMTS degraded with a half-life of 9.6 days and residues are expected to partition to 

water rather than sediment (MRID 42177201). Data on parent DIMTS have not been submitted 

for leaching-adsorption-desorption and are anticipated to be required. 

In the environment, DIMTS is relatively insoluble (<2 mg/l, Table 4), but will largely partition to 

water in the presence of sediment based on the results of the environmental fate data in Appendix 

B. Even with its relatively low water solubility, DIMTS is not likely to bioconcentrate in aquatic 

organisms based on its log P value of 2.66 (<3, Table 4). Based on its low vapor pressure and 

Henry’s law constant (Table 4), it is unlikely to move from soil or water into air. Although the 

water solubility of parent DIMTS is lower than for the degradates (Table 5), the environmental 

behavior of the degradates is expected to be similar to parent compound.

The degradates of DIMTS do not completely mineralize in the environment. MIMPTS was a 

terminal degradate (~10 % of applied parent) for photodegradation in water, but degraded with 

half-lives of 12.5 days in irradiated soil, 32 days in aerobic soil, 21 days in anaerobic soil, and 11 

days in the anaerobic aquatic metabolism studies. MPTS was a minor degradate in the 

hydrolysis study, did not degrade in the photodegradation in water or the anaerobic soil and 

anaerobic aquatic metabolism studies, and was relatively persistent in aerobic soil with a half-life 

of 53 days. PTSOA was the main terminal degradate (~90 % of applied parent) in the 

photodegradation in water study and was a minor degradate in the hydrolysis study. Acceptable 

data on leaching-adsorption-desorption in soils and sediment have not been submitted for 

MIMPTS and MPTS and are anticipated to be required. Leaching-adsorption-desorption data on 

PTSOA are not anticipated to be required because the only study with significant quantities of 

PTSOA formed was photodegradation in water, and this route of dissipation is expected to be 

limited because of suspended sediment and shading.

Based on a wood leaching study using submerged blocks (MRID 47375907), DIMTS leached 

from treated wood (5.6 mg/cm3

) with maximum, minimum, and average rates of 23.5, 19.1, and 

20.4 μg/cm2

/day and cumulative rates of 309 μg/cm2. The leached portion of DIMTS was 17.9 

% (Table B1). The leaching rate was relatively constant in the study. These leaching rates are 

the most relevant because the treatment rate in the study (1 % w/w) was the closest to 0.12-0.32 

% w/w rate in Label Reg. No. 464-673. 
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4.1.1 Waste Water Treatment Plants (WWTP)

DIMTS was readily biodegradable in WWTP simulations studies at 0.05 and 0.5 mg/L (MRID 

47024601) but was not readily biodegradable at 28-67 mg/L (MRID 47338401). Even though 

DIMTS was readily biodegradable in MRID 47024601, DIMTS was only primarily 

biodegradable but not ultimately biodegradable at 0.05 and 0.5 mg/L because the test material 

primarily formed terminal degradates other than CO2 and water. The half-lives of the degradate 

MIMPTS were 1.2 day at 0.05 mg/L and 12.6 days at 0.5 mg/L. The degradate MPTS did not 

degrade in MRID 47024601. In a modified Zahn-Wellens test (OECD 302B), the degradate 

MPTS was studied as a parent compound, and was not ultimately biodegradable because only 

about 48 % (<70 %) of dissolved organic carbon (DOC) was removed in 28 days (MRID 

47375909). In an ASRI study (MRID 47373803), DIMTS was not toxic to WWTP organisms 

when tested at up to >4.5 times the water solubility (<2 mg/L, Table 4). Because DIMTS is not 

expected to reach concentrations as high as 9 mg/L based on its solubility of <2 mg/L, no further 

ASRI testing is needed for DIMTS or its degradates.

4.1.2 Water Quality

DIMTS and its degradates are not identified as a cause of impairment for any water bodies listed 

as impaired under section 303(d) of the Clean Water Act. 2 In addition, no Total Maximum 

Daily Loads (TMDL) have been developed for DIMTS and its degradates. 3 More information 

on impaired water bodies and TMDLs can be found at EPA’s website. 4

4.2 Conceptual Models for Environmental Exposure Pathways

Based on the registered use of DIMTS as well as physical/chemical properties and environmental 

fate data for DIMTS and its degradates, the agency cannot rule out the possibility that aquatic 

organisms downstream of wastewater treatment facilities that receive discharges have the 

potential to be exposed to DIMTS and/or its degradates. The agency has created conceptual 

models for potential routes of environmental exposure which are included in “Conceptual 

Models for Environmental Exposure Pathways of Antimicrobial Pesticides”, found in the docket 

at www.regulations.gov, EPA-HQ-OPP-2014-0638-0002. A conceptual model of pulp and paper 

mill systems can be found on page 26, and for the antisapstain use, may be seen on p. 29. 

Conceptual models for textiles (including rubber, plastics, and leather) may be seen on pp. 15-16, 

and for adhesives, caulks, and sealants, may be seen on p. 17. Based on the summary of 

registered uses of DIMTS presented in Table 6, the chemical/physical properties of parent 

DIMTS in Table 4 and the degradates in Table 5, and the environmental fate data presented in 

Appendix B, the agency has developed conceptual model diagrams for exposure of ecological 

organisms to DIMTS and its major degradates. 

In the environmental fate studies, DIMTS forms MIMPTS and MPTS degradates, which are 

more persistent and water soluble than the parent compound. The PTSOA degradate, while also 

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

3

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

group_name=PESTICIDES

4 http://www.epa.gov/owow/tmdl/
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formed, was only detected at significant concentrations in the photodegradation in water study, 

and this route of dissipation is expected to be limited because of suspended sediment and shading 

in surface water. Therefore, PTSOA is not expected to be included in the planned risk 

assessment. MPTS is the terminal degradate under most environmental conditions and did not 

mineralize in a Zahn-Wellens biodegradation simulation test (MRID 47375909). As a result, 

MPTS is expected to be present in the water phase of effluent with Down-the-Drain exposure 

and from treated paint used outdoors. 

The screening-level risk assessment that will be conducted as part of this registration review will 

evaluate potential risks to ecological organisms from exposure to parent DIMTS and the

degradates MIMPTS and MPTS.

4.3 Ecological Effects Assessment

4.3.1 Mechanism of Action

In diiodomethyl p-tolyl sulfone, the bonds between the methyl carbon and both halogen 

substituents are highly polarized by the electronegative iodide and sulfone groups, destabilizing 

the bonds and contributing to their partial ionic character. The toxicity of the chemical results 

from the successive liberation of each halide substituent. Free iodide may then react with nucleic 

acids, fatty acids, and proteins.

In vertebrates, iodine complexes with the amino acid tyrosine to form hormones with important 

roles in the regulation of homeostasis, growth and development, and metabolism. Some effects in 

vertebrates may result from the influence of excess iodine on the production of these hormones. 

4.3.2 Measures of Effect (Ecotoxicology Endpoints)

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

available ecotoxicity endpoints in the agency’s files for DIMTS studies submitted by registrants

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

Appendix C along with the data requirements and data gaps. There are currently no ecotoxicity 

data for DIMTS degradates. The most sensitive values for each receptor group used for the 

previous risk assessment are seen in Table 13. These selected endpoints will be updated during 

the risk assessment phase for registration review based on any additional submitted data or data 

found in the public literature. 

Table 13 – Selected Ecological Effects Endpoints for Risk Assessment of DIMTS

Receptor 

Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID)

Freshwater fish

Rainbow trout Acute 96-h LC50 = 66.7 ug/L 47234001

Rainbow trout Chronic Data Gap --

Freshwater 

invertebrates Daphnia magna Acute 48-h EC50 = 279 ug/L 47234002

Chronic Data Gap --

Estuarine/marine fish Sheepshead minnow Acute Data Gap --

Chronic Not requiredA --
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Receptor 

Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID)

Estuarine/marine 

invertebrates

Eastern oyster Acute Data Gap --

Mysid Shrimp Acute Data Gap --

Chronic Not requiredA --

Algae Green alga Non-listed Data Gap --

Blue-Green Algae Cyanobacteria Non-listed Data Gap --

Aquatic vascular 

plants Duckweed Non-listed Data Gap --

Seedling Emergence Rice Non-listed Not requiredB--

Vegetative vigor Rice Non-listed Not requiredB --

Birds

Northern bobwhite 

quail Acute LD50 = >2000 mg/kg 123643

Mallard duck Subacute 

dietary

LC50 = >5620 mg/kg 124488

Chronic Not requiredA --

Mammals See Table 9C Acute LD50 = >5000 mg/kg (males)

LD50 = >5000 mg/kg (females) 41765401,43608702,

42586801

Chronic NOAEL = 10 mg/kg/day 46913301

Nontarget insects Honey bee Acute Data Gap --

A Not required for this use pattern. 

B Not required. No significant exposure anticipated. CTest species used in Human Health Risk Assessment will be used as surrogates for mammalian ecotoxicity 

assessment. 

4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available 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 to determine the potential for aquatic organisms downstream of domestic wastewater 

treatment plants that receive discharges from end-use of DIMTS to be exposed to DIMTS 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 conservative assumption of no removal during wastewater 

treatment was used in DtD model runs.
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The DtD analysis for DIMTS is intended to serve two purposes: (1) to demonstrate the 

maximum WWTP influent volume of DIMTS that would trigger potential concerns for aquatic 

organisms exposed to DIMTS or its degradates downstream of domestic wastewater treatment 

plants and (2) to evaluate potential exposures based on the assumptions that the total production 

volume of DIMTS enters domestic wastewater treatment plants. A key purpose of the DtD 

analysis for DIMTS is to determine the lowest maximum annual WWTP influent volumes of 

DIMTS that would trigger potential concerns for aquatic organisms downstream of domestic 

WWTPs.

Table 14 presents results of a screening-level DtD analysis for DIMTS which is based on 

laboratory toxicity data for freshwater organisms. Based on these aquatic toxicity data and the 

estimated production volume which is expected to be no greater than 250,000 kilograms per 

year, the DtD model predicted 89 days per year exceedances of concentrations of concern for 

endangered freshwater fish (acute). However, using the average case scenarios, the exceedance

for endangered fresh water fish (acute) was less than 10 days per year. 

Table 14 – Summary of Screening Level Down-the-Drain Analysis Results for Aquatic 

Organisms

 

High End Scenario

WWTP Influent Volume Freshwater Fish Acute 

(COC = 33.35 ug/L) Endangered Freshwater Fish Acute (COC = 3.33 ug/L)

250,000

kilograms/year Exceeded 2 days per year Exceeded 89 days per year

WWTP Influent Volume

Freshwater 

Invertebrates Acute 

(COC = 139.5 ug/L)

Endangered Freshwater Invertebrates Acute (COC = 13.95

ug/L)

250,000

kilograms/year No exceedance Exceeded 13 days per year

 

Average –Case Scenario

WWTP Influent Volume Freshwater Fish Acute 

(COC = 33.35 ug/L) Endangered Freshwater Fish Acute (COC = 3.33 ug/L)

250,000 

kilograms/year

Exceeded less than a day 

per year

Exceeded 10 days per year

WWTP Influent Volume

Freshwater 

Invertebrates Acute 

(COC = 139.5 ug/L)

Endangered Freshwater Invertebrates Acute (COC = 13.95

ug/L)

250,000 

kilograms/year No exceedance Exceeded 1 day per year

This screening level analysis assumes that DIMTS and degradates are released to domestic 

wastewater treatment plants. Based on registered uses of DIMTS and degradates presented in 

Table 6 of this PWP, there are some uses, such as paper production, for which discharges may 

enter industrial WWTPs rather than domestic WWTPs prior to entering surface water. Different 
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methods and tools for assessing potential exposures and associated ecological risks will be 

applied for these other types of uses.

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 DIMTS 

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 Table 13 and or which satisfy an existing data gap(s) will 

be used during the risk assessment phase of DIMTS to update Table 13. ECOTOX was created 

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

and Environmental Effects Research Laboratory's (NHERL) Mid-Continent Ecology Division.

5 Endocrine Disruptor Screening Program (EDSP)

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

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

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

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

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

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

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

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

taxonomic groups. As part of its reregistration decision for DIMTS, 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), DIMTS 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 
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identified for EDSP screening was published on June 14, 20135 and includes some pesticides 

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

construed as a list of known or likely 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.

6

6 Optional Label Changes

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

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

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

clarity. Additionally, as discussed in Section 3.2.1., if the registered DIMTS labels intend to treat 

paper that may contact food, the labels should be revised to comply with the FDA food additive 

regulation level of 0.2 lb a.i. per ton of dry weight fiber. 

7 Guidance for Commenters

7.1 Preliminary Work Plan

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

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

timely manner prior to issuing a final work plan for the DIMTS registration review case. 

7.1.1 Trade Irritants

Through the registration review process, the agency intends to solicit information on trade 

irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The agency

will work to harmonize tolerances and international maximum residue limits (MRLs) and may 

modify tolerance levels to do so, when possible. Stakeholders are asked to comment on any 

trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and 

MRLs in key export markets, providing as much specificity as possible regarding the nature of 

the concern.

7.1.2 Water Quality

The agency invites submission of water quality data for this pesticide. To the extent possible, 

data should conform to the quality standards in Appendix A of the OPP Standard Operating 

Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s 

Registration Review Risk Assessment and Management Process7 in order to ensure they can be 

used quantitatively or qualitatively in pesticide risk assessments.

 5 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals. 6 http://www.epa.gov/endo/.

7 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm.
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7.1.3 Environmental Justice 

EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all 

people, regardless of race, color, national origin, or income, in the development, implementation, 

and enforcement of environmental laws, regulations, and policies. To help address potential 

environmental justice issues, the agency seeks information on any groups or segments of the 

population who, as a result of their location, cultural practices, or other factors, may have 

atypical, unusually high exposure to DIMTS compared to the general population. Please 

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

exposure compared to the general population.

7.1.4 Structure Activity Relationships 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DIMTS case, then the agency invites submission of this information. The submitter would be 

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

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

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

consultation with the agency is encouraged. 

7.1.5 Additional Information 

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

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

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

1. Confirmation on the following label information: 

A. Sites of application 

B. Formulations 

C. Application methods and equipment 

D. Maximum application rates 

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

applications 

F. Geographic limitations on use 

2. Use or potential use distribution 

3. Use history 

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

5. Typical application interval 

6. State or local use restrictions 

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

mammalian mortalities) not already reported to the agency

8. Monitoring data 

8 Next Steps

After the 60-day comment period closes in November 2015, the agency will review and respond 

to any comments received and then issue a Final Work Plan for the DIMTS case.
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9 References 

Chemical Book. 2010. METHYL P-TOLYL SULFONE. 

http://www.chemicalbook.com/ChemicalProductProperty_EN_CB8463935.htm.

Dow MSDS. August 11, 2011. Material Safety Data Sheet: DIMTS. 

http://msdssearch.dow.com/publishedliteraturedowcom/dh_0819/0901b80380819eaa.pdf?filepat

h=.

EPI-WEB 4.11. 2012. http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm. 

Mostaghimi, Siroos. November 1, 2007. Antisapstain Modeling for AMICAL ((Benzene, 1-

((diiodomethyl)sulfonyl)-4-methyl). No DP Barcode.

MRID 42177202. Laster, W.; McGowan, N. (1991) Octanol/ Water Partition Coefficient of 

DIMTS: Final Report: Lab Project Number: 39209. Unpublished study prepared by ABC Labs, 

Inc. 377 p.

MRID 47234003. Lopez, A. (2007) Determination of UV/Visible Absorption Characteristics of 

DIMTS Antifungal Agent. Project Number: 1654W. Unpublished study prepared by PTRL West, 

Inc. 29 p.

MRID 47373801. Sinning, D. (2003) Physical and Chemical Characteristics of DIMTS: Melting 

Point, Boiling Point, Density, Water Solubility, and Vapor Pressure. Project Number: 2310/16, 

020030. Unpublished study prepared by Case Consulting Laboratories, Inc. 12 p.

MRID 47338402. Hunziker, R.W. (2007) Estimation of Water Solubility Limit, Octanol-Water 

Partitioning Constant, and Aquatic Toxicity of Monoiodo-p-methyltolysulphone and pMethyltolylsulphone Which Are Breakdown Products of the Biocidal Active di-iodo-methylpara-tolyl-sulphon (DIMTS). Project Number: DR/0122/8542/003. Unpublished study prepared 

by Dow Chemical Europe and Dow Chemical Co. 16 p. 

MRID 47373801. Sinning, D. (2003) Physical and Chemical Characteristics of DIMTS: Melting 

Point, Boiling Point, Density, Water Solubility, and Vapor Pressure. Project Number: 2310/16, 

020030. Unpublished study prepared by Case Consulting Laboratories, Inc. 12 p.

MRID 48511201. O'Connor, B.; Woolley, S. (2011) DIMTS: Determination of Dissociation 

Constants in Water. Project Number: 41005025, 24P/2010/030, GLP/2011/024. Unpublished 

study prepared by Harlan Laboratories, Ltd. 13 p.

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

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

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

http://www.epa.gov/hpvis/.
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Appendix A Toxicology Profile

Acute Toxicity for Product Labeling 

As listed in Table A1, diiodomethyl p-tolyl sulfone was found to be minimally toxic for acute 

oral and dermal toxicity (Toxicity Category IV for both) and low toxic for inhalation toxicity 

(Toxicity Category III). It caused severe irritation to the ocular tissue of rabbits (Category I) but 

minimal irritation to the skin of rabbits (Category IV). Diiodomethyl p-tolyl sulfone is a dermal 

sensitizer.

Table A1 – Acute Toxicity Studies for Diiodomethyl p-tolyl Sulfone

Guideline No./ Study Type MRID No. Results Toxicity 

Category

870.1100/ 

Acute oral toxicity 41765401/43008702 LD50 >5000 mg/kg for both males and females IV

870.1200/ 

Acute dermal toxicity 00123023 LD50 (male rats) > 20000 mg/kg IV

870.1300/ 

Acute inhalation toxicity 43660901 & 00087842

LC50 (combined)= 0.96 mg/L

LC50 (male) = 1.15 mg/L 

LC50 (female) = 0.77 mg/L

III

870.2400/ 

Acute eye irritation 41765402/43008703 Severe irritant (rabbit) I

870.2500/ 

Acute dermal irritation 41765403/43008704 Minimum irritant (rabbit) IV

870.2600/ 

Skin sensitization 48293901 A dermal sensitizer

Subchronic Toxicity 

Adequacy of Database for Subchronic Toxicity: The database for subchronic toxicity is 

considered adequate. There are several studies in the agency’s hazard database to address 

subchronic oral toxicity, including two 90-day oral (diet) toxicity studies in rats (MRIDs

42054402/43246401 and 47338201), a 90-day oral (capsule) toxicity study in dogs (MRID 

42054403/43246402), a 28-day dermal study in rats (MRID 48236901), and a 90-day inhalation

toxicity study (MRID 48264901). A brief summary of each of the studies is provided below.

870.3100 90-Day (13-Week) Oral Toxicity – Rat

(1) In a subchronic oral toxicity study (MRID 42054402/43246401), groups of Crl:CD(SD)BR 

rats (10/sex/group) received the test material diiodomethyl p-tolyl sulfone (≥ 95% a.i.; Lot #68-

332-CB) at concentrations of 0, 5, 20, or 80 (15/sex) mg/kg/day, in the diet, for 90-94 days.

No significant difference in body weight and mean weight gains were noted among treatment 

groups. The only significant findings in the treated animals were statistically significant
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elevations in mean phosphorus and cholesterol levels in the high dose group males and squamous 

metaplasia of the salivary gland ducts in three males in the high dose group. All of the effects 

noticed in the treatment groups were not considered toxicologically significant. The highest dose 

does not reach the maximum tolerated dose (MTD). The study is classified as Core-Minimum

and can be considered for hazard assessment. 

(2) In a subchronic oral toxicity study (MRID 47338201), groups of Sprague-Dawley (CD) rats 

(8/sex/group) received the test material diiodomethyl p-tolyl sulfone (97.4±0.01% a.i.; Lot # 

PB1631LA01) at concentrations of 0, 5, 20, 100, or 250 mg/kg/day, in the diet, for at least 13 

weeks. Data generated in this study were used to establish the doses for a subsequent twogeneration reproduction study. 

There were no treatment-related deaths or signs of clinic toxicity. Feed consumption was 

significantly decreased during the first half of the study in males in the two high-dose groups and 

in females in the highest dose group, accompanied with a lower termination body weight 

(approximately 10% relative to the controls) in both the highest dose males and females. 

Slightly higher liver and salivary glands weights were noted in rats in the highest dose group

compared to the controls, with the relative weights of these organs statistically identified. 

Histopathological alterations were noted in the stomach, liver, and salivary glands of the highest 

dose animals, including hyperplasia of the non-glandular mucosa in all highest dose (250 

mg/kg/day) animals with erosions, ulcers or inflammatory changes, generalized slight 

hypertrophy of the hepatocytes, and squamous metaplasia of the salivary gland ducts, primarily 

the intra-lobular duct of the submandibular gland. Some rats given 100 mg/kg/day also exhibited 

hyperplasia of the non-glandular mucosa of the stomach and squamous metaplasia of the salivary 

glands. “Based on these data, the no-observed-adverse effect level (NOAEL) was considered to 

be 20 mg/kg/day.” A final conclusion will be provided after the agency’s comprehensive review 

of the study.

870.3150 90-Day (13-Week) Oral Toxicity – Dog

In a subchronic oral toxicity study (MRID 42054403/43246402), groups of beagle dogs 

(4/sex/group) were administered the test material diiodomethyl p-tolyl sulfone ((≥ 95% a.i.; Lot 

# 68-332-CB) at doses of 0, 2, 10, or 60 mg/kg/day, in gelatin capsules, for 96-100 days. 

Clinical signs of toxicity, which were observed 1-4 hours after dosing in the high dosage group, 

included decreases activity, dehydration, mucoid eye discharge, weakened condition and 

abnormal feces (mucoid and occasionally blood-tinged). Eye discharge and abnormal feces in the

intermediate dosage group were also considered treatment related. 

Females in the high dosage group had at least 20% decreases in mean body weight gain, in 

comparison to the control value, from day 0 to 91.

Mean hematology evaluations of the treated animals were not statistically significant from those

of the control animals, although the white blood cell count and neutrophil counts of the males in 

the 60 mg/kg/day group were higher than the control and other treated groups. The high dosage 

group males also had significantly decreased mean calcium, albumin, albumin:globulin ratio, and 

total protein values on one of two evaluations during the treatment period. 
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On gross necropsy, the only findings were changes in the gastrointestinal tract (patchy-red 

discoloration of the stomach and mucoid appearance of the small intestines) in three males in the 

high dosage group. Absolute and relative organ weight did not differ from the control values. 

On histopathology, degeneration of the thyroid gland (mineralization within colloid clumping of 

sloughed follicular cells and colloid depletion) was observed in males and females in the high 

and intermediate dosage groups. Sialadenitis (ductal and periductal inflammation of the salivary 

gland), hemorrhagic gastritis, necrosis of the small intestine and keratitis were also observed in 

the high dose group. 

The no-observed-adverse-effect-level (NOAEL) was determined to be 2 mg/kg/day, based on 

histopathological changes observed in the thyroid glands, salivary gland and gastrointestinal (GI) 

tract. 

The study is classified as Core-Minimum and can be considered for hazard assessment.

870.3200 Subchronic (21/28-day dermal) Toxicity 

(1) In a subchronic dermal study (MRID 48236901), diiodomethyl p-tolyl sulfone (purity 97.7%, 

Lot # PB1631LA01) was applied to a semi-occluded skin of 10 Crl:CD(SD) rats/sex/dose at dose 

levels of 0, 20, 100, or 500 mg/kg bw/day, 6 hours/day, 7 days/week, for 28 consecutive days. 

The animals were acclimated to dermal wraps for three days prior to dosing. The fur of each test 

animal was clipped from the dorsal area of the trunk over an area of at least 10% of the body 

surface, starting at the scapulae (shoulders) to the wing of the ilium (hipbone) and half way down 

to the flank on each side of each animal.

There were no compound-related effects in body weights, body weight gains or feed 

consumption in dosed male and female animals as compared to the controls. 

Systemic effects related to the treatment included increased absolute and relative thyroid weights 

in high-dose males. Thyroid histopathologic changes were observed in all treated males and 

females in the mid- and high-dose groups. The thyroid effects included very slight hypertrophy 

of thyroid follicular epithelial cells and altered tinctorial properties of the colloid, characterized 

by the presence of pale to very pale eosinophilic colloid in the follicles of treated male and 

female animals as compared to the bright eosinophilic and homogeneous colloid in the controls. 

Dermal reactions attributed to the test compound were observed in the high-dose males including 

scratches, very slight edema, scabs of varying severities, and slight scaling. Similar dermal 

observations, as well as erythema, were reported in females in the mid- and high-dose groups. 

Necropsy and histopathological findings in the high-dose males and the mid- and high-dose 

females, at the dermal application site, were multifocal scabs, slight epidermal hyperplasia 

(acanthosis) with very slight parakeratosis, and very slight multifocal subacute to chronic 

inflammation in the dermis. The histopathology of the treatment-related scabs at the dermal 

application site consisted of multifocal epidermal ulceration, moderate epidermal hyperplasia, 

slight hyperkeratosis with parakeratosis, subcorneal pustules in the epidermis, and slight 

subacute to chronic multifocal inflammation of the dermis, which were attributed to scratching of 

the treated skin due to irritation of the test compound.
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Additional changes considered to be secondary to the treatment-related ulcerative dermal lesions 

were marginally higher serum aspartate aminotransferase activity in mid- and high-dose females, 

and very slight myeloid cell hyperplasia in the bone marrow, very slight splenic extramedullary 

hematopoiesis, and increased white blood cell count with increased percentage of neutrophil 

cells in high-dose females. 

The NOAEL for systemic toxicity is 20 mg/kg/day for females, based on thyroid effects but is

not established for males. The NOAEL for dermal effects is 20 mg/kg/day for both males 

and females.

This 28-day dermal toxicity study in the rat is classified Acceptable/Guideline and satisfies the 

guideline requirement for a 28-day dermal toxicity study (OPPTS 870.3200; OECD 410) in rats.

870.3465 Subchronic (90-day inhalation) Toxicity – Rat

In a subchronic inhalation study (MRID 48264901), 1-((Diiodomethyl)sulfonyl)-4-methylbenzene (97.3% a.i.; Lot # PB1631LA01) was administered to 10 

Crl:CD(SD)rats/sex/concentration by dynamic nose-only exposure at analytic concentrations of 

0, 1, 7, or 30 mg/m3 for 6 hours/day, 5 days/week, for 13 weeks (65 total exposure days). The 

average mass median aerodynamic diameter (MMAD) of the test material aerosol was 2.6, 2.7, 

and 2.6 μm for exposure concentration groups 1, 7, and 30 mg/m3, respectively.

Nine deaths occurred during the exposure phase of the study. These deaths included: two control

males, one control female, one mid-concentration male, five high-concentration males, and one

high-concentration female. Study authors did not report whether deaths in the high concentration

groups were considered treatment related. Gross pathology observations were performed in only 

the high-concentration group males and revealed mottled lungs and failure of lung deflation. No 

treatment-related changes regarding food consumption, in-life body weights, ophthalmology, 

clinical chemistry, or coagulation parameters were observed. The mid- and high-concentration 

group males and females were observed with a slight, unilateral or bilateral parakeratosis with 

inflammation of the ventral meatus of the anterior nasal cavity. All affected males and females 

were also observed with irritation of the nasal septum. There were other treatment-related effects 

in the nasolacrimal duct, larynx, and trachea in males and females of the highest concentration 

group, including degeneration with or without inflammation, necrosis, and necrotizing 

inflammation.

In addition, 4 of 10 high-concentration males were observed with moderate to severe necrotizing

bronchioalveolar inflammation of the lungs. Most high-concentration group males and females

exhibited inflammation of the alveolar septa. Minor treatment-related systemic effects were

observed in the thyroid glands (colloid with altered tinctorial properties) of males and females

exposed to mid to high concentrations of the test material.

High-concentration group males had hemoglobin and hematocrit levels that were statistically

significantly higher than controls. Although considered treatment related, these levels were not

interpreted to be toxicologically relevant by study authors. High-concentration group female rats

had a slight increase in neutrophils, and this increase was considered treatment related. In

addition, these female rats had an increase in alanine aminotransferase (ALT) and a non-
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statistically identified increase in aspartate aminotransferase (AST) without accompanying

histopathological changes in the liver.

Terminal body weights for high-concentration group males were decreased relative to controls,

but although this difference was not statistically significant, study authors considered it related to

treatment. The high-concentration group males were the only group to have a statistically

significant organ weight alteration, which was an increase in mean lung weight.

The LOAEC is 7 mg/m3

, based on minor systemic effects in the thyroid glands and parakeratosis 

with inflammation in the anterior nasal cavity in both male and female rats. The NOAEC is 1 

mg/m3

.

This subchronic inhalation toxicity study in the rat is classified Acceptable/Guideline and 

satisfies the guideline requirement for a subchronic inhalation study OPPTS 870.3465;

OECD 413 in the rat.

Developmental Toxicity 

Adequacy of Database for Developmental Toxicity: There are several studies in the agency’s 

hazard database to address developmental toxicity in both species, rats (MRIDs 

42054404/42054405/43246403 and 47373805) and rabbits (MRIDs 42243801/43246404, 

47242202, and 47214601). The available studies appear adequate, and a brief summary of each 

of the studies is provided below.

870.3700a Prenatal Developmental Toxicity (Gavage) Study – Rat

(1) In a developmental toxicity study (MRIDs 42054404/42054405/43246403), Crl:CD®(SD)BR 

albino rats (22/group) received 0, 100, 300, or 1000 mg/kg/day diiodomethyl p-tolyl sulfone

(95% a.i; Lot No. 66-207-CB) by oral gavage from gestation days 6 through 15. Another 

developmental toxicity study (MRID 42054405) was conducted using the same strain of 

Crl:CD®(SD)BR albino rats (25/group) receiving the same test substance diiodomethyl p-tolyl 

sulfone (95% a.i; Lot No. 66-207-CB) at 0 or 1000 mg/kg/day by oral gavage from gestation 

days 6 through 15.

Maternal toxicity was evident as reduced body weight gain and food consumption in the mid and 

high dose groups and as increased clinical signs of toxicity in the high dose group. The maternal 

toxicity LOAEL is 300 mg/kg/day and the maternal toxicity NOAEL is 100 mg/kg/day,

based on reduced body weight gain and food consumption. 

Developmental toxicity was noted in the high dose group as slightly decreased mean litter size, 

increased number of resorptions relative to the number of implantation sites, reduced mean fetal 

body weight, increased incidences of umbilical hernia and incomplete ossification of the 

supraoccipital bones. The developmental toxicity LOAEL is 1000 mg/kg/day and the 

developmental toxicity NOAEL is 300 mg/kg/day, based on decreased mean litter size, 

increased number of resorptions relative to the number of implantation sites, reduced mean 
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fetal body weight, increased incidences of umbilical hernia, and incomplete ossification of 

the supraoccipital bones.

The study is classified Core-Guideline and satisfies the guideline requirement (OCSPP 

870.3700), developmental toxicity (teratology) study in rats.

(2) In a developmental toxicity study in rats published by Ema et al (MRID 47373805 [Ema et al, 

1992]), pregnant Wistar rats (22/group) were administered diiodomethyl p-tolyl sulfone (>95% 

a.i.) at doses of 0, 0.125, 0.25, 0.5 or 1.0% in the diet on gestational days 6-15. The estimated 

daily intakes of diiodomethyl p-tolyl sulfone were 0, 100, 182, 288, or 411 mg/kg/day, 

respectively. Significant lower maternal body weight gain and food consumption were observed 

in the 0.25, 0.5 and 1.0% groups during the administration period. No significant changes induced 

by the test substance were detected in the numbers of resorption, fetal death, or body weight of 

live fetuses. No evidence of teratogenesis was revealed in fetuses during morphological 

examination. 

870.3700b Prenatal Developmental Toxicity (Gavage) Study – Rabbit

(1) In a developmental toxicity study (MRIDs 42243801/43246404), pregnant New Zealand 

White rabbits received 0, 4, 15, or 60 mg/kg bw/day diiodomethyl-p-tolylsulfone (95% a.i.; Lot 

No. 66-207-CB) by oral gavage from gestation day 6 through 18, inclusive.

Maternal toxicity was noted as deaths and abortions primarily in the high dose group, clinical 

signs in the mid and high dose group, reduced body weight gain and food consumption in the mid 

and high dose groups. The maternal toxicity LOAEL is 15 mg/kg/day and the maternal 

toxicity NOAEL is 4 mg/kg/day, based on clinical signs (deaths) and decreased body weight 

gain and food consumption.

Developmental toxicity was noted in the mid and high dose in the form of decreased mean litter 

size, increased number of resorptions relative to the number of implantation sites as degenerating 

fetuses, and decreased postnatal survival and reduced mean fetal body weight in the mid dose 

(data only available for mid dose). At the mid dose, developmental effects also occurred in the 

form of increased incidences of hydrocephalus (which was also noted at a low incidence in the rat 

developmental studies) and a slight increase in fetal and litter incidence of gnarled forepaw(s). An 

increase in incidence of unossified olecranon and sternebrae was noted in the low- and mid-dose 

groups. The developmental toxicity LOAEL is less than or equal to (≤) 4 mg/kg/day, based 

on the increased fetal and litter incidence of unossified olecranon and unossified sternebrae. 

The developmental toxicity NOAEL was not established (< 4 mg/kg/day). 

The study is classified Core-Supplementary and does not satisfy the guideline requirement 

(OPPTS 870.3700) for developmental toxicity (teratology) study in rabbits, due to the lack of a 

NOAEL for developmental toxicity. In addition, in the study, the fetuses were incubated at 

approximately 34°C for approximately 24 hours. A record of survival was kept over that period. 

Following incubation all fetuses in each litter were fixed in alcohol and examined for internal 

abnormalities. This is a procedure that is different from the current guideline requirement for a

developmental toxicity (teratology) study in rabbits. However, this study is considered an 
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acceptable study for maternal effects and can be used for risk assessment purposes, despite its 

limitation in developmental effects.

(2) In the developmental toxicity study (MRID 47242202), diiodomethyl p-tolyl sulfone (97.7% ± 

0.1% a.i.; batch/lot PB1631LA01) was administered to 26 rabbits/dose by gavage at dose levels of 

0, 0.05, 0.5, or 2.0 mg/kg bw/day from days 7 through 27 of gestation. 

Maternal toxicity was observed at 2 mg/kg/day, including slightly increased absolute and relative 

thyroid weights. An increased incidence of very slight thyroid follicular dilatation was also 

noted, which was consistent with iodine toxicity, likely due to the high iodine content (60% by 

weight) of diiodomethyl p-tolyl sulfone. All the maternal effects are not toxicologically 

significant. The maternal NOAEL is 2 mg/kg bw/day.

No signs of developmental toxicity were observed at any dose level. The developmental 

NOAEL is 2.0 mg/kg bw/day, and the developmental LOAEL was not established.

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

the guideline requirement for a developmental toxicity study (OPPTS 870.3700) in rabbits.

(3) In a range-finding developmental toxicity study (MRID 47214601), diiodomethyl p-tolyl 

sulfone (97.7% ± 0.1% a.i.; batch/lot PB1631LA01) was administered to 7 New Zealand White

rabbits/dose by gavage at dose levels of 0, 1, 4, 8, or 15 mg/kg bw/day from days 7 through 27 of 

gestation.

Maternal toxicity was evidenced, at all tested dose levels, by increases in absolute and relative 

thyroid gland weights with corresponding thyroid follicle dilatation (slight to moderate) and

distension with colloid. No appreciable follicular cell hyperplasia or hypertrophy was noted. One 

rabbit in each of the high-dose groups (8 and 15 mg/kg/day) aborted (GD 23, 24) following a 

period of decreased feed consumption, feces production, and body weight gain.

There was higher incidence of post-implantation loss in the two high-dose groups of 8 and 15 

mg/kg/day (26.4% and 20.6%, respectively vs. 4.6% in control), which corresponded with

increases in resorptions per litter and litters with resorptions, and decreases in litter size. There 

were no treatment-related developmental effects at 1 or 4 mg/kg/day. Both the maternal thyroid 

effects and the increases in post-implantation loss are consistent with iodine toxicity, most likely 

due to the iodine moieties of diiodomethyl p-tolyl sulfone. The agency will reach a final 

conclusion after a comprehensive review of the study.

Reproductive Toxicity

Adequacy of Database for Reproductive Toxicity: The database for reproductive toxicity is 

considered adequate. There are two reproductive toxicity studies (one-generation and twogeneration) in rats in the agency’s hazard database. A brief summary of each of the studies is 

provided below.

870.3800 Reproduction and Fertility Effects
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(1) In an one-generation reproductive toxicity study in rats (MRID 46913302), diiodomethyl ptolyl sulfone (97.4%; Lot # PB1631LA01) was administered in the diet to 30 Sprague-Dawley 

(Crl:CD [SD] IGS BR) rats/sex/dose group, at dietary levels of 0, 20, 80, or 200 mg/kg/day 

(adjusted time-weighted average of 0/0, 21.8/20.7, 86.1/82.0, or 213.9/204.0 mg/kg/day in 

males/females, respectively), for approximately ten weeks prior to mating to produce the F1 

litters. This study was originally designed as a two-generation reproductive toxicity study, but 

was terminated during F1 littering due to high mortality in pups of the two highest treatment 

groups.

Signs of toxicity occurred at all dose levels in the parental generation. Low-dose females 

exhibited treatment-related perinasal soiling. Toxic effects observed in the mid-dose group 

included the following: decreased food consumption and body weights in males and females; 

increased mortality in females; increased incidence of pale skin/mucous membranes and 

perinasal soiling in females; decreased feces, and palpebral closure in females. At the high-dose 

level, decreased food consumption and body weights in males and females was observed, as well 

as an increased mortality in females. 

Serum T3 (triiodothyronine) was decreased significantly (p≤0.05) by 26%, and TSH (thyroid 

stimulating hormone) was increased significantly (p≤0.05) by 98% compared to the surrogate 

controls. Grossly, diffuse roughened surface of the non-glandular mucosa of the stomach was 

observed, and additional treatment-related, non-specific findings of multifocal erosion/ulcer of 

the glandular mucosa of the stomach, decreased amount of fat, and decreased ingesta were noted. 

The following microscopic findings were also observed: (i) very slight chromophobe 

hypertrophy of the pars distalis of the pituitary gland; (ii) very slight to slight multifocal 

metaplasia of the intralobular duct of the salivary gland; (iii) very slight to slight diffuse 

hyperplasia of the non-glandular mucosa of the stomach; (iv) very slight altered tinctorial 

properties of the colloid of the thyroid gland; (v) very slight dilatation of the follicle of the 

thyroid gland; and (vi) very slight hypertrophy of the follicular cell of the thyroid gland.

The parental systemic NOAEL could not be established as all dose levels showed toxic 

effects. The parental systemic LOAEL is 20 mg/kg/day (adjusted time-weighted average of 

21.8/20.7 mg/kg/day in males/females), based on decreased body weights, body weight gains, 

and food consumption in the males and clinical signs of toxicity (red perinasal soiling that 

occurred around parturition in the females). 

The offspring LOAEL is 20 mg/kg bw/day, based on decreased body weights at all levels. The

offspring NOAEL could not be established.

The reproductive LOAEL is 80 mg/kg bw/day in females, based on decreased gestation 

survival index. The reproductive NOAEL is 20 mg/kg bw/day in females. There were no 

treatment-related toxic effects in males at any dose level, so a reproductive LOAEL for males 

cannot be calculated.

Many of the effects observed were due to iodine toxicity since diiodomethyl p-tolyl sulfone is 

60% iodine by weight. Consequently, a subsequent 2-generation study was conducted, using 
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more appropriate dose levels (MRID 46913301). This study instead became the basis for dose 

selection in the two-generation reproduction toxicity study. 

This study is UNACCEPTABLE/GUIDELINE and does not satisfy the guideline requirement 

for a 2-generation reproductive study (OPPTS 870.3800, OECD 416) in rats due to the high 

mortality and iodine toxicity. A subsequent 2-generation study was conducted, using more 

appropriate dose levels; therefore, this study can be used as a dose-range finding study. 

(2) In a two-generation reproductive toxicity study in rats (MRID 46913301), diiodomethyl ptolyl sulfone (97.4% a.i.; Lot # PB1631LA01) was administered to 30 Sprague Dawley 

rats/sex/group at dietary levels of 0, 2.5, 10, or 40 mg a.i./kg/day for two successive generations. 

The P generation animals were fed the test diets for approximately 10 weeks prior to mating to 

produce the F1 litters. All litters were weaned on PND 21, and one F1 weanling/sex/litter was 

randomly selected to be a parent of the next generation, following the same procedures described 

for the first generation (treated for 10 weeks prior to mating beginning at weaning). 

There were two treatment-related mortalities (one high-dose P and one high-dose F1 adult

female), although a total of 7 animals died during the study. Decreased body weight occurred in 

high-dose males from both generations due to decreased food consumption. F1 females had low 

body weights beginning at birth through 34 days after weaning. P females had lower body 

weights sporadically during gestation and lactation, but F1 females had a consistently lower body 

weight through gestation and lactation mainly due to the low body weight gains during gestation. 

There was a dose-dependent significant increase in absolute and relative thyroid weights in male 

rats of both generations and in P female rats (mid- and high-dose) and F1 (high-dose; NS). This 

was accompanied by microscopic lesions in the thyroid (altered staining of the colloid in the 

follicle, hypertrophy, hyperplasia and/or follicular dilatation, consistent with hypothyroidism) 

observed at all doses in both sexes in both generations, males were generally more affected than 

females. Relative weights of the pituitary gland were increased for all treated P males and F1

mid- and high-dose males. Absolute and relative weights of the pituitary gland were increased 

for all treated F1 females; microscopic lesions (hypertrophy and hyperplasia of the chromophobe 

cells of the pars distalis of the anterior pituitary) were observed in high-dose animals (lower 

doses not examined).

There was a significant increase in relative salivary gland weights in P males. This is considered 

treatment-related as it had been noted in previous studies, but is considered of minor 

toxicological significance due to the lack of histopathological findings. This increase was not 

noted in the F1 males or in females from either generation.

Absolute testes weights and epididymal weights were significantly decreased for all treated F1

males, at a greater degree for the mid- and high-dose groups, with total sperm per epididymis 

decreased at both the mid- and high-dose levels and total sperm per testis decreased at the high 

dose. Relative testes weights of the high-dose F1 males were decreased significantly. These 

weight changes of the testes and epididymis are considered to be treatment-related, although 

their toxicological significance and causation are not quite clear yet.
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The parental systemic LOAEL is 2.5 mg/kg bw/day, based on thyroid weight increases and 

thyroid histopathology changes in males and females. The parental systemic NOAEL could 

not be established because effects on the thyroid were observed in both genders at every dose 

level. 

There was a decrease in offspring survival in the high-dose group as measured by significant 

increases in post-implantation loss and decreases in live birth index and viability index for both 

generations. There was also a decrease in lactation index that was outside the historical control 

range. In the F2 generation, there was also a decrease in survival in the mid-dose group. The 

decrease in live birth index, viability index, and lactation index did not reach statistical 

significance, but was outside the historical control range and is considered treatment-related. 

Body weights were reduced in the high-dose offspring from both generations. Gross and 

microscopic evaluation indicated an increase in the incidence of dilation of the renal pelvis in 

high-dose offspring of both generations.

The offspring LOAEL is 10 mg/kg bw/day, based on decreased offspring survival at this level. 

The offspring NOAEL is 2.5 mg/kg bw/day.

The mating indices for F1 males and females were lower in the high-dose compared to the 

controls. While the decrease was not statistically significant, it was outside of the historical 

control range and is considered treatment-related. High-dose F1 adult males had a decrease in 

absolute and relative testes weight that correlated with a decreased total sperm count in the testes 

and epididymis (only absolute epididymis weights were decreased). However, when measured 

on a gram of tissue basis, the sperm counts were similar to the control.

The reproductive LOAEL is 40 mg/kg bw/day in males and females, based on a biologically 

significant decrease in male and female mating indices, female conception index, and male and 

female fertility indices. The reproductive NOAEL is 10 mg/kg bw/day in males and females. 

This study is ACCEPTABLE/GUIDELINE and satisfies the guideline requirement for a twogeneration reproductive study (OPPTS 870.3800); OECD 416 in rats.

Chronic Toxicity/Carcinogenicity 

Adequacy of Database for Chronic Toxicity/Carcinogenicity: There are no (combined) chronic 

toxicity/carcinogenicity studies in the agency’s hazard database. These studies are anticipated to 

be required for registration review risk assessment. Based on the currently registered uses for 

diiodomethyl p-tolyl sulfone, the agency is anticipated to conduct a drinking water assessment 

for registration review, which may trigger the requirement of chronic toxicity/carcinogenicity

studies, for adequately assessing the risk associated with the registered uses of diiodomethyl ptolyl sulfone.

Mutagenicity 

Adequacy of Database for Mutagenicity: The database for mutagenicity is considered adequate 

for the currently registered uses. Several mutagenicity studies, including in vitro and in vivo
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studies, have been submitted and reviewed by the Office of Pesticide Programs (OPP). 

Diiodomethyl p-tolyl sulfone is found to be non-mutagenic. The summaries of these studies are 

provided below.

 

Gene Mutation

(1) In a bacterial reverse mutation assay (MRID 47307306), following a range-finding toxicity 

testing with S. typhimurium tester strain TA 100 and E. coli tester strain WP2uvrA in doses 

ranging from 10.0 to 5000 μg/plate (duplicate, with/without S9 mix), diiodomethyl p-tolyl 

sulfone (97.4% a.i.; Lot No. PB1631LA01) was administered, in triplicate, to cultures of S. 

typhimurium tester strains TA98, TA100, TA1535, and TA1537 and E. coli tester strain 

WP2uvrA at dose levels of 5.0, 10.0, 25.0, 50.0, 100, 250, and 500 μg/plate for all tester strains 

in the presence of S9 mix. In the absence of S9 mix, dose levels were 0.5, 1.0, 2.5, 5.0, 10, 25, 

and 50 μg/plate for the S. typhimurium tester strains and 2.5, 5.0, 10, 25, 50, 100, and 250 

μg/plate with E. coli tester strain WP2uvrA for the initial assay. The concentrations tested in the 

confirmatory assay with all S. typhimurium tester strains were 2.5, 5.0, 10, 25, 50, 100, and 250 

μg/plate in the presence of S9 mix and 0.5, 1.0, 2.5, 5.0, 10, 25, and 50 μg/plate for the absence 

of S9 mix; the tested concentrations for E. coli tester strain WP2uvrA were 5.0, 10, 25, 50, 100, 

250, and 500 μg/plate both in the presence and absence of S9 mix. “The results of the 

Salmonella-Escherichia coli/mammalian-microsome reverse mutation assay pre-incubation 

method with a confirmatory assay with AMICALTM 48 indicate that under the condition of the 

study, the test article did not cause a positive increase in the mean number of revertants per plate 

with any of the tester strains either in the presence or absence of microsomal enzymes prepared 

from AroclorTM-induced rat liver (S9).” A final conclusion will be reached upon completion of 

the agency’s comprehensive review. 

(2) In a mouse lymphoma forward mutation assay (MRIDs 00160070/94039011), the mouse 

lymphoma cell line, L5178Y TK+/

̵–

, were exposed to diiodomethyl p-tolyl sulfone (99% a.i.; Lot 

# 66-207-CB) for four hours, in the absence and presence of rat liver S9 metabolic activation 

system. Diiodomethyl p-tolyl sulfone was assayed from 0.3 to 2.0 μg/ml (0.3, 0.5, 0.6, 0.8, 1.0, 

and 2.0 μg/ml) under the non-activation conditions; the highest concentration was excessive 

toxic. But the remaining five lower treatments caused low to moderate toxicity with no 

significant increased mutant frequency above the background. In the presence of S9 metabolic 

activation, the concentrations tested (ranged from 0.5 to 5.0 μg/ml) induced a wide range of 

toxicity; however, no significant increases in the mutant frequency were identified. 

Diiodomethyl p-tolyl sulfone did not demonstrate mutagenic potential in the mouse lymphoma

assay.

This study is classified Acceptable.

Cytogenetics

(1) Diiodomethyl p-tolyl sulfone (96.5% a.i.; Lot # 3-0410) was administered to Chinese 

Hamster Ovary (CHO) cells cultures at dose levels of 0.125, 0.25, 0.5, 1, 2, and 4 μg/ml in the 

non-activated study and at 0.5, 1, 2, 4, 8, and 16 μg/ml in the S-9 activated study (MRID
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43120601). At the highest doses, there were sufficient indications of a cytotoxic response 

(reduction in mitotic index). Under the condition of this assay, there was no indication of a 

positive clastogenic and/or aneugenic response in the absence (harvested at 18 hours) or S-9 

activation (harvested at 12 hours). Diiodomethyl p-tolyl sulfone (Amical® 48 Preservative) was 

concluded to be negative in the chromosome aberrations in Chinese Hamster Ovary cells (CHO) 

cells cytogenetics assay.

This study is classified Acceptable/Non-guideline and satisfies the Guideline requirement for a 

structural chromatic aberration assay (OCSPP 870.5375). 

(2) In an in vivo mouse micronucleus assay (MRIDs 00160071), diiodomethyl p-tolyl sulfone

(99% a.i.; Lot # 66-207-CB) was administered, at concentrations of 0.5, 2.5, and 5.0 g/kg (based 

on an oral LD50), to 5 ICR mice/sex/group intraperitoneally (i.p.) by individual weight with 

volumes based on 10 ml/kg. Animals were dosed on an acute regimen with groups killed 24, 48, 

and 72 hours post-dosing. The negative and positive control groups were killed 24 hours after 

dosing. An additional group of 5 mice/sex were treated with 5.0 g/kg dose concentration and 

were only used to replace animals which died in the primary dose groups. Bone marrow cells 

were harvested at the sacrificing schedule stated above (24, 48, and 72-hours post-treatment). 

The positive control was triethylenemelamine (TEM) used at 1.5 mg/kg, administered by one i.p. 

injection. Diiodomethyl p-tolyl sulfone did not induce toxic signs in any animals, nor did 

positive or negative controls. 

No significant increases in number of micronucleated polychromatic erythrocytes (MN-PCEs) 

frequencies were reported in any dose group over the negative control animals, whereas a 

significant increase in the frequencies of MN-PCEs was observed in the positive control group. 

The mean percent PCE values were significantly reduced at 500 mg/kg and for the positive 

control groups compared to the corresponding negative controls. Diiodomethyl p-tolyl sulfone

did not demonstrate mutagenic potential in the mouse bone marrow micronucleus assay under 

the test condition.

This study is classified Acceptable.

Other Genotoxicity

(1) In an in vitro primary rat hepatocyte unscheduled DNA synthesis (UDS) assay (MRIDs 

00160072/94039012), fresh hepatocytes from rat liver were exposed to diiodomethyl p-tolyl 

sulfone (99% a.i.; Lot # 66-207-CB) at concentrations ranged from 0.052 to 5.19 μg/mL. The 

positive control used was a-acetylaminofluorene (2-AAF) at 0.05 and 0.10 μg/mL; the test 

material solvent served as the negative control.

. 

No significant increases in mean net nuclear grains (NNG), or in the percent of nuclei with six or 

more net grains, were reported at any dose level at any time point. This was comparable to the 

solvent controls. There was no evidence of induction of unscheduled DNA synthesis in rat 

primary hepatocytes over the background. The positive control elicited a clear positive response. 

It was concluded that, under the condition of the present test, diiodomethyl p-tolyl sulfone did 
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not demonstrate mutagenic potential in the present in vitro primary rat hepatocyte unscheduled 

DNA synthesis (UDS) assay.

This study is classified Acceptable.

Neurotoxicity

870.6200 Neurotoxicity Screening Battery

Adequacy of Database for Neurotoxicity: The database for neurotoxicity is considered 

incomplete. There are no neurotoxicity studies in the agency’s hazard database. A neurotoxicity 

screening battery is anticipated to be required for registration review risk assessment, based on 

the currently registered uses for DIMTS.

Immunotoxicity

870.7800 Immunotoxicity Study

Adequacy of Database for Immunotoxicity: The database for immunotoxicity is considered 

incomplete. There are no immunotoxicity studies in the agency’s hazard database. An 

immunotoxicity study is anticipated to be required for registration review risk assessment, based 

on the currently registered uses for diiodomethyl p-tolyl sulfone.

Other Toxicological Effects 

Metabolism and Pharmacokinetics

In a metabolism study (MRID 47076601), AmicalTM 48 Antifungal Agent (1-

((diiodomethyl)sulpfonyl)-4-methyl benzene,; 97.7% a.i., Lot no. 172-015-032) and 14C-Amical 

methyl substituted to the aromatic ring was radiolabeled; 99.8% a.i., Lot no. PB1631LA01) was 

administered to Fisher 344 or Sprague-Dawley rats following the exposure schemes described 

below. Five oral absorption, distribution, and elimination studies in F-344 rats were performed 

each using 4 rats/sex/dose at target dose levels of 5.0 or 50 mg/kg. In these studies a single oral 

dose was administered via gavage at calculated doses of 5.0 mg/kg (Groups 1, 3, and 5; actual 

concentrations were for Group 1, 5.03 mg/kg in males and 5.02 females; Group 3, 5.26 mg/kg in 

males and 5.14 females; Group 5, 5.06 mg/kg in males and 5.13 females) or 50 mg/kg (Groups 2 

and 4; actual concentrations were for Group 2, 51.44 mg/kg in males and 51.19 mg/kg in 

females; Group 4, 51.09 mg/kg in males and 51.99 mg/kg in females). In a multi-dosing study, 

animals were administered 5.0 mg/kg unlabeled AmicalTM 48 (actual concentration was not 

determined for unlabeled AmicalTM 48) via the diet for 14 days, then dosed with a comparable 

single oral dose of radiolabeled AmicalTM 48 via gavage (Group 6; actual concentrations were 

5.10 mg/kg in males and 4.96 mg/kg in females). A single 6 hour dermal dose was utilized with 

both males and females (Group 8) receiving 5.0 mg/kg 14C-AmicalTM 48, the actual measure 

doses were 6.99 mg/kg in males and 9.14 mg/kg in females; volatility studies showed that 
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ambient temperatures did not cause dermal doses of AmicalTM 48 to dissipate. A single oral dose 

of 5.0 mg/kg 14C- AmicalTM 48 (actual concentration 5.04 mg/kg) was given to 4 SpragueDawley females (Group 7). Metabolite distribution was determined in Groups 1, 2, 5, 7, and 8 

(Group 8 excreta had metabolite concentrations too low to analyze) from urine and plasma; free 

iodine was determined in all Groups. Pharmacokinetic parameters were determined in Groups 1, 

2, 7, and 8. 

After a single oral dose of 5.0 or 50 mg/kg 14C-AmicalTM 48, the maximum concentration of 

AmicalTM 48 (Cmax) in the blood is reached within an 15 minutes at the low dose and 30 minutes 

for the high dose, and the plasma half-life at the low doses were between 1-2 hours and a 2-fold 

increase was noted at the high dose with a plasma half-life of 2-4 hours; oral dose was available 

in a dose proportionate manner. Plasma radioactivity levels were non-detectible after 24 hours 

except in the high-dose males that were non-detectable the next day, this coincides with higher 

levels of glutathione conjugated parent compound observed in the males. Free iodine elimination 

was slower than the rapid elimination of the radiolabeled AmicalTM 48 equivalent; the half-life of 

free iodine was approximately 2.5 hours in the low oral doses and 4-5 hours in the high oral 

dosed F344 rats. No difference in absorption, route of elimination, or pharmacokinetics were 

observed when comparing F344 rats and Sprague-Dawley rats; however, the Sprague-Dawley 

rats displayed a decreased elimination of free iodine, with a plasma half-life of 7 hours, a 3 fold 

increase over the F344 rats dosed at the same rate of 5 mg/kg. The maximum concentration 

(Cmax) and time to maximum concentration (tmax) was the same in F344 and Sprague-Dawley 

rats, but the area under the curve (AUC) and half-life (t1/2) were longer suggesting greater 

bioavailability of iodine in the Sprague-Dawley rats. Radioactivity elimination in SpragueDawley rats was comparable to F344 rats. 

After multiple doses of unlabeled AmicalTM 48, one dose of radioactive AmicalTM 48 displayed 

no difference in absorption, elimination, pharmacokinetics, metabolism, or route of elimination. 

Dermal AmicalTM 48 was absorbed 7-10% of the applied dose; plasma radioactivity and iodine 

were negligible, 5-7% were found in the urine and fecal elimination was <0.3%. The dermal dose 

was slowly absorbed and rapidly eliminated mainly in the urine with 23-30% of the absorbed 

dose in the urine after 24 hours and 38-45% after 48 hours. The dermal application site wash was 

the major depot of radioactivity with 80% rinsed off the males and 90% in females. The 

application site had 1.1 and 2.4% of the applied dose, in males and females, respectively; stratum 

conrneum (tape strips) had 0.1-0.2% of the applied dose. Tissues had 0.3% of the applied dose or 

3-5% of the absorbed dose at the end of the study. Recoveries were between 90-97%. 

The major route of elimination was through the urine for all exposure methods with 87-97% 

excreted and most was within the first six hours (78-92%); elimination in the feces accounted for 

7-13% of the radioactivity. Organ/tissue radioactivity levels were <1% of the dose received after 

7 days, this also included the plasma. Results indicate that orally administered AmicalTM 48 is 

rapidly and almost completely absorbed from the gastro-intestinal tract and eliminated quickly. 

Expired air and volatiles was not a major route of elimination, negligible findings were noted in 

all air traps. 

Distribution patterns in the orally dosed animals were similar between the single- and repeatdosed Groups with the highest residual radioactivity found in the major elimination 

organs/tissue, i.e., the kidney, liver, and plasma; however, the levels were low. No organ 
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demonstrated accumulation of AmicalTM 48 with highest levels of AmicalTM 48 equivalent in the 

plasma 7 days after dosing. The plasma, kidney, and liver eliminates AmicalTM 48 equivalent 

rapidly with most of the concentration eliminated by the 6th hour. 

Upon absorption, iodine is liberated from the AmicalTM 48 reaching maximum concentration at 4 

hours in the low-dose groups and 2 hours in the high-dose groups. Elimination of iodine is 

slower than the radioactive portion of AmicalTM 48, with 9-13% of free iodine in the urine and 5-

7% of the radioactivity in the urine. The total free iodine detected in the urine was 59-73% and 

41-43% of the total radioactivity, in low- and high-dose groups, respectively. Fecal iodine 

elimination was between 7-13% and most was within the first 24 hours. Dermal exposures 

produced an iodine profile in the urine that was different than oral exposures; the total amount of 

iodine in the urine was higher than oral exposure groups, indicating a higher metabolism of one 

or both of the iodine groups from DIMTS. 

In the blood and excreta analyzed for metabolites, no parent compound was found. The major 

metabolites were the parent conjugated with glucuronide and 3 non-parent oxidated benzylic 

methyl moiety or minor ring hydroxylation. Two major metabolites in the blood, in order of 

concentration, were p-iodomethylsulphone benzoic acid and p-methylsulfone benzoic acid. 

Major metabolites in the urine for the low-dose group, in order of concentration, were pmethylsulfone benzoic acid, p-iodomethylsulphone benzoic acid, and methyl-p-tolylsulpfone, 

which accounted for 62-88% of the dose; whereas, p-iodomethylsulphone benzoic acid, pmethylsulfone benzoic acid, and methyl-p-tolylsulpfone (in order of concentration), which 

accounted for 75-88% of the dose, were the major metabolites in the urine for the high-dose 

group. Major fecal metabolites were p-methylsulfone benzoic acid and p-iodomethylsulphone 

benzoic acid, which accounted for 5-9% of the dose. 

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.

Dermal Penetration Study

There is no acceptable guideline dermal penetration study. There is some dermal absorption 

information in the pharmacokinetics and metabolism study (MRID 47076601) summarized 

above.

In the pharmacokinetics and metabolism study (MRID 47076601), 4 Fischer 344 rats/sex (Group 

8) dermally received a single dose of 14C-diiodomethyl p-tolyl sulfone on the shaved back 

(between scapula). The application site was covered with mesh and was washed 6 hours after 

application. Dose suspension for the dermal application was prepared at the target concentration 

of ~ 8.8 mg/ml and applied at a dose volume of 10 μl/cm2 to 12 cm2, which resulted in a dose of 

~ 5 mg/kg (the actual measure doses were 6.99/9.14 mg/kg in males/females). Volatility studies 

showed that ambient temperatures did not cause dermal doses of 14C-diiodomethyl p-tolyl 

sulfone to dissipate. Absorption of the dermally applied diiodomethyl p-tolyl sulfone was 7-12% 

of the dose. The dermally applied dose was slowly absorbed from the site of application and 

rapidly eliminated in urine accounting for 23-30% and 38-45% of the absorbed dose within 24 

hours and 48 hours, respectively. Between 5 and 7% of the applied dose was excreted in urine, 

fecal elimination was negligible (~0.3%). The level of radioactivity and free iodide in the plasma 
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of the dermally dosed animals remained below the level of quantification (< LOQ) throughout 

the study. The total amount of iodide found in the urine of the dermally dosed rats was 10-40% 

higher than the total radioactivity, which was opposite to what was observed in the orally dosed 

animals, indicating higher metabolism/liberation of one or both of the iodide from the parent 

molecule. Elimination of radioactivity and iodide in urine continued during the analysis period 

due to slow continuous absorption of 14C-diiodomethyl p-tolyl sulfone from the application site. 

It is anticipated to have variations ranging from 90-110% recovery rates for the dermal 

absorption study. Therefore, the agency concluded that the appropriate dermal absorption factor 

in the risk assessment should be approximately 10%.
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Table A2 – Toxicity Profile for DIMTS

Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

Subchronic Toxicity

870.3100

90-day Oral (Rat)

MRID 

42054402/43246401

Core-Minimum

Purity 95%

Crl:CD(SD)BR rats (10/sex/dose)

0, 5, 20, or 80 (15/sex) mg/kg/d, in 

diet, for 90-94 days.

NOAEL ≥ 80 mg/kg/d

The only significant findings in the 

treated animals were statistically 

significant elevations in mean 

phosphorus and cholesterol levels in 

the high dose group males and 

squamous metaplasia of the salivary 

gland ducts in three males in the high 

dose group. All of the effects noticed 

in the treatment groups were not 

considered toxicologically 

significant. The highest dose does not 

reach the maximum tolerated dose 

(MTD).

870.3100

90-day Oral (Rat)

MRID 47338201

Under agency review

Purity 97.4%

Sprague-Dawley (CD) (8

rats/sex/dose)

0, 5, 20, 100, or 250 mg/kg/d, in 

diet, for at least 13 weeks

The study author concluded:

NOAEL = 20 mg/kg/d, based on 

hyperplasia of the non-glandular 

mucosa of the stomach and 

squamous metaplasia of the salivary 

glands at 100 mg/kg/d

870.3150

90-day Oral (Dog)

MRID 

42054403/43246402

Core-Minimum

Purity 95%

Beagle dogs (4/sex/group)

0, 2, 10, or 60 mg/kg/day, in 

gelatin capsules, for 96-100 days

NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day, based on 

histopathological changes observed 

in the thyroid glands (degeneration of 

the thyroid gland [mineralization 

within colloid clumping of sloughed 

follicular cells and colloid 

depletion]), salivary gland 

(Sialadenitis [ductal and periductal 

inflammation of the salivary gland]) 

and gastrointestinal (GI) tract

(hemorrhagic gastritis, necrosis of 

the small intestine and keratitis). 
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Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

870.3200 

21/28 day dermal 

(rats)

MRID 48236901

Acceptable/Guideline

Purity 94.6%

Crl:CD(SD)BR rats (10/sex/dose)

0, 20, 100, or 500 mg/kg/day, 

semi-occlusion, 6 hr/day, 7 

days/wk, for 28 consecutive days.

NOAELsystemic = 20 mg/kg/day (♀)

and not established for males

LOAELsystemic = 100 mg/kg/day (♀), 

based on thyroid effects (very slight 

hypertrophy of thyroid follicular 

epithelial cells and altered tinctorial 

properties of the colloid, 

characterized by the presence of pale 

to very pale eosinophilic colloid in 

the follicles). 

NOAELdermal = 20 mg/kg/day

LOAELdermal = 100 mg/kg/day, 

based on multifocal scabs, slight 

epidermal hyperplasia (acanthosis) 

with very slight parakeratosis, and 

very slight multifocal subacute to 

chronic inflammation in the dermis.

870.3465

90-day inhalation

Subchronic (Rat)

MRID 48264901

Acceptable/Guideline

Purity 97.3%

Crl:CD(SD) rats 

(10/sex/concentration)

0, 1, 7, or 30 mg/m3

, nose only, 6 

hr/d, 5 days/wk, for 13 wks (65 

total exp. days).

The average mass median 

aerodynamic diameter (MMAD) of 

the test material aerosol was 2.6, 

2.7, and 2.6 μm for exposure 

concentration groups 1, 7, and 30 

mg/m3, respectively.

NOAEC = 1 mg/m3

LOAEC = 7 mg/m3, based on 

treatment-related systemic effects 

were observed in the thyroid glands 

(colloid with altered tinctorial 

properties) and unilateral or bilateral

parakeratosis with inflammation in 

the anterior nasal cavity in both male 

and female rats. 

Developmental Toxicity

870.3700a

Developmental 

Toxicity (Rat)

MRIDs 

42054404/42054405/

43246403

Core-Guideline

Purity 95%

Crl:CD(SD) albino rats (22/group)

0, 100, 300, or 1000 mg/kg/day,

oral gavage, gestation days (GD)

6-15

For MRID 42054405:

Crl:CD(SD) albino rats (25/group)

0 or 1000 mg/kg/day, oral gavage, 

gestation days (GD) 6-15

NOAELmaternal = 100 mg/kg/d

LOAELmaternal = 300 mg/kg/d, 

based on ↓ body weight gain and 

food consumption.

NOAELdevelopmental = 300 mg/kg/d

LOAELdevelopmental = 1000 mg/kg/d, 

based on ↓ mean litter size, ↑ number 

of resorptions relative to the number 

of implantation sites, ↓ mean fetal 

body weight, ↑ incidences of 

umbilical hernia, and incomplete 

ossification of the supraoccipital 

bones.
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Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

870.3700a

Developmental 

Toxicity (Rat)

MRIDs 47373805

Under agency review

Purity > 95%

Wistar rats (22/group)

0, 0.125, 0.25, 0.5, or 1.0% 

(estimated daily intakes of test 

material 0, 100, 182, 288, or 411 

mg/kg/d, respectively), in the diet, 

gestation days (GD) 6-15

Significant lower maternal body 

weight gain and food consumption 

were observed in the three higher 

dose groups. No significant changes 

induced by the test substance were 

detected in the numbers of 

resorption, fetal death, or body 

weight of live fetuses. No evidence 

of teratogenesis was revealed in 

fetuses during morphological 

examination.

870.3700b

Developmental 

Toxicity (Rabbit)

MRIDs 

42243801/43246404

Core-Supplementary

Purity 95%

Pregnant New Zealand White 

rabbits

0, 4, 15, or 60 mg/kg/day, oral 

gavage, gestation day (GD) 

6-18, inclusive

NOAELmaternal = 4 mg/kg/d

LOAELmaternal = 15 mg/kg/d, based 

on clinical signs (deaths) and ↓ body 

weight gain and food consumption

NOAELdevelopmental < 4 mg/kg/d (not 

established)

LOAELdevelopmental ≤ 4 mg/kg/d, 

based on increased fetal and litter 

incidence of unossified olecranon 

and unossified sternebrae

870.3700b

Developmental 

Toxicity (Rabbit)

MRID 47242202

Acceptable/Guideline

Purity 97.7% 

26 rabbits/dose

0, 0.05, 0.5, or 2.0 mg/kg/day, 

gavage, gestation days (GD) 7-27

NOAELmaternal = 2 mg/kg/d (HDT)

LOAELmaternal not established.

NOAELdevelopmental = 2 mg/kg/d

(HDT)

LOAELdevelopmental not established.

870.3700b

Developmental 

Toxicity (Rabbit)

MRIDs 47214601

Under agency review

Purity 97.7% 

New Zealand White rabbits

(7/dose)

0, 1, 4, 8, or 15 mg/kg/day, gavage, 

gestation days 7-27

NOAELmaternal < 1 mg/kg/d (LDT)

LOAELmaternal = 1 mg/kg/d, based 

on ↑ in absolute and relative thyroid 

gland weights with corresponding 

thyroid follicle dilatation (slight to 

moderate) and distension with colloid

at all tested dose levels. 

NOAELdevelopmental = 4 mg/kg/d

(HDT)

LOAELdevelopmental = 8 mg/kg/d, 

based on higher incidence of postimplantation loss (26.4% and 20.6%, 

respectively vs. 4.6% in control), 

which corresponded with increases in 

resorptions per litter and litters with 

resorptions, and decreases in litter 

size. 

The agency will reach a final 

conclusion after a comprehensive 

review of the study.

Reproduction Toxicity
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Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

870.3800

Reproduction

MRID 46913302

Unacceptable/Guideline

Purity 97.4%

Sprague-Dawley Crl:CD [SD] IGS 

BR rats (30/sex/dose group)

0, 20, 80, or 200 mg/kg/day 

(adjusted time-weighted average of 

0/0, 21.8/20.7, 86.1/82.0, or 

213.9/204.0 mg/kg/day in 

males/females, respectively), in 

diet, for approximately ten weeks 

prior to mating to produce the F1 

litters. 

This study was originally designed 

as a two-generation reproductive 

toxicity study, but was terminated 

during F1 littering due to high 

mortality in pups of the two 

highest treatment groups.

NOAELparental < 5 mg/kg/d (not 

established)

LOAELparental = 20 mg/kg/d

(adjusted time-weighted average of 

21.8/20.7 mg/kg/day in 

males/females), based on decreased 

body weights, body weight gains, 

and food consumption in the males 

and clinical signs of toxicity (red 

perinasal soiling that occurred around 

parturition in the females).

NOAELoffspring < 20 mg/kg/d (not 

established);

LOAELoffspring = 20 mg/kg/d, based 

on decreased body weights at all 

levels.

NOAELreproductive = 20 mg/kg/d (♀)

LOAELreproductive = 80 mg/kg/d (♀), 

based on decreased gestation survival 

index. There were no treatmentrelated toxic effects in males at any 

dose level, so a reproductive LOAEL 

for males cannot be calculated

870.3800

Reproduction

MRID 46913301

Acceptable/Guideline

Purity 97.4% 

Sprague Dawley rats

(30/sex/group)

0, 2.5, 10, or 40 mg a.i./kg/day, in 

diet, for two successive 

generations (P: approx. 10 weeks 

prior to mating to produce the F1 

litters. All litters were weaned on 

PND 21, and one F1 

weanling/sex/litter was randomly 

selected to be a parent of the next 

generation and treated for 10 

weeks prior to mating beginning at 

weaning).

NOAELparental < 2.5 mg/kg/d (not 

established)

LOAELparental = 2.5 mg/kg/d, based 

on ↑ thyroid weight increases and 

thyroid histopathology changes in 

males and females at every dose 

level. 

NOAELoffspring = 2.5 mg/kgd

LOAELoffspring = 10 mg/kg/d, based 

on decreased offspring survival. 

NOAELreproductive = 10 mg/kg/d

LOAELreproductive = 40 mg/kg/d,

based on a biologically significant ↓

in male and female mating indices, 

female conception index, and male 

and female fertility indices. 

Chronic Toxicity

870.4100

Chronic Toxicity

A chronic toxicity study is not available for DIMTS.

Carcinogenicity

870.4200

Carcinogenicity

A carcinogenicity study is not available for DIMTS.

Mutagenicity
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Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

870.5100

Bacterial reverse 

mutation test

MRID 47307306

Under agency review

Purity 97.4%

S. typhimurium TA98, TA100, 

TA1535, and TA1537 and E. coli

WP2uvrA

The initial assay:

5.0, 10.0, 25.0, 50.0, 100, 250, and 

500 μg/plate for all tester strains

(+S9);

0.5, 1.0, 2.5, 5.0, 10, 25, and 50 

μg/plate for the S. typhimurium

tester strains (- S9) and 2.5, 5.0, 

10, 25, 50, 100, and 250 μg/plate 

with E. coli WP2uvrA (-S9) for. 

The confirmatory assay:

S. typhimurium tester strains – 2.5, 

5.0, 10, 25, 50, 100, and 250 

μg/plate (+S9) and 0.5, 1.0, 2.5, 

5.0, 10, 25, and 50 μg/plate (-S9) 

E. coli WP2uvrA – 5.0, 10, 25, 50, 

100, 250, and 500 μg/plate (+/-S9)

The study author concluded that 

“The results of the SalmonellaEscherichia coli/mammalianmicrosome reverse mutation assay 

pre-incubation method with a 

confirmatory assay with AMICALTM

48 indicate that under the condition 

of the study, the test article did not 

cause a positive increase in the mean 

number of revertants per plate with 

any of the tester strains either in the 

presence or absence of microsomal 

enzymes prepared from AroclorTM-

induced rat liver (S9).” 

870.5300

Mammalian cell 

gene mutation test

MRIDs 

00160070/94039011

Acceptable

Purity 99% 

mouse lymphoma cells (L5178Y 

TK+/-

)

0.3 – 2.0 μg/ml (0.3, 0.5, 0.6, 0.8, 

1.0, and 2.0 μg/ml) (-S9) and 0.5 –

5.0 μg/ml (+S9), for a period of 4 

hours

Negative

870.5300

Mammalian cell 

gene mutation test

MRID 43120601

Acceptable/Nonguideline

Purity 94.5%

Chinese hamster ovary (CHO) 

cells

0.125, 0.25, 0.5, 1, 2, and 4 μg/ml 

(-S9) and 0.5, 1, 2, 4, 8, and 16 

μg/ml (+S9)

Negative

870.5385

In vivo mouse

micronucleus 

assay

MRID 00160071

Acceptable

Purity 99%

ICR mice (5/sex/group)

0.5, 2.5, and 5.0 g/kg (based on an 

oral LD50), intraperitoneally (i.p.), 

by individual weight with volumes 

based on 10 ml/kg. Animals were 

killed and bone marrow cells at 24, 

48, and 72 hours post-dosing. The 

negative and positive control 

groups were killed 24 hours after 

dosing. 

Negative
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Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

870.5550

(In vitro)

Unscheduled 

DNA synthesis 

MRIDs

00160072/94039012

Acceptable

Purity 99%

Rat hepatocyte cells

0.052 to 5.19 μg/mL. The positive 

control used was aacetylaminofluorene (2-AAF) at 

0.05 and 0.10 μg/mL; the test 

material solvent served as the 

negative control

Negative

870.5550

Unscheduled 

DNA synthesis

MRID 41298503

Acceptable

Purity 81%

Rat (male) hepatocyte cells

5x10-7 – 1x10-3 mL/mL

Negative

870.6200

Neurotoxicity 

screening battery

A neurotoxicity screening battery is not available.

870.7800

Immunotoxicity

An immunotoxicity study is not available.

Metabolism
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870.7485

Metabolism and 

Pharmacokinetics

MRID 47076601

Acceptable/Guideline

Purity 99.8% (radiolabeled); 

97.7% (non-radiolabeled)

Fisher 344 or Sprague-Dawley rats

(4/dose group)

Exposure schemes:

- Single oral dose: 5.0 mg/kg 14CAmicalTM 48 (actual conc. [♂/♀]: 

5.03/5.02; 5.26/5.14; and 5.06/5.13

mg/kg for Groups 1, 3, and 5, 

respectively) or 50 mg/kg 14CAmicalTM 48 (actual conc. [♂/♀]: 

51.44/51.19 and 51.09/51.99

mg/kg for Groups 2 and 4, 

respectively), via gavage 

- Multiple oral doses (Group 6): 

5.0 mg/kg unlabeled AmicalTM 48 

(actual conc. not determined), via 

the diet, for 14 days; then dosed 

with a comparable single oral dose 

of 14C-AmicalTM 48 via gavage 

(actual conc. [♂/♀]: 5.10/4.96

mg/kg);

- Single dermal dose (Group 8): 

5.0 mg/kg 14C-AmicalTM 48 (actual 

measure doses [♂/♀]: 6.99/9.14 

mg/kg) for 6 hr;

- Single oral dose (Group 7): 5.0 

mg/kg 14C-AmicalTM 48 (actual 

conc.: 5.04 mg/kg) given to 4

Sprague-Dawley females

Metabolite distribution was 

determined in Groups 1, 2, 5, 7, 

and 8 (Group 8 excreta had 

metabolite concentrations too low 

to analyze) from urine and plasma; 

free iodine was determined in all 

Groups. Pharmacokinetic 

parameters were determined in 

Groups 1, 2, 7, and 8.

After a single oral dose of 14C-AmicalTM 

48, the plasma concentrations peaked 

(Cmax) within15 minutes and 30 minutes 

for the low dose (5 mg/kg) and the high 

dose (50 mg/kg), respectively, and the 

plasma half-life at the low doses were 

between 1-2 hours and 2-4 hours (2-fold 

increase) at the high dose. Plasma 

radioactivity levels were non-detectible 

after 24 hours except in the high-dose 

males that were non-detectable the next 

day, this coincides with higher levels of 

glutathione conjugated parent compound 

observed in the males. Free iodine 

elimination was slower than the rapid 

elimination of the radiolabeled 

AmicalTM 48 equivalent; the half-life of 

free iodine was approximately 2.5 hours 

in the low oral doses and 4-5 hours in the 

high oral dosed F344 rats. 

No difference in absorption, route of 

elimination, or pharmacokinetics were 

observed when comparing F344 rats and 

Sprague-Dawley rats; however, the 

Sprague-Dawley rats displayed a 

decreased elimination of free iodine, with 

a plasma half-life of 7 hours, a 3 fold 

increase over the F344 rats dosed at the 

same rate of 5 mg/kg. The maximum 

concentration (Cmax) and time to 

maximum concentration (tmax) was the 

same in F344 and Sprague-Dawley rats, 

but the area under the curve (AUC) and 

half-life (t1/2) were longer, suggesting 

greater bioavailability of iodine in the 

Sprague-Dawley rats. Radioactivity 

elimination in Sprague-Dawley rats was 

comparable to F344 rats. 

After multiple doses of unlabeled 

AmicalTM 48, one dose of 14CAmicalTM 48 displayed no difference in 

absorption, elimination, 

pharmacokinetics, metabolism, or route 

of elimination.

Dermal 14C-AmicalTM was absorbed 7-

10% of the applied dose; plasma 

radioactivity and iodine were negligible, 

5-7% were found in the urine and fecal 

elimination was <0.3%. The dermal dose 

was slowly absorbed and rapidly 

eliminated mainly in the urine with 23-

30% of the absorbed dose in the urine 

after 24 hours and 38-45% after 48 hours. 

The dermal application site wash was the 

major depot of radioactivity with 80% 

rinsed off the males and 90% in females. 

Tissues had 0.3% of the applied dose or 

3-5% of the absorbed dose at the end of 
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the study. Recoveries were between 90-

97%.

The major route of elimination was 

through the urine for all exposure 

methods with 87-97% excreted and most 

was within the first six hours (78-92%); 

elimination in the feces accounted for 7-

13% of the radioactivity. Organ/tissue 

radioactivity levels were <1% of the dose 

received after 7 days, this also included 

the plasma. Results indicate that orally 

administered AmicalTM 48 is rapidly and 

almost completely absorbed from the 

gastro-intestinal tract and eliminated 

quickly. Expired air and volatiles was not 

a major route of elimination.

Distribution patterns in the orally dosed 

animals were similar between the singleand repeat-dosed Groups with the highest 

residual radioactivity found in the major 

elimination organs/tissue, i.e., the kidney, 

liver, and plasma; however, the levels 

were low. No organ demonstrated 

accumulation of AmicalTM 48 with 

highest levels of AmicalTM 48 equivalent 

in the plasma 7 days after dosing. The 

plasma, kidney, and liver eliminates 

AmicalTM 48 equivalent rapidly with 

most of the concentration eliminated by 

the 6th hour. 

Upon absorption, iodine is liberated from 

the AmicalTM 48 reaching maximum 

concentration at 4 hours in the low-dose 

groups and 2 hours in the high-dose 

groups. Elimination of iodine is slower 

than the radioactive portion of AmicalTM

48, with 9-13% of free iodine in the urine 

and 5-7% of the radioactivity in the urine. 

The total free iodine detected in the urine 

was 59-73% and 41-43% of the total 

radioactivity, in low- and high-dose 

groups, respectively. Fecal iodine 

elimination was between 7-13% and most 

was within the first 24 hours. Dermal 

exposures produced an iodine profile in 

the urine that was different than oral 

exposures; the total amount of iodine in 

the urine was higher than oral exposure 

groups, indicating a higher metabolism of 

one or both of the iodine groups from 

AmicalTM 48.

14C-AmicalTM 48 was highly 

metabolized. No parent compound was 

identified in the blood and excreta. The 

major metabolites were the parent 

conjugated with glucuronide and 3 non-
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Guideline No./

Study Type

MRID No./

Study Classification Dosing and Animal Information Results

parent oxidated benzylic methyl moiety 

or minor ring hydroxylation.
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Toxicology References for Appendix A

MRID

00123023 Kesterson, J.: Majors, K.; Moore, L.; et al. (1976) Acute Dermal Toxicity of 

DIMTS (Dry Powder) and an DIMTS Dispersion in Rabbits: Study Nos. 76-245 

and 76-246. (Unpublished study received Jun 16, 1976 under 275-30; submitted 

by Abbott Labora- tories, North Chicago, IL; CDL:225439-A).

00087842 Horath, L.L. (1975) Report to Abbott Laboratories: Acute Vapor Inhalation 

Toxicity Study with DIMTS Solution in Albino Rats: IBT No. 663-07250. 

(Unpublished study received Dec 18, 1981 under 275-41; prepared by Industrial 

Bio-Test Laboratories, Inc., submitted by Abbott Laboratories, North Chicago, 

Ill.; CDL:246501-E).

41765401 Kreuzmann, J. (1990) Acute Oral Toxicity in Rats-Limit Test: DIMTS: Lab 

Project Number: 90-4015-21 A. Unpublished study pre- pared by Hill Top 

Biolabs, Inc. 14 p.

41765402 Kreuzmann, J. (1990) Primary Eye Irritation Study in Rabbits: DIMTS: Lab 

Project Number: 90-4015-21 C. Unpublished study prepared by Hill Top Biolabs, 

Inc. 15 p.

41765403 Kreuzmann, J. (1990) Primary Skin Irritation Study in Rabbits: DIMTS: Lab 

Project Number: 90-4015-21 B. Unpublished study prepared by Hill Top Biolabs, 

Inc. 14 p.

42054402 Dudley, R. (1986) Three-Month Toxicity Study of DIMTS Administ- ered Via the 

Diet to Rats: Lab Project Number: TA85-096. Unpub- lished study prepared by 

Abbott Labs. 206 p.

42054403 Creighton, J. (1986) Three-Month Toxicity Study of DIMTS Admin- istered 

Orally to Dogs: Lab Project Number: TB85-158. Unpubli- shed study prepared by 

Abbott Labs. 194 p.

42054404 Lehrer, S. (1985) Evaluation of the Effects of Orally Administered DIMTS on the 

Embryonic and Fetal Development of the Rat: Segment II, TFR: Lab Project 

Number: TE85-022. Unpublished study prepared by Abbott Labs. 56 p.

42054405 Lehrer, S. (1986) Evaluation of the Effects of Orally Administered DIMTS on the 

Embryonic and Fetal Development of the Rat: Segment II, TFR: Supplement to 

Study TA85-022: Lab Project Numb- er TE85-230. Unpublished study prepared 

by Abbott Labs. 33 p.

42243801 Lehrer, S. (1985) Evaluation of the Effects of Orally Administered DIMTS on the 

Embryonic and Fetal Development of the Rabbit--Segment II, TFR: Lab Project 

Number: TE85-054. Unpublished study prepared by Abbott Labs. 64 p.
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43008702 Kreuzmann, J. (1990) Acute Oral Toxicity in Rats--Limit Test of DIMTS: 

Supplemental Information: Lab Project Number: 90/4015/21/A. Unpublished 

study prepared by Hill Top Biolabs, Inc. 17 p.

43008703 Kreuzmann, J. (1990) Primary Eye Irritation Study in Rabbits of DIMTS: 

Supplemental Information: Lab Project Number: 90/4015/21/C. Unpublished 

study prepared by Hill Top Biolabs, Inc. 19 p.

43008704 Kreuzmann, J. (1990) Primary Skin Irritation Study in Rabbits of DIMTS: 

Supplemental Information: Lab Project Number: 90/4015/21/B. Unpublished 

study prepared by Hill Top Biolabs, Inc. 16 p.

43120601 Putman, D.; Curry, P.; Schadly, E. (1994) Chromosome Aberrations in Chinese 

Hamster Ovary (CHO) Cells (DIMTS Preservative): Final Report: Lab Project 

Number: TD585/337. Unpublished study prepared by Microbiological Associates, 

Inc. 30 p.

43246401 Dudley, R.; Bollmeier, A. (1986) Three-Month Toxicity Study of DIMTS

Administered via the Diet to Rats: Supplemental Data: Lab Project Number: 

TA85/096. Unpublished study prepared by Abbott Labs. 25 p.

43246402 Creighton, J.; Bollmeier, A. (1986) Three-Month Toxicity Study of DIMTS

Administered Orally to Dogs: Supplemental Data: Lab Project Number: 

TB85/158. Unpublished study prepared by Abbott Labs. 22 p. 

43246403 Lehrer, S.; Bollmeier, A. (1985) Evaluation of the Effects of Orally Administered 

DIMTS on the Embryonic and Fetal Development of the Rat--Segment II, TFR: 

Supplement: Lab Project Number: TE85/022. Unpublished study prepared by 

Abbott Labs. 188 p.

43246404 Lehrer, S.; Bollmeier, A. (1985) Evaluation of the Effects of Orally Administered 

DIMTS on the Embryonic and Fetal Development of the Rabbit--Segment II, 

TFR: Supplement: Lab Project Number: TE85/054. Unpublished study prepared 

by Abbott Labs. 179 p.

43660901 Wnorowski, G. (1995) Amical: Acute Inhalation Toxicity Defined LC50 (in 

Rats): Lab Project Number: 3515. Unpublished study prepared by Product Safety 

Labs. 43 p.

46913301 Carney, E.; Zablotny, C.; Quast, J.; et al. (2006) DIMTS: Two-Generation Dietary 

Reproductive Toxicity Study in CD Rats. Project Number: 031007, 031007A, 

031007A/2. Unpublished study prepared by Dow Chemical Co. 1661 p.

46913302 Carney, E.; Zablotny, C.; Johnson, K. (2006) DIMTS: One-Generation Dietary 

Reproduction Toxicity Study in CD Rats. Project Number: 031007. Unpublished 

study prepared by Dow Chemical Co. 440 p.
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47076601 Saghir, S.; Brzak, K.; Clark, A.; et al. (2007) DIMTS Antifungal Agent: 

Pharmacokinetics and Metabolism in Fischer 344 Rats. Unpublished study 

prepared by Dow Chemical Co. 204 p.

47214601 Carney, E.; Zablotny, C.; Card, T.; et. al. (2007) DIMTS Antimicrobial Agent: 

Oral Gavage Developmental Toxicity Probe Study in New Zealand White 

Rabbits. Unpublished study prepared by The Dow Chemical Co. 149 p.

47242202 Carney, E.; Brooks, K.; Rasoulpour, R.; et al. (2007) DIMTS Antifungal Agent: 

Oral Gavage Developmental Toxicity Study in New Zealand White Rabbits. 

Project Number: 061146. Unpublished study prepared by Dow Chemical Co. 337 

p.

47292704 Saghir, S. (2007) DIMTS: De-Iodinated Amical: Determination of Oral 

Absorption in Female CRL:CD(SD) Rats. Project Number: 061162. Unpublished 

study prepared by The Dow Chemical Co. 35 p.

47292705 Miksztal, M. (2007) DIMTS: Data Waiver for Chronic Toxicity and 

Carcinogenicity in Two Species. Unpublished study prepared by The Dow 

Chemical Co. 25 p.

47307306 Mecchi, M. (2007) Salmonella escherichia coli Mammalian - Microsome Reverse 

Mutation Assay Preincubation Method with a Confirmatory Assay with DIMTS: 

Amended Final Report. Project Number: 6736/182, 29117/0/422OECD, 071075. 

Unpublished study prepared by Covance Laboratories, Inc. 72 p.

47338201 Carney, E.W.; Zablotny, C.L.; Johnson, K.A. (2003) DIMTS: 13-Week Dietary 

Reproduction Probe Study in CD Rats. Project Number: 021121. Unpublished 

study prepared by Dow Chemical, USA. 200 p.

47338403 Miksztal, M. (2007) DIMTS: Acute Toxicity and Range Finding. Project Number: 

DR/0365/7838/060, 1073093, APR/76/377. Unpublished study prepared by 

Abbott Laboratories. 142 p.

48236901 Thomas, J.; Murray, J. (2010) DIMTS: 28-Day Dermal Toxicity Study in 

Crl:CD(SD) Rats. Project Number: 091015. Unpublished study prepared by Dow 

Chemical Co. 325 p.

48264901 Hotchkiss, J.; Krieger, S.; Sura, R. (2010) DIMTS Antifugal Agent: 90-Day 

Inhalation Toxicity Study in Crl:CD(SD) Rats. Project Number: 091053. 

Unpublished study prepared by The Dow Chemical Company. 412 p.

48293901 Durando, J. (2010) DIMTS Antimicrobial: Local Lymph Node Assay (LLNA) in 

Mice. Project Number: P327/DOW, 30508, 100171. Unpublished study prepared 

by Eurofins/Product Safety Laboratories. 41 p.

94039001 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 

00050924. 21-Day Subacute Dermal Toxicity in the Rabbit with DIMTS: Project 

No. 7820. Prepared by Pharmacopathics Research Labs., Inc. 29 p.
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94039010 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 

00054961. Mutagencity [sic] Evaluation of DIMTS: Project No. 2683. Prepared 

by Litton Bionetics, Inc. 11 p.

94039011 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 

00160070. Mutagenicity of DIMTS in a Mouse Lymphoma Mutation Assay: 

Project #20989. Prepared by Litton Bionetics, Inc. 11 p.

94039012 Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 

00160072. Evaluation of DIMTS in the Rat Primary Hepatocyte Unscheduled 

DNA Synthesis Assay: Project No. 20991. Prepared by Litton Bionetics, Inc. 10 

p.

US EPA Guidance for Thyroid Assays in Pregnant Animals, Fetuses and Postnatal 

Animals, and Adult Animals. Internal guidance document, October 24, 2005. 

Office of Pesticide Programs, Health Effects Division, Washington, DC.
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Appendix B Environmental Fate

Environmental Fate and Transport Properties of DIMTS and its 

Degradation Products 

Water and Sediment

Hydrolysis

DIMTS is stable to hydrolysis at pH 5, but degrades rapidly in pH 7 and 9 buffered solutions 

with linear half-lives of 2.1-3.6 days. The major degradate was MIMPTS, whose concentrations 

did not decline in the study and reached 90-100 % of applied by the end of the study. The minor 

degradates MPTS and PTSOA were formed in the study (MRID 43008701). 

Aqueous Photolysis

DIMTS degraded with a half-life of 1.4 hours and no degradation occurred in the dark controls, 

which is consistent with the results of the hydrolysis study. Two significant degradates increased 

until the end of the study, including PTSOA which increased to 90 % by 24 hours, and MPTS, 

which increased to about 10 % (MRID 47343001). 

Octanol-Water Partition Coefficient and Bioconcentration in Fish

The log P value for parent DIMTS (2.66) in Table 4 indicates that there is little potential for 

bioconcentration of fish, and the log P values for the degradation compounds (-0.62 to 2.3) in 

Table 5 also indicate little potential for bioconcentration of the degradation compounds.

Aerobic Aquatic Metabolism

Aerobic aquatic metabolism data have not been submitted but are not required because the

results from the hydrolysis and aerobic soil studies both indicate that parent DIMTS degrades to 

the MIMPTS and MPTS degradates. Also, data on the persistence of DIMTS and MIMPTS 

under aquatic conditions are also available. 

Anaerobic Aquatic Metabolism

Under anaerobic aquatic conditions, the total system, non-linear half-lives of parent DIMTS and 

the degradation compound MIMPTS were 9.6 and 11 days, respectively. Parent compound was 

associated more with water than sediment through 7 days and more in sediment afterwards. 

MIMPTS reached 16.2 % by 7 days, and then declined to <1 % by 3-6 months. MIMPTS was 

associated more in water than sediment for 60 days and then in equal portions thereafter. The 

degradation compound MPTS increased to 94.5 by 4-6 months, and was associated with water 

rather than sediment over the duration of the study. The degradation compound PTSOA did not 

reach significant levels in the study. Extractable residues were 23-31 % (0-14 days) and 16-18 
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% by 30-180 days, and non-extractable residues never exceeded 2 %. Water soluble residues 

ranged from 68 to 85 % and volatiles did not exceed 0.8 % (MRID 42177201).

Leaching from treated wood

In a submerged wood block study (E11-06, MRID 47375907), DIMTS leached from wood 

treated with 5.6-16 mg/cm3 with maximum rates of 23.5-49.3 μg/cm2/day and cumulative rates 

of 309-413 μg/cm2. The percentages of leached DIMTS leached were 17.9 % for the 5.6 

mg/cm3 treatment rate, 9.9 for the 11.2 mg/cm3 treatment rate, and and 8.1 % for the 16 mg/cm3

treatment rates. Table B1 contains additional information on wood leaching. 

Soil

Soil Leaching/Adsorption/Desorption Batch Equilibrium

Data on sorption of parent DIMTS to soil are required, along with the degradation products 

MIMPTS and MPTS are required because these compounds can be present in significant 

amounts (>10 %) in the environment based on the results of both chemical and microbial 

degradation studies.

Aerobic Soil Metabolism

In aerobic soil (the top layer of non-flooded soil), the non-linear parent, MIMPTS, and MPTS 

half-lives were 1.5, 32, and 53 days, respectively. The linear half-life of MPTS was 173 days. 

PTSOA did not exceed 0.7 % in the study (MRID 41765405). 

Anaerobic Soil Metabolism

In the anaerobic soil metabolism study (flooded top layer of soil or the second layer of soil), the 

half-lives of parent DIMTS were 1.7 and 4.2 days in aerobic (non-flooded) and anaerobic 

(flooded soil) portions of the study, respectively. DIMTS was found in equal portions in water 

and sediment. MIMPTS was a major degradate with a half-life of 21 days and was found 

predominantly in water. MPTS reached 81 % by the end of the study and was primarily found in 

water (MRID 41765406).

Soil Photolysis

Soil photolysis half-lives of 13 days (linear) and 5.3 days (non-linear) were observed for parent 

compound. MIMPTS was stable in the dark control but degraded with a half-life of 12.5 day in 

irradiated sample. Volatiles and non-extractables were negligible (MRID 47323601).

Fate and Transport in WWTP

Activated Sludge Sorption Isotherm

Data have not been submitted for activated sludge sorption isotherm (ASSI) for DIMTS but it is 

not required. The log P for DIMTS is 2.66 (<3), and according to the Final 158W Rule, ASSI 
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data are not required if the log Kow is <3 (Testnote 19 of Environmental Fate Requirements 

Table).

Activated Sludge Biodegradation

In a ready biodegradability study (MRID 47338401, OECD 301F), DIMTS was not readily 

biodegradable at 28 and 67 mg/L because <60 % degraded within a 10-day window after 10 % 

degradation in the 28-day study. For the 67 mg/L test concentration, the amount of degradation 

by 10 days after 10 % degradation was 35-45 % % (28 mg/L data not provided). Degradate 

identification was not conducted in this study. On the other hand, the reference compound, 

sodium benzoate, was readily biodegradable because >60 % degraded in a 10-day window after 

10 % degradation in the 28-day study. 

In another ready biodegradability study (MRID 47024601, OECD 301B), DIMTS was readily 

biodegradable because >60 % degraded within a 10-day period after 10 % degradation occurred. 

In fact, DIMTS reached non-detectable concentrations by two days in the study. However, it 

was only primarily biodegradable and not ultimately biodegradable at 0.05 and 0.5 mg/L because 

the test material primarily formed terminal degradates other than CO2 and water. For DIMTS

residues, limited mineralization to CO2 and water (11-14 %) was observed in the study. The 

degradate MIMPTS (parent minus one iodine) was readily biodegradable at 0.05 mg/L but not at 

0.5 mg/L. The half-lives of the degradate MIMPTS (parent minus one iodine) were 1.2 day at 

0.05 mg/L and 12.6 days at 0.5 mg/L, indicating that biodegradation is highly dependent on 

concentration. At 0.05 mg/L, MIMPTS declined to non-significant (<10 % of applied parent) 

concentrations by 7 days and was non-detectable by 21 days. At 0.5 mg/L, MIMPTS declined to 

15.2 % by study termination (29 days). The terminal degradate MPTS accumulated and reached 

81-96 % of applied at 0.05 mg/L and 74 % at 0.5 mg/L by study termination. The recoveries at 

0.05 mg/L were 98.5 + 5.5 %, and for 0.5 mg/L, were 112.4 + 4.7 %. The reference compound 

(sodium benzoate) degraded completely and was both readily biodegradable and ultimately 

biodegradable

In a Zahn-Wellens study (OECD 302B, OCSPP 835.3200), the biodegradation of the degradate 

methyl-p-tolyl sulfone (MPTS) was studied at 5 and 75 mg/L. Inherent biodegradation 

(including primary and ultimate) was measured. The reference compound (aniline) was 

ultimately biodegradable based on the fact that 90 % of DOC was removed in four days, which is 

more than 70 % in 28 days. MPTS was not ultimately biodegradable because only about 48 % of 

DOC was removed in 28 days (MRID 47375909). 

Activated Sludge Respiration Inhibition (ASRI)

DIMTS is not toxic to WWTP organisms when tested at >4.5 times its water solubility of 

<2 mg/L (Table 4). In other words, based on results from an ASRI test, DIMTS was not 

observed to inhibit activated sludge microorganisms at test concentrations as high as 9 mg/L. 

The results of the positive controls were within 15 % of each other and the IC50 value for the 

reference substance (sodium benzoate) was 12 mg/l, which is in the acceptable range of 5-30 

mg/l (MRID 47373803). DIMTS would not be expected to reach concentrations as high as 9 

mg/L based on its solubility of <2 mg/L. Consequently, no further ASRI testing is needed for 

DIMTS or its degradates. 
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Table B1. Environmental Fate Data Requirements for Diiodomethyl p-tolyl sulfone

Data Requirement 

(OCSPP guideline unless 

specified)

Study result Degradate results

Reference (MRID 

unless specified)

Status

Hydrolysis (835.2120) Stable at pH 5

Half-lives of 2.1days at pH 

7 and 3.6 days at pH 9

MIMPTS reached 90-100 % 

(end of study, 30 days)

MPTS and PTSOA were 

minor degradates

43008701

Acceptable

Photodegradation in Water 

(835.2240)

Half-life of 1.4 hours PTSOA (90 %) and MPTS 

(10 %)

Stable in dark control

47343001

Acceptable

Photodegradation on Soil 

(835.2410)

Half-life of 5.3 days MIMPTS half-life of 12.5 

days (irradiated)

Stable in dark controls

47323601

Acceptable

Aerobic Soil Metabolism 

(835.4100)

Half-life of 1.5 day MIMPTS (32 days)

MPTS (53 days)

41765405

Acceptable

Anaerobic Soil Metabolism 

(835.4200)

Half-life of 1.7 day 

(aerobic phase)

Half-life of 4.2 days 

(anaerobic phase)

MIMPTS half-life of 21 

days

MPTS reached 81 % by the 

end of the study and did not 

decline.

41765406

Acceptable

Anaerobic Aquatic 

Metabolism (835.4400)

Half-life of 9.6 days MIMPTS half-life of 11 

days

MPTS reached 95 % by end 

of study (180 days)

42177201

Acceptable

Aerobic Aquatic 

Metabolism (835.4300)

No data N/A Required

Leaching-AdsorptionDesorption (835.1230)No data No data Required for DIMTS, 

MIMPTS, and MPTS

Bioaccumulation in Fish 

(850.1730)

No data N/A Not required because 

log P <3 for parent and 

degradates

Special Leaching Study 

(AWPA E11-06)

Leaching rates

5.6 mg/cm3 trt rate (1 % 

w/w)

23.5 (max)

19.1 (min)

20.4 (average)

19.9 (median)

309 (cumulative)

17.9 (% leached)

N/A 47375907

Acceptable

Max, min, average, and 

median leaching rates 

in μg/cm2

/day

Cumulative leaching in 

μg/cm2

Most relevant leaching 

rate is 5.6 mg/cm3

treatment based on 1 % 

(w/w) treatment rate in 

study and 0.12-0.32 % 

AI treatment rate in 

Label Reg. No. 464-673

11.2 mg/cm3 trt rate (2 % 

w/w)

34.4 (max)

19.4 (min)

23.3 (average)

22.7 (median)

351 (cumulative)

9.9 (% leached)

16 mg/cm3 trt rate (3 % 

w/w)
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49.3 (max)

21.1 (min)

25.8 (average)

23.5 (median)

413 (cumulative)

8.1 (% leached)

Ready Biodegradability 

(835.3110)

DIMTS not readily 

biodegradable at 28 and 67 

mg/L

Not measured 47338401

Acceptable

OECD 301F

DIMTS was primarily 

biodegradable at 0.05 and 

0.5 mg/L 

Not detectable after 2 days 

MIMPTS not detectable 

after 7 days in 0.05 mg/L 

DIMTS treatment

MIMPTS detected 

throughout the 29-day study 

at 0.5 mg/L DIMTS

treatment

MIMPTS half-lives of 1.2 

day at 0.05 mg/L and 12.6 

days at 0.5 mg/L

MPTS did not degrade in 

study 

47024601

Supplemental

OECD 301B

Inherent Biodegradability 

Zahn Wellens/EMPA Test 

(835.3200)

No data MPTS (as parent 

compound) was not 

ultimately biodegradable at 

5 and 75 mg/L

47375909

Acceptable 

Inhibition of Sewage Sludge 

Respiration (850.3300)

Not inhibitory at >9 mg/L 

(4.5X water solubility 

based on Table 5) 

N/A 47373803

Acceptable
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Environmental Fate References

MRID 41765405. Cranor, W. (1990) Aerobic Soil Metabolism of ?carbon 14|-Abbott- 9248 

(DIMTS): Lab Project Number: 36608. Unpublished study prepared by Analytical BioChemistry Labs., Inc. 955 p.

MRID 41765406. Madsen, S.; Williams, M. (1990) Anaerobic Soil Metabolism of ?carbon 14|-

DIMTS: Lab Project Number: 38730. Unpublished study prepared by Analytical Bio-Chemistry 

Labs., Inc. 461 p.

MRID 42177201. Madsen, S.; Williams, M. (1991) Anaerobic Aquatic Metabolism of ?carbon 

14| DIMTS: Final Report: Lab Project Number: 38729. Unpublished study prepared by ABC 

Labs, Inc. 532 p.

MRID 43008701. Williams, M.; Heim, L. (1993) Hydrolysis of DIMTS as a Function of pH at 

25 (degrees) C: Lab Project Number: 40886. Unpublished study prepared by ABC Laboratories, 

Inc. 63 p.

MRID 47024601. Davis, J.; Erhardt, S. (2005) DIMTS: Determination of Biodegradability 

Using a Modified OECD 301B CO2 Evolution Test. Project Number: 041126. Unpublished 

study prepared by The Dow Chemical Company. 29 p.

MRID 47323601. Madsen, S.; Williams, M. (1991) Determination of the Photolysis Rate of 

(Carbon 14)-DIMTS on the Surface of Soil. Project Number: 38727. Unpublished study prepared 

by ABC Laboratories, Inc. 691 p.

MRID 47338401. Gonsoir, S.J.; Stock, M.K.; Rivard, M.A. (2002) Evaluation of the Ready 

Biodegradability of DIMTS Preservative Using the OECD Method 301F: Manometric 

Respiratory Test. Project Number: 011091. Unpublished study prepared by Dow Chemical, 

USA. 29 p.

MRID 47343001. Williams, M.; Madsen, S.; Quinn, B. (1991) Determination of the Photolysis 

Rate of (Carbon 14)-DIMTS in pH 5 Buffered Solution at 25 Degrees Celsius. Project Number: 

38728. Unpublished study prepared by ABC Laboratories, Inc. 45 p.

MRID 47373803. Gonsior, S.; Rivard, M.; Stock, M. (2002) Activated Sludge, Respiration 

Inhibition Test (OECD 209) for DIMTS Preservative. Project Number: 011213. Unpublished 

study prepared by Dow Chemical Co. 15 p.

MRID 47375909. Gonsior, S.; Hales, C. (2007) Methyl-P-Tolylsulfone: Biodegradation in an 

Activated Sludge Die-Away Study. Project Number: 071065. Unpublished study prepared by 

Dow Chemical, USA. 21 p.
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U.S. EPA. May 8, 2013. Data Requirements for Antimicrobial Pesticides; Final Rule. Docket 

identification number EPA-HQ-OPP-2008-0110. 

https://www.federalregister.gov/articles/2013/05/08/2013-10162/data-requirements-forantimicrobial-pesticides.
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Appendix C Ecotoxicology Profile

Toxicity to Terrestrial Receptors

Birds

Based on studies in the agency’s files, DIMTS appears to be practically nontoxic to birds when 

ingested on an acute or dietary basis. It is not anticipated that any further studies in birds will be 

required at this time. 

C1 Birds (Acute Oral Toxicity & Dietary Toxicity)

Species Chemical % Active 

Ingredient

Endpoint Toxicity 

Category

Satisfies 

Guidelines

MRID

Bobwhite 

quail Colinus 

virginianus) 

Diiodomethyl 

p-tolyl sulfone 

(Acute Oral) 

95 LD50 > 2000

(mg ai/kg 

bw) 

Practically NonToxic Yes (core) 123643 

Diiodomethyl 

p-tolyl sulfone 

(Dietary) 

95 LD50 = 5620 

(ppm) 

Practically NonToxic Yes (core) 123642 

Mallard duck 

(Anas 

platyrhynchos) 

Diiodomethyl 

p-tolyl sulfone 

(Dietary) 

95 LD50 = 5620

(ppm) 

Practically NonToxic Yes (core) 124488 

Mammals

Based on the results of mammalian studies conducted to meet human toxicity data requirements, 

diiodomethyl p-tolyl sulfone exhibits low acute oral and acute dermal toxicity (Toxicity Category 

IV), and high acute inhalation toxicity (Toxicity Category II). Diiodomethyl p-tolyl sulfone is 

classified as an eye corrosive (Toxicity Category I). For dermal irritation, diiodomethyl p-tolyl 

sulfone is a low irritant (Toxicity Category IV) and is not classified as a dermal sensitizer. It is not 

anticipated that any further studies in mammals will be required to assess the ecological risk posed 

by DIMTS. For further data refer to Appendix A. 

Beneficial Insects

Per 40 CFR 158W, a honeybee acute contact study is typically required for chemicals labeled for 

use as wood preservatives. It is anticipated that an acute toxicity study in honeybees will be 

required to assess the risk posed by DIMTS to insect pollinators (see Guideline 850.3020).

Terrestrial Plants

Terrestrial plants are not expected to have significant exposure to DIMTS when used as directed. 

It is not anticipated that any studies in terrestrial plants will be required at this time. 
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Toxicity to Aquatic Receptors

Freshwater Fish

The agency requires higher tier testing based on a chemical’s properties and fate in the environment.

Diiodomethyl p-tolyl sulfone is acutely toxic to freshwater organisms and forms soluble and 

persistent major degradates. As such, chronic toxicity data is required to gain a more complete 

understanding of the chemical’s toxicity in aquatic environments. The requirement for chronic 

toxicity data in freshwater fish will be satisfied by a fish early-life stage study (see Guidelines 

850.1400). Because DIMTS is highly susceptible to reductive dehalogenation in aqueous solution, 

the preferred experimental test substance is the major degradate, MIMPTS (parent minus one iodo 

group) degradate. The preferred freshwater test species is rainbow trout. This data is anticipated to be 

required. 

C2 Freshwater Fish and Amphibian Toxicity Data

Species Chemical % Active 

Ingredient

Endpoint Toxicity 

Category

Satisfies 

Guidelines

MRID

Rainbow trout 

Oncorhynchus

mykiss) 

Diiodomethyl 

p-tolyl sulfone 

97.7% 96-h LC50 = 

66.7 (μg 

ai/L) 

Very highly

toxic 

Supplemental 47234001 

Diiodomethyl 

p-tolyl sulfone 

95% 96-h LC50 = 

130 (μg ai/L) 

Highly toxic Yes (core) 149730 

Bluegill 

sunfish 

Lepomis 

macrochirus) 

Diiodomethyl 

p-tolyl sulfone 

95% 96-h LC 50 = 

750 (μg ai/L) 

Highly toxic Yes (core) 149731 

Freshwater Invertebrates

The agency requires higher tier testing based on a chemical’s properties and fate in the environment.

Diiodomethyl p-tolyl sulfone is acutely toxic to freshwater organisms and forms soluble and 

persistent major degradates. As such, chronic toxicity data is required to gain a more complete 

understanding of the chemical’s toxicity in aquatic environments. The requirement for chronic 

toxicity data in freshwater invertebrates will be satisfied by an aquatic invertebrate life-cycle study 

(see Guidelines 850.1300). Because DIMTS is highly susceptible to reductive dehalogenation in 

aqueous solution, the preferred experimental test substance is the major degradate, MIMPTS (parent 

minus one iodo group) degradate. The preferred freshwater test species is Daphnia magna. This data

is anticipated to be required.

C3 Freshwater Invertebrates Toxicity Data

Species Chemical % Active 

Ingredient

Endpoint Toxicity 

Category

Satisfies 

Guidelines

MRID

Diiodomethyl 

p- tolyl sulfone 

97.7% 48-h EC50 = 

279 (μg ai/L) 

Highly toxic Yes (core) 47234002 
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Waterflea 

(Daphnia 

magna) 

Diiodomethyl 

p- tolyl sulfone 

95% 48-h EC50 = 

7,400 (μg 

ai/L)4 

Moderately 

Toxic 

Yes (core) 149729 

Diiodomethyl 

p- tolyl sulfone 

95% 48-h EC =50 

71 (μg ai/L)5

Very Highly 

Toxic 

Supplemental 123644 

Estuarine/Marine Fish

Acute toxicity testing with estuarine/marine organisms using the TGAI is required when an end-use 

product is intended for direct application to the marine/estuarine environment or the active ingredient 

is expected to reach this environment in significant concentrations because of its expected use and 

mobility. As such, the agency requires acute toxicity data in estuarine/marine fish for DIMTS (see 

Guideline 850.1075). There are currently no acute toxicity data for diiodomethyl p-tolyl sulfone in 

estuarine/marine fish. This data is anticipated to be required. 

Estuarine/Marine Invertebrates

Acute toxicity testing in estuarine marine organisms using the TGAI is required when an end-use 

product is intended for direct application to the marine/estuarine environment, or the active 

ingredient may reach the aquatic environment in significant concentrations as a result of leaching and 

environmental mobility, as in the use of DIMTS as a wood preservative. There are currently no 

acceptable acute toxicity data for estuarine/marine shrimp (see Guideline 850.1035), or 

estuarine/marine mollusk (see Guideline 850.1025) for diiodomethyl p-tolyl sulfone. This data is 

anticipated to be required. 

Aquatic Plants

Microphytes and Floating Vascular Macrophytes

Acute toxicity testing in aquatic plants is required when an end-use product is intended for direct 

application to the marine/estuarine environment, or the active ingredient may reach the aquatic 

environment in significant concentrations as a result of leaching and environmental mobility, as in 

the use of DIMTS as a wood preservative. There are currently no acceptable toxicity data for 

diiodomethyl p-tolyl sulfone in vascular aquatic plants (see Guideline 850.4400), green algae (see 

Guideline 850.4500), or cyanobacteria (see Guideline 850.4550). This data is anticipated to be 

required. 
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Ecotoxicology References for Appendix C

Fink, R.; Beavers, J.; Grimes, J.; et al. (1978) Acute Oral LD50-- Bobwhite Quail: A-9248: 

Project No. 161-104. Final rept. (Unpublished study received Sep 7, 1979 under 275-21; 

prepared by Wildlife International Ltd. and Washington College, submitted by Abbott 

Laboratories, North Chicago, IL; CDL:240936-C)

Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00123643. Acute 

Oral Toxicity Study of DIMTS in Bobwhite Quail: Project #161-104. Prepared by 

Wildlife International, Ltd. 13 p.

Fink, R.; Beavers, J.; Joiner, G.; et al. (1978) Eight-day Dietary LC50--Bobwhite Quail: A-9248: 

Project No. 161-105. Final rept. (Unpublished study received Sep 7, 1979 under 275-21; 

prepared by Wildlife International Ltd. and Washington College, submitted by Abbott 

Laboratories, North Chicago, IL; CDL:240936-B)

Fink, R.; Beavers, J.; Grimes, J.; et al. (1978) Eight-day Dietary LC50--Mallard Duck: A-9248: 

Project No. 161-106. Final rept. (Unpublished study received Sep 7, 1979 under 275-21; 

prepared by Wildlife International Ltd. and Washington College, submitted by Abbott 

Laboratories, North Chicago, IL; CDL:240936-A)

Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00123642. EightDay Dietary Toxicity Study of DIMTS in Bobwhite Quail: Project #161-105. Prepared by 

Wildlife International Ltd. 12 p.

Trueblood, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00124488. EightDay Dietary Toxicity Study of DIMTS in the Mallard Duck; Project No. 161-106. 

Prepared by Wildlife International, Ltd. 12 p.

Forbis, A.; Georgie, L.; Burgess, D. (1984) Acute Toxicity of Ami- cal 48 to Rainbow Trout 

(Salmo gairdneri): Static Acute Toxicity Report #31946. Unpublished study prepared by 

Analytical Bio- chemistry Laboratories, Inc. 60 p.

Marino, T.; McClymont, E.; Yaroch, A. (2007) DIMTS Antifungal Agent: An Acute Toxicity 

Study with the Rainbow Trout, Oncorhynchus mykiss. Unpublished study prepared by 

The Dow Chemical Company. 42 p.

Hunziker, R.W. (2007) Estimation of Water Solubility Limit, Octanol-Water Partitioning 

Constant, and Aquatic Toxicity of Monoiodo-p-methyltolysulphone and pMethyltolylsulphone Which Are Breakdown Products of the Biocidal Active di-iodomethyl-para-tolyl-sulphon (DIMTS). Project Number: DR/0122/8542/003. Unpublished 

study prepared by Dow Chemical Europe and Dow Chemical Co. 16 p.

Miksztal, M. (2007) DIMTS: Acute Toxicity and Range Finding. Project Number: 

DR/0365/7838/060, 1073093, APR/76/377. Unpublished study prepared by Abbott 

Laboratories. 142 p.
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Bollmeier, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00149731. Acute 

Toxicity of DIMTS to Bluegill Sunfish: Static Acute Toxicity: Report No. 31945. 

Prepared by ABC Labs. Inc. 10 p.

Bollmeier, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00149730. Acute 

Toxicity of DIMTS to Rainbow Trout: Static Acute Toxicity: Report No. 31946. 

Prepared by ABC Labs., Inc. 1 p.

Suprenant, D.; Ziencina, M. (1978) Acute Toxicity of A-9248 to the Water Flea (Daphnia 

magna): Report #BW-78-9-308. (Unpublished study received Sep 7, 1979 under 275-21; 

prepared by EG & G, Bionomics, submitted by Abbott Laboratories, North Chicago, IL; 

CDL:240936-D)

Forbis, A.; Burgess, D.; Georgie, L. (1984) Acute Toxicity of DIMTS to Daphnia magna: Static 

Acute Toxicity Report # 31947. Unpublished study prepared by Analytical Biochemistry 

Laboratories, Inc. 38 p.

Marino, T.; Yaroch, A.; Arnold, B.; et al. (2007) DIMTS Antifungal Agent: An Acute Toxicity 

Study with the Daphnid, Daphnia magna. Unpublished study prepared by Dow Chemical 

Co. 42 p.

Bollmeier, A. (1990) Angus Chemical Company Phase 3 Summary of MRID 00149729. Acute 

Toxicity of DIMTS to Daphnia magna: Static Acute Toxicity: Report No. 31947. 

Prepared by ABC Labs., Inc. 1 p.

Hamlin, J. (1972) Report to: Abbott Laboratories, Chemical Division: Four-Day Static Fish 

Toxicity Studies with DIMTS and Amical 77 in Rainbow Trout and Bluegills: IBT No. 

A1244. (Unpublished study received Mar 9, 1972 under 275-22; prepared by Industrial 

Bio-Test Laboratories, Inc., submitted by Abbott Laboratories, North Chicago, Ill.; 

CDL:002251-H)

Kirk, H.; Staley, J.; McClymont, E.; et al. (2002) DIMTS Antimicrobial: Growth Inhibition Test 

with the Freshwater Green Alga. Selenastrum capricornutum. Project Number: 011189. 

Unpublished study prepared by Dow Chemical Co. 43 p.
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Appendix D Screening Level Down-theDrain 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 DIMTS and its degradates. The Down-the-Drain 

module uses daily per capita release of household wastewaters, stream dilution factors, and 

wastewater treatment plant removal efficiency to provide both high-end and median (average) 

time-averaged surface water concentrations of chemicals discharged by domestic wastewater 

treatment plants. The high-end scenario uses surface water concentrations downstream of 

domestic wastewater treatment plants based on the 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. In the absence of data on removal of 

DIMTS during wastewater treatment, no removal of DIMTS during wastewater treatment was 

assumed.

The Down-the-Drain module was first run using a high-end scenario to determine whether the 

model predicted exceedances of concentrations of concern. If the high-end scenario predicted 

exceedances of the concentration of concern, the model was also run using the average scenario.
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Appendix E Product Chemistry

The product chemistry information for parent DIMTS relevant to risk assessment is summarized 

in Table E1, while the product chemistry information for the degradates monoiodo-pmethyltolylsulfone (MIMPTS, parent compound minus one iodo group), methyl-p- tolylsulfone 

(MPTS, parent compound minus both iodo groups) and p-toluene sulfonic acid (PTSOA, parent 

compound minus both iodo groups and a methyl group with added hydroxyl group) are 

summarized in Table E2. 

Table E1 – Physical-Chemical and Environmental Fate Properties for Parent DIMTS

Guideline No.

Parameter DIMTS

Reference (MRID 

unless specified)

Comments

830.7050 UV/Visible Absorption Max sorption at 288 nm, 

some tailing through 409 nm 47234003

830.7370 Dissociation constant (pKa) Not applicable 48511201

830.7550 Octanol-water partition coefficient 

at 25 oC (Log Kow) 2.66 42177202

830.7840 Solubility in water (mg/L) <2 47373801

830.7950 Vapor pressure (mmHg) 4.9 x 10-7 47373801

None Henry's law constant at 25 oC 

(atm-m3/mol) 1.4 x 10-7 Calculated

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

millimeters of mercury;

Table E2 – Physical-Chemical and Environmental Fate Properties for Monoiodo-pmethyltolylsulfone (MIMPTS), methyl-p- tolylsulfone (MPTS), and p-toluene sulfonic acid 

(PTSOA) Degradates 

Guideline 

No. Parameter

Monoiodo-pmethyltolylsulfone 

(MIMPTS)

Methyl-p-tolyl 

sulfone

(MPTS)

P-toluene sulfonic 

acid (PTSOA)

Reference (MRID 

unless specified)

Comments

None Structure None

None Description Parent minus 1 iodine Parent minus two 

iodines

Hydroxylated, 

once-demethylated 

MPTS None

None PC Code None None None Not applicable

None CAS No. 37891-96-6 59203-01-9 104-15-4 Dow MSDS 

(MIMPTS)

O

S

O

H3C

I O

H3C S O

CH3
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Guideline 

No. Parameter

Monoiodo-pmethyltolylsulfone 

(MIMPTS)

Methyl-p-tolyl 

sulfone

(MPTS)

P-toluene sulfonic 

acid (PTSOA)

Reference (MRID 

unless specified)

Comments

Chemical Book 

(MPTS)

None Smiles code O=S(=O)(c(ccc(c1)C)

c1)C(I)

O=S(=O)(c(ccc(c1)C)

c1)C

O=S(O)(=O)(c(ccc(

c1)C)c1) EPI-WEB 4.11

None Molecular 

formula C8H9IO2S C8H10O2S C7H8O3S EPI-Web 4.11

None Molecular 

weight 296.12 170.23 172.20 EPI-WEB 4.11

830.7050 UV/Visible 

Absorption No data No data No data Similar to parent

830.7370 Dissociation 

constant (pKa) Not applicable Not applicable Not applicable Similar to parent 

830.7550

Octanol-water 

partition 

coefficient at 

25 o

C (Log 

Kow)

2.3 1.94 -0.62

47338402 (MIMPTS 

and MPTS)

EPI-WEB 4.11 

(PTSOA)

830.7840 Solubility in 

water (mg/L) 140.4 1,352 6.2 x 105

47338402 (MIMPTS 

and MPTS)

EPI-WEB 4.11 

(PTSOA)

830.7950 Vapor pressure 

(mmHg) 2.3 x 10-5 2 x 10-3 2.9 x 10-6 EPI-WEB 4.11

None Henry's law 

constant at 25 

o

C (atmm3

/mol)

6.4 x 10-8 3.3 x 10-7 1.1 x 10-12 Calculated

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

millimeters of mercury.
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Product Chemistry References

Chemical Book. 2010. METHYL P-TOLYL SULFONE. 

http://www.chemicalbook.com/ChemicalProductProperty_EN_CB8463935.htm

Dow MSDS. August 11, 2011. Material Safety Data Sheet: DIMTS. 

http://msdssearch.dow.com/publishedliteraturedowcom/dh_0819/0901b80380819eaa.pdf?filepat

h=..

EPI-WEB 4.11. 2012. http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

MRID 42177202. Laster, W.; McGowan, N. (1991) Octanol/ Water Partition Coefficient of 

DIMTS: Final Report: Lab Project Number: 39209. Unpublished study prepared by ABC Labs, 

Inc. 377 p.

MRID 47234003. Lopez, A. (2007) Determination of UV/Visible Absorption Characteristics of 

DIMTS Antifungal Agent. Project Number: 1654W. Unpublished study prepared by PTRL West, 

Inc. 29 p.

MRID 47373801. Sinning, D. (2003) Physical and Chemical Characteristics of DIMTS: Melting 

Point, Boiling Point, Density, Water Solubility, and Vapor Pressure. Project Number: 2310/16, 

020030. Unpublished study prepared by Case Consulting Laboratories, Inc. 12 p.

MRID 47338402. Hunziker, R.W. (2007) Estimation of Water Solubility Limit, Octanol-Water 

Partitioning Constant, and Aquatic Toxicity of Monoiodo-p-methyltolysulphone and pMethyltolylsulphone Which Are Breakdown Products of the Biocidal Active di-iodo-methylpara-tolyl-sulphon (DIMTS). Project Number: DR/0122/8542/003. Unpublished study prepared 

by Dow Chemical Europe and Dow Chemical Co. 16 p. 

MRID 47373801. Sinning, D. (2003) Physical and Chemical Characteristics of DIMTS: Melting 

Point, Boiling Point, Density, Water Solubility, and Vapor Pressure. Project Number: 2310/16, 

020030. Unpublished study prepared by Case Consulting Laboratories, Inc. 12 p.

MRID 48511201. O'Connor, B.; Woolley, S. (2011) DIMTS: Determination of Dissociation 

Constants in Water. Project Number: 41005025, 24P/2010/030, GLP/2011/024. Unpublished 

study prepared by Harlan Laboratories, Ltd. 13 p.