Dimethyi_Disulfide Regi~~ation Revi::V Human-Health Assessmen! Scoping ~~ument 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: November 27, 2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Dimethyl disulfide. Human-Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 0290R8 

Decision No.: Jl7l!P.Z/ 

Petition No.: N/A 

Risk Assessment Type: N/ A 

TXR No.: N/A 

MRID No.: N/A 

DP Barcode: 0412525 

Registration No.: N/A 

Regulatory Action: Registration Review Scoping 

Document 

Case No.: 2390 

CAS No.: 624-92-0 

40 CFR: N/A 

FROM: Shalu Shelat, Industrial Hygienist ~ llft;jn ~ _p 

Nancy McCarroll, Toxicologist " Yt1t-1 /ltc~'--

Risk Assessment Branch 6 (RABVI) · 1 

Health Effects Division (7509P) 

THROUGH: Jeffery Dawson, Acting Branch Chief 

Risk Assessment Branch 6 (RABVI) 

Health Effects Division (7509P) 

TO: Garland Waleko, Chemical Review Manager 

Risk Management and Implementation Branch II 

Pesticide Re-Evaluation Division (7508P) 

Attached is the HED human-health risk assessment scoping document for dimethyl disulfide 

(DMDS) to support registration review. 

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---··--·--D~ethyJ Disulfi~e ~e.gistration Review Human-Hea!th Asse~s~ nt ~~p_in~ Docu!llent ______ _ 

Executive Summary 

Dimethyl disulfide (DMDS) is a broad-spectrum fumigant used for the control or suppression of 

nematodes, various soil borne pathogens, and weeds. DMDS is currently registered for use as a 

pre-plant soil fumigant in strawberry, fruiting vegetable (e.g., tomato, peppers, and eggplant), 

cucurbit (e.g., cucumbers, squash, and melons), blueberry, and ornamental fields. There are also 

industrial and commercial uses of DMDS. The largest industrial use of DMDS is in the refining 

and petrochemical industries but it is also used to dissolve elemental sulfur for unplugging sour 

natural gas wells, as an additive during manufacturing of 'Sponge Iron' to prevent metal dusting, 

and as a thiomethylating agent in organic synthesis. The Health Effects Division (HED) has 

evaluated the status of the human-health assessments for DMDS to determine whether sufficient 

data are available to support Registration Review. HED has also considered the most recent 

human-health risk assessments for DMDS with respect to toxicity, exposure, and usage 

databases, and the most updated Agency science policy and risk assessment methodologies to 

determine the scope of work necessary to support Registration Review. 

The most recent Human Health Risk Assessment document for DMDS was issued in April2010. 

At that time, DMDS was registered as a new active ingredient for agricultural use in the United 

States to be applied to strawberry, fruiting vegetable (e.g., tomato, peppers, and eggplant), 

cucurbit (e.g., cucumbers, squash, and melons), blueberry, and ornamental fields. Since that 

time, no new uses have been proposed for DMDS. 

The residue chemistry and dietary-exposure databases are adequate to support current 

registration requirements. Although DMDS is used as an agricultural pesticide, it is considered a 

non-food use chemical since it is quickly degraded or metabolized into non-toxic degradates in 

the soil. Furthermore, DMDS residues must dissipate in the soil prior to planting or transplant 

damage may occur. Therefore, this fumigant does not require food tolerances and is not subject 

to the amendments of the Federal Food, Drug, and Cosmetic Act (FFDCA) and the Federal 

Insecticide, Fungicide and Rodenticide Act (FIFRA) promulgated under the Food Quality 

Protection Act (FQP A) of 1996. As a result, a risk assessment has not been conducted for the 

dietary exposure scenario. Based on environmental fate data and modeling estimates the Agency 

does not expect the pesticidal uses ofDMDS to adversely impact ground water or surface water. 

Dietary (food and drinking water) assessments are not anticipated during Registration Review for 

the currently registered uses. 

The toxicity database is adequate for Registration Review. Dermal irritation was observed in rat 

and rabbit irritation studies with severity of irritation varying based on length of exposure. 

However, the Agency does not anticipate dermal exposure resulting from typical use ofDMDS 

based on the enclosed systems that are required to keep DMDS as a liquid. As a result, HED has 

not conducted a quantitative dermal risk assessment. DMDS has a robust inhalation toxicity 

database with studies varying in duration from acute to repeated exposures. Port-of-entry 

irritation (i.e., nasal irritation) is the most sensitive endpoint for DMDS. Irritation typically 

increases in severity and progresses deeper in the nose with increasing concentrations. 

The robust inhalation database for DMDS clearly shows that the duration of exposure does not 

impact the no observed adverse effect levels (NOAELs) or the lowest observed adverse effect 

levels (LOAELs). Therefore, the acute inhalation and nasal irritation study is adequate and health 

protective of all durations of exposure for the DMDS inhalation risk assessment. 

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There was no indication of developmental or reproductive toxicity via the inhalation route below 

maternally toxic concentrations in rats or rabbits. DMDS has not been classified with respect to 

its carcinogenic potential via the oral or inhalation route. There are no chronic/carcinogenic 

inhalation studies, the major route of concern, available for DMDS. However, the mutagenic 

studies available for DMDS are negative and thus a cancer assessment is not warranted for 

DMDS. The requirement for an immunotoxicity study was waived because the most sensitive 

endpoint for the inhalation risk assessment is nasal irritation, which occurs at concentrations that 

are protective of systemic effects (HASPOC TRX # 0056747). The Agency does not anticipate 

the need to reevaluate the points of departure (PODs) and uncertainty factors (UFs) for the 

residential and occupational exposure assessments during Registration Review.

The occupational and residential exposure database for DMDS is adequate for Registration 

Review with the exception of a worker exposure and flux study conditionally required as part of 

the 2010 risk assessment. This study will examine the use of high barrier tarps for raised bed 

shank, flat bed (broadcast) shank, and drip irrigation applications. HED recently reviewed a 

protocol for this study submitted by the DMDS registrant (Smith and Shelat; D408338; 2/22/13). 

The Agency will review and incorporate the study results during Registration Review. HED 

may be required to update occupational and residential (bystander) assessments during 

Registration Review to incorporate any new findings based on the worker exposure and flux 

study.

No data deficiencies outside those previously discussed were identified for DMDS.

EPA anticipates conducting the following risk assessment updates during Registration Review:

Toxicology: None

Residue Chemistry: None

Dietary Exposure: None

Occupational/Residential Exposure:

o Revised occupational handler risk assessments may be necessary based on 

submission of the conditionally required worker exposure and flux study.

o Additional or revised residential bystander risk assessments may be necessary 

based submission of the conditionally required worker exposure and flux study.
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1.0 Introduction

DMDS is a broad-spectrum fumigant used for the control or suppression of nematodes, various 

soil borne pathogens, and weeds. The registered uses are for tomatoes, peppers, eggplant, 

cucumbers, squash (all), melons (all), strawberries, onions, field grown ornamentals, and forest

nursery crops. DMDS end-use products are packaged as Paladin (98.8% active ingredient) and 

Paladin EC (93.8% active ingredient). DMDS is stored as a liquid but volatilizes rapidly 

following soil injection. A maximum effective broadcast application rate is 450 lb ai/acre per 

year for all uses. It is applied to the soil prior to planting via shank injection (broadcast or raised 

bed) or drip irrigation equipment. Treated areas of the field are required by the label to be 

covered by high-barrier tarps in an effort to reduce emissions of DMDS. The label prohibits tarp 

removal for 12 days after application. 

HED has evaluated the status of the human-health assessment for DMDS to determine whether 

sufficient data are available to support Registration Review. HED has also considered the most 

recent human-health risk assessment for DMDS with respect to toxicity, exposure, and usage 

databases, and the most updated Agency science policy and risk assessment methodologies to 

determine the scope of work necessary to support Registration Review. The Dimethyl Disulfide: 

Section 3 Health Effects Division Human Health Risk Assessment was completed in April 2010. 

The assessment focused on the new occupational uses of DMDS and utilized DMDS specific 

worker exposure and flux studies. No new uses of DMDS have been registered since the 

assessment was completed.

The 2010 assessment listed a number of data needs for the DMDS:

Toxicology

o OPPTS Guideline 870.7800 - Immunotoxicity study-Rat

o OPPTS Guideline 870.5300 - Mutagenicity—Gene Mutation-Mammalian

Occupational and Residential Exposure

o OPPTS Guideline 835.8100 - Field volatility from soil

 Broadcast Shank Injection Applications

 Raised Bed Shank Injection Applications

 Raised Bed Drip Irrigation Applications

o OPPTS Guideline 835.1300 – Estimation of Inhalation Exposure, Outdoor Sites

These data needs are discussed in further detail within this document.

2.0 Hazard Identification/Toxicology

The DMDS toxicology database is adequate for registration review. Attachment 2 provides a 

summary of the acute, subchronic, and chronic toxicity profile for DMDS. The relevant data has

been incorporated into the toxicity profile. Attachment 2B provides a summary of the relevant 

toxicological endpoints used in 2010 DMDS risk assessment. 

There is neither a pharmacokinetic nor a metabolism study available for DMDS and the 

metabolic pathway has not been determined. The insecticidal mode of action acts through the 

dysfunction of mitochondria. The mammalian mode of action or metabolic pathway has not 

been determined. Based on the lack of systemic toxicity in any of the DMDS toxicity studies, a 

rat metabolism study would not provide significant information for risk assessment.
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There are currently no oral toxicity studies available for DMDS. However, the proposed use 

pattern does not require tolerances and the use pattern is not suggestive of exposure through the 

oral pathway (i.e., no incidental oral exposure scenarios); therefore, oral studies are not required 

for DMDS at this time. Although, dermal irritation was observed in rat and rabbit irritation 

studies with severity of irritation varying based on length of exposure, the Agency does not 

anticipate dermal exposure resulting from typical use of DMDS due to the enclosed systems that 

are required to keep DMDS as a liquid. As a result, HED has not anticipated the need for 

conducting a quantitative dermal exposure and risk assessment for DMDS.

The inhalation route of exposure is the main exposure of concern for both workers and 

bystanders. DMDS has a robust inhalation toxicity database with studies varying in duration 

from acute to repeated exposures. For example, acceptable inhalation studies in rats and rabbits 

are available in exposure durations ranging from single day (4 and 24 hours) to repeated 

exposures (over 13 weeks) that evaluate port-of-entry irritation, systemic toxicity, neurotoxicity, 

reproductive toxicity, and developmental toxicity. There are no chronic inhalation studies for 

DMDS, however, the current use profile does not warrant this duration of toxicity study (i.e., 

long-term exposure is not expected). Based on current DMDS labels, exposures can be acute 

(less than 24 hours), short-term (1-30 days), and/or intermediate-term (1 month-6 months) in 

duration. 

The robust inhalation database for DMDS clearly shows that the duration of exposure does not 

impact the NOAELs or LOAELs. Therefore, the 24-hour acute inhalation study with nasal 

microscopy in the Sprague-Dawley rat (MRID 47785501) provides the most useful information 

for establishing a point of departure (PoD) for risk assessment and is adequate and health

protective of all durations of exposure for the DMDS inhalation risk assessment. A port-of-entry 

NOAEL was identified at 9 ppm and LOAEL at 12.5 ppm. The Reference Concentration (RfC) 

methodology was used to estimate a human equivalent concentration (HEC) of 1.25 ppm for 

DMDS. Since the RfC methodology takes into consideration pharmacokinetic (PK) differences 

but not pharmacodynamic (PD) differences, the uncertainty factor (UF) for interspecies 

extrapolation may be reduced to 3X (to account for the PD differences) while the UF for 

intraspecies variation is retained at 10X. Thus, the total UF for DMDS is 30X.

 

There is no quantitative or qualitative susceptibility observed in the developmental and 

reproductive inhalation toxicity studies with DMDS. All of the developmental NOAELs are 

equal to or larger than the NOAELs for maternal toxicity.

The odor of DMDS has been described in the literature as pungent garlic, decaying fish, or as 

decomposing materials. A literature review conducted by the registrant suggests the mean odor 

threshold for DMDS is 7 ppb to 12 ppb (0.007 – 0.012 ppm), depending on inclusion of outlier 

data (Clem McKown, 10-3-2008, 3 pgs). The estimated odor threshold is approximately three 

orders of magnitude below the dose at which nasal irritation is observed in rodent inhalation 

studies. The concentration at which the odor is identified also suggests that individuals near a 

treated field may detect the odor of DMDS before a concentration is reached that would produce 

nasal irritation. However, the time required for a person to detect the odor as well as the 

variability and aversions among individuals to the odor is currently not available for DMDS.

At this time, DMDS has not been classified with respect to its carcinogenic potential via the oral 

or inhalation route. For the major route of concern, there are no chronic/carcinogenic inhalation 

studies available for DMDS. An in vitro mammalian cell gene mutation assay is not available at 

this time. Nevertheless, the negative data from a comprehensive battery of in vitro and in vivo
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mutagenicity studies suggest that carcinogenicity is not a concern for DMDS at this time. A 

cancer assessment is not needed for Registration Review.

The requirement for an immunotoxicity study was waived because the most sensitive endpoint 

for the inhalation risk assessment is nasal irritation, which occurs at concentrations that are 

protective of systemic effects. Overall, no data deficiencies were identified that would impact 

the Registration Review. 

Conclusions: The toxicity database for DMDS is adequate for Registration Review. 

The Agency does not anticipate the need to reevaluate the points of departure (PODs) and 

uncertainty factors (UFs) for the residential and occupational exposure assessments during 

Registration Review.

3.0 Residue Chemistry

The residue chemistry database for DMDS is adequate for Registration Review. Given the 

available crop field trial data and the results of the aerobic soil metabolism study, the uses on the 

DMDS labels (strawberries, blueberries, fruiting vegetables, cucurbits, and ornamentals) are 

considered nonfood uses. Accordingly, the current uses of DMDS do not require food tolerances 

and are not subject to the amendments of the Federal Food, Drug, and Cosmetic Act (FFDCA) 

and the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) promulgated under the 

Food Quality Protection Act (FQPA) of 1996 (Smith; D339675; 4/20/2010). However, given the 

lack of a plant metabolism study, more field trial data may be required in the future if DMDS 

registrations for uses on other crops are requested.

Conclusions: The residue chemistry database for DMDS is adequate for Registration Review. 

4.0 Dietary Exposure

The dietary exposure database for DMDS is adequate for Registration Review. As described in 

Section 3.0, the Agency previously decided that the currently registered uses of DMDS are 

considered non-food and do not require food tolerances. 

Environmental fate data suggest that there is a low potential for DMDS to be present in drinking 

water because rapid volatilization of DMDS from surface water is expected to be an important 

route of dissipation. DMDS may transport to nearby surface water through runoff and erosion, 

especially if an application of DMDS coincides with, or is closely followed by a rain event. 

However, the Henry’s Law Constant of 1.21 x 10-3 atm-m

3

/mol for DMDS suggests that it 

would volatilize quickly from surface water. Based on environmental fate data and the residual 

contents in soils, the Agency does not expect DMDS to adversely impact the drinking water 

sources such as surface water and ground water.

Based on the discussion above, no drinking water assessments have been previously performed

nor are warranted for DMDS.

Conclusions: The dietary exposure database for DMDS is adequate for Registration Review. 

Dietary (food and drinking water) assessments are not anticipated during Registration Review.

5.0 Residential Exposure
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DMDS, like the other soil fumigants, has the potential to move off-site following field 

applications, resulting in exposure to bystanders near treated areas and to people far away from 

treated areas through ambient air. Exposure to DMDS may also occur to those handling the 

pesticide or working in treated fields. Acute inhalation exposures to bystanders and workers 

appear to present the greatest risk concern.

The DMDS labels require the use of high barrier tarps; however, HED currently has only two 

field volatility studies that use high barrier tarps. The two available high barrier studies quantify

emissions from shank injection raised bed applications using high barrier tarps (performed in 

Dover, FL using a metalized tarp and in Tifton, GA using a VIF tarp). HED has no field 

volatility studies that quantify emissions from shank injection broadcast applications using high 

barrier tarps or from drip irrigation applications using high barrier tarps. As part of the 2010 risk 

assessment, HED conditionally required a study to address these scenarios. The registrant has 

submitted a protocol for a worker exposure and flux study to quantify the exposures from raised 

bed shank, flat bed (broadcast) shank, and drip irrigation applications with the use of high barrier 

films. HED has recently reviewed this protocol (Smith and Shelat; D408338; 2/22/13). The 

Agency will review and incorporate this study during Registration Review.

There are currently no registered residential uses of DMDS. However, there is the potential for 

residential bystander inhalation exposure to DMDS after a soil fumigation application. The 

Agency has specifically focused on assessing acute DMDS inhalation exposures resulting from 

applications because peak DMDS air concentrations typically occur in the first 24 or 48 hours 

after application. There is also the potential for inhalation exposure to DMDS via ambient air. 

These exposures can be acute as well as longer-term in nature.

The 2010 Human Health Risk Assessment document analyzed acute residential bystander 

inhalation exposure to DMDS based on numerous field volatility studies and PERFUM 

(Probabilistic Exposure and Risk model for Fumigants) air modeling for a variety of DMDS

applications (Smith; D339675; 4/20/2010). The results of these assessments show that bystander 

inhalation exposure to DMDS after a soil fumigation application can vary depending on a variety 

of factors such as application method, agricultural tarps, and a number of soil parameters (i.e., 

soil moisture, organic content, etc.). For many application scenarios, the PERFUM air modeling 

results showed that acceptable DMDS air concentrations were attainable at some distance from a 

treated field and thus buffer zones were required to protect residential bystanders. The 2010 

Dimethyl Disulfide: Section 3 Health Effects Division Human Health Risk Assessment provides

more information on buffer zone development.

In order to qualitatively characterize the potential for exposure to DMDS in ambient air, HED 

compared the DMDS inhalation toxicity endpoints to the ambient air levels that were quantified 

for methyl bromide (by the California Air Resource Board or CARB) which is a highly used and 

highly volatile fumigant. In all cases, this comparison resulted in risks that do not exceed HED’s 

level of concern for DMDS (MOEs ≥ 30). This comparison should be considered conservative 

in nature because there is less potential for exposure to DMDS in ambient air than with methyl 

bromide because of the environmental fate characteristics of DMDS relative to methyl bromide 

(i.e., DMDS is not as volatile as methyl bromide, DMDS dissipates/degrades faster in the 

environment than methyl bromide). 

Conclusions: 
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The residential exposure database for DMDS is adequate for Registration Review except for the 

conditionally required worker exposure and flux study. HED will review and incorporate this

study during Registration Review.

During Registration Review, HED also plans to update the fumigant factors document (Dawson, 

Smith, and Shelat; D385314; 1/11/2011). The fumigant factors document provides a discussion 

of values and parameters used as the basis for buffer reduction credits (i.e., tarps) as well as for 

establishing Good Agricultural Practices (i.e., soil moisture) for the fumigants. This document 

impacts all of the soil fumigants including DMDS.

6.0 Aggregate-Risk Assessment

Acute and chronic aggregate-risk assessments were not previously performed for DMDS because 

no dietary exposure assessments were performed (see Section 3.0 and 4.0 above).

Conclusions: 

Acute and chronic aggregate risk assessments are not anticipated during Registration Review.

7.0 Occupational Exposure

There is potential for occupational handler and post-application inhalation exposure to DMDS to 

occur based on the registered uses. The most recent HED document that analyzed the potential 

occupational handler and post-application risks to DMDS is the 2010 risk assessment (Smith; 

D339675; 4/20/2010). HED assessed the inhalation exposure to occupational handlers, to 

occupational reentry workers who could be exposed when entering DMDS treated areas to 

perform crop-production tasks, and to occupational bystanders who could be exposed when 

performing crop-production tasks (but not inside) DMDS treated areas. 

The 2010 assessment utilized DMDS specific exposure studies to perform the occupational 

handler and post-application inhalation exposure and risk assessment for the handler tasks listed:

 Fumigation Equipment Driver/Operator/Observer 

 Tarp Equipment Driver/Operator 

 Tarp Monitor 

 Bed Driver 

 Shoveler 

 Tarp Cutter 

 Tarp Remover 

 Hole Puncher 

 Planter 

Acute inhalation risks exceed HED’s level of concern (MOEs < 30) for many occupational 

activities at the baseline level (no respirator). However, with the addition of an organic vapor 

respirator (with an assumed protection factor of 10), almost all of the acute handler risks did not 

exceed HED’s level of concern (MOE ≥ 30).

The DMDS labels require the use of high barrier tarps; however, HED currently has limited 

worker exposure data for use of high barrier tarps. Three of the four DMDS specific studies 

utilized in the 2010 assessment used standard polyethylene tarps and not the high barrier tarps 

required on the proposed DMDS labels. As part of the 2010 risk assessment, HED conditionally 

required a study to address these scenarios. The registrant has submitted a protocol for a worker 
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exposure and flux study to quantify the exposures from raised bed shank, flat bed (broadcast) 

shank, and drip irrigation applications with the use of high barrier films. HED has recently 

reviewed this protocol (Smith and Shelat; D408338; 2/22/13).

8.0 Public Health and Pesticide Epidemiology Data

An updated review of DMDS incident reports was recently prepared by HED (Recore and Evans, 

D413869, 08/20/2013). For this evaluation, both OPP Incident Data System (IDS) and the 

Centers for Disease Control and Prevention/National Institute for Occupational Safety and 

Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides 

(SENSOR) databases was consulted for pesticide incident data on the active ingredient dimethyl

disulfide. Dimethyl disulfide is not included in the Agricultural Health Study (AHS) and 

therefore no information from AHS was included in this report.

The IDS includes reports of alleged human health incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports 

from registrants, other federal and state health and environmental agencies and individual 

consumers. IDS contain reports from across the U.S. and most incidents have all relevant 

product information recorded. Reports submitted to the IDS represent anecdotal reports or 

allegations only, unless otherwise stated in the report. IDS records incidents resulting in higher

severity outcomes in more detail, in a module called the Main IDS module. This system stores 

incident data for death, major and moderate incidents, and it includes more details about the 

location, date and nature of the incident.

In Main IDS, from January 1, 2008 to June 11, 2013, there was one incident reported for single 

chemical only (dimethyl disulfide). This incident was classified as moderate severity. There 

were two additional incidents reported involving more than one chemical. These incidents were 

classified as minor severity. For the Aggregate IDS, from January 1, 2008 to February 19, 2013,

there were 0 reported incidents involving DMDS.

The SENSOR-Pesticides database covers 11 states from 1998-2009, although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers’ 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. Although both occupational 

and non-occupational incidents are included in the database, SENSOR-Pesticides focuses on 

occupational pesticide incidents, and is of particular value in providing that information. The 

state coordinator at the 11 respective state Departments of Health conducts case follow-up 

activities such as obtaining medical records to verify symptoms and severity. Using standardized 

protocol and case definitions derived from poison center reporting, the state SENSOR-Pesticide 

coordinator enters the incident information into the state-based system which is sent to NIOSH 

annually to be aggregated. 

A query of SENSOR-Pesticides 1998-2009 finds no cases involving DMDS.

Based on the low frequency and severity of incident cases reported for DMDS in both IDS and 

SENSOR-Pesticides, there does not appear to be a concern at this time that would warrant further 

investigation. The Agency will continue to monitor the incident information and if a concern is 

triggered, additional analysis will be included in the risk assessment.
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9.0 Tolerance Assessment and International Harmonization

There are currently no tolerances for DMDS (see Section 3.0 above).

 

10.0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

most recent DMDS human-health risk assessment, in accordance with U.S. Executive Order 

12898, “Federal Actions to Address Environmental Justice in Minority Populations and LowIncome Populations,” 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP 

typically considers the highest potential exposures from the legal use of a pesticide when 

conducting human-health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and 

people who may be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information.

11.0 Cumulative

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 DMDS and any other substances. For the purposes of this assessment, therefore, EPA has not 

assumed that DMDS 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 the policy statements 

released by EPA’s Office of Pesticide Programs concerning common mechanism determinations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

12.0 Endocrine Disruption

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 most recent registration decision for potassium and sodium 

nitrate, 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), potassium and sodium nitrate are 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 
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determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

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

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

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

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

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

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

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

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

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

chemicals identified for EDSP screening was published on June 14, 2013aand includes some 

pesticides scheduled for Registration Review and chemicals found in water. 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.b

In the interim, EPA is making no human health or environmental safety findings associated with 

the EDSP screening of [insert chemical/case]. Before completing this Registration Review, the 

Agency will make an EDSP FFDCA section 408(p) determination.

13.0 Human Studies

Previous assessments relied in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), are subject to ethics review 

pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics 

requirements. Future assessments will rely on the most current and updated data from a variety 

of sources. All future data used are subject to ethics review pursuant to 40 CFR 26. 

Descriptions of data sources as well as guidance on their use can be found at 

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

14.0 Risk Assessment Updates and Data Deficiencies

No data deficiencies outside those previously discussed were identified for DMDS.

EPA anticipates conducting the following risk assessment updates during Registration Review:

Toxicology: None

Residue Chemistry: None

Dietary Exposure: None

Occupational/Residential Exposure:

o Revised occupational handler risk assessments may be necessary based on 

submission of the conditionally required worker exposure and flux study.

o Additional or revised residential bystander risk assessments may be necessary 

based submission of the conditionally required worker exposure and flux study.

 

a

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

chemicals.

b

http://www.epa.gov/endo/
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15.0 References

Memoranda Relevant to Registration Review.

Author Barcode Date Title

Arthur, J D332932 5/10/2007

Dimethyl Disulfide (DMDS): Screening Human Health 

Assessment of EUP Application for Fumigant Use on 

Several Vegetable Crops 

C. Smith, E. 

Reaves, S. Shelat D339675 4/20/2010 Dimethyl Disulfide Section 3 HED Human Health Risk Assessment.

C. Smith and S.

Shelat D408338 2/22/2013

Response to Revised Protocol for “Evaluation of Worker 

Exposures (Observational Study) and Associated Flux for 

Application of Paladin®and Paladin EC® Using Three 

Application Methods.”

Habiba, U NA 8/27/2013

Dimethyl disulfide: Report of the Hazard and Science 

Policy Council (HASPOC) Meeting of August 1, 2013: 

Waiver for the Immunotoxicity Study (870.7800).

E. Evans and S. 

Recore D413869 8/20/2013 Dimethyl disulfide (DMDS): Tier I Review of Human Incidents
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Attachments: 

Attachment 1: Chemical Identity Table.

Attachment 2: DMDS Acute, Subchronic, and Chronic Toxicity Profile

Attachment 3: DMDS Endpoint Selection Tables.
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Attachment 1: Chemical Identity Table.

Attachment 1A: Test Compound Nomenclature

Chemical structure

Common name Dimethyl Disulfide, DMDS

Molecular formula C2H6S2

Molecular weight 94.2 g/mol

IUPAC name (methyldisulfanyl)methane

CAS name Dimethyl Disulfide

CAS number 624-92-0

PC Code 029088

Attachment 1B: Physicochemical Properties of the Technical Grade Test Compound

Parameter Value/Description Reference (MRID)

Physical State Pale yellow liquid 46903505 and 46903511

Melting point/range -84.7 °C 46903506

Boiling point/range 109-110 °C 46903509

Density 1.062 g/mol @ 20 °C 46903509 and 46903511

Water Solubility 1-10 g/L @ 20 °C 46903510

Solvent Solubility Completely miscible with n-hexane at all temperatures. 46903509

Vapor Pressure 29.0 mmHg @ 25 °C

22.5 mmHg @ 20 °C

4690306

Dissociation constant (pKa) This substance does not dissociate. 46903510
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Attachment 2: Dimethyl Disulfide Acute, Subchronic, and Chronic Toxicity Profile (as of 

August 2013)

DMDS Toxicity Profile

Guideline No./Study 

Type

MRID No. 

(year)/Classification/Exposure 

Conditions

Results

870.1100 

Acute Oral – Rat

46917001 (1985)

Acceptable/Guideline.

Wistar Rat 5/sex

DMDS mixed with 3% slurry of 

carboxymethylcellulose

LD50 combined = 190 mg/kg (150-240 mg/kg)

Toxicity Category II

125 mg/kg: 0/5M, 1/5 F died

188 mg/kg: 5/5M, 1/5F died

250 mg/kg: 3/5M, 4/5F died

All died at 375 and 500 mg/kg. Deaths within 2.5 

hours. Signs: immobility, salivation, lethargy, 

hunched position, watery ocular discharge. Survivors 

recovered by Day 6. Necropsy: pulmonary 

hemorrhage, enlarged spleen, GI hemorrhage and/or 

discolored heart. Unremarkable findings in recovered 

animals.

870.1200

Acute Dermal - Rabbit

46917002 (1985)

Acceptable/Guideline.

New Zealand Rabbit

LD50 > 2000mg/kg

Toxicity Category III; No deaths. 

Within 5 minutes: all heavy breathing, spasms, 

rearing, jumping, loss of balance. 10 minutes: lying 

down, excess salivation, flared nostrils, heavy 

breathing. By 4 hours all lethargic, although righting 

reflex had returned.

Irritation: removal of patch revealed green 

discoloration and irritation (erythema) at the site. By 

Day 6 eschar formation, sloughing off by Day 9. 

Cracking and thickening on Day 7 until Day 14 along 

with sloughing of the skin.

Necropsy: dark foci on all lobes and surfaces of the 

lungs, spleen abnormalities (pale purple/cloudy 

discoloration, rough texture and edges). Renal 

hemorrhage, dark foci and indentations on surface of 

kidneys. 

Special Inhalation

24 hour- Rat

47785501(2009)

Acceptable/Non-Guideline

Male Sprague-Dawley rat

10 male rats/concentration

0, 5, 9, 12.5, 18 ppm (0, 0.019, 

0.034, 0.049, and 0.071 mg/L)

24 hour continuous exposure

Microscopic evaluations 24 hrs 

after end of exposure

Port-of-Entry

NOAEL 9 ppm

LOAEL 12.5 ppm, based on the incidence of 

microscopic lesions (degeneration in the olfactory 

epithelium) of the nasal tissues (Nasal Levels II-VI), 

the incidence of degeneration in multiple nasal levels 

(3 to 5 levels) and inflammation of the olfactory and 

respiratory epithelia (Nasal Levels III and IV). No 

effect on lung wts; lung histo not performed.

Systemic NOAEL 18 ppm (HDT)

Systemic LOAEL not established

Special Inhalation

1-Day & 5-Day 

Inhalation-Rat

47471201 (2008)

Acceptable/Non-Guideline

Sprague-Dawley rat

20 rats/sex/concentration

0, 50, 150, 300, or 600 ppm (0, 

0.19, 0.58, 1.16, 2.27 mg/L)

Exposure 6 hrs/day for 1 day or 

5 consecutive days

10 rats/sex/concentration 

euthanized 24 hrs after acute 

exposure with remaining 10 

Day 1:

Port-of Entry NOAEL was not established (<50 

ppm)

Port-of-Entry LOAEL = 50 ppm (0.19 mg/L), based 

on changes (acute inflammation, degeneration, and 

hyperplasia) in the nasal tissues in both sexes. No 

effect on lung wts; lung histo not performed.

Day 5:

Systemic NOAEL was not established
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DMDS Toxicity Profile

Guideline No./Study 

Type

MRID No. 

(year)/Classification/Exposure 

Conditions

Results

rats/sex/conc. following 4 days.

Microscopic examination 

performed for 6 levels of the 

nose.

Systemic LOAEL was 50 ppm (0.19mg/L), based on 

decreased body weights and body weight gains.

Port-of Entry NOAEL was not established (<50 

ppm)

Port-of-Entry LOAEL = 50 ppm (0.19 mg/L), based 

on changes (acute inflammation, degeneration, and 

hyperplasia) in the nasal tissues in both sexes. 

Relative lung weights increased at 300 and 600 ppm. 

Regeneration of the olfactory epithelium occurred in 

nasal levels II through VI. 

870.1300

Acute Inhalation - Rat

46903516 (2005)

Acceptable/Guideline

Sprague-Dawley rat

4-hour whole body

847, 1188, 1308, 1650 ppm 

(3.18, 4.46, 4.91, 6.19 mg/L)

Clinical obs. at 1, 2, 4, 6, 8 hrs.

LC50 males >3.18 mg/L 3.18-6.19 mg/kg)

LC50 females= 5.22 mg/L (4.56-5.97 mg/L)

LC50 combined=4.91 mg/L (4.38-5.52 mg/L)

Toxicity Category IV

Deaths: 0/5M, 0/5 F 847ppm; 3/5M, 1/5F 1188 ppm, 

2/5M, 2/5 F 1308 ppm, 5/5M, 4/5F 1650 ppm during 

or immediately following exposure. Signs: tremors, 

low ease of handling, low arousal, salivation, ataxia 

(highest two doses). Peak effect 1 hour post-exposure. 

Rales Day 1, 2, 4, gone by Day 5.

External findings: soiled fur, red deposits of eyes, 

nose/mouth.

Necropsy: dark red discoloration of lungs (all lobes), 

collapsed lungs (1308 ppm) of rats dying prematurely.

870.2400

Primary Eye Irritation -

Rabbit

46917003 (1985)

Acceptable/Guideline

New Zealand White

4M, 5F

Transient corneal opacity, reversible within 7 days, 

No iridial damage in any of the rabbits. Conjunctival 

redness (grade 2) in 1/3 washed and 5/6 unwashed 

eyes at 24 hrs. None positive at 48 hrs. Chemosis 

(grade 2 or above) in 4/6 unwashed at 24 hrs, but none 

positive (score≥2) at 48hrs.

MMTS unwashed=14.8

MMTS washed = 6

Toxicity Category III

870.2500

Primary Skin Irritation -

Rabbit

46917004 (1985)

Acceptable/Guideline

New Zealand White

4M & 2F

0.5 ml aliquot DMDS at 4 (2 

abraded, 2 intact) dermal sites 

with 24 hr exposure.

PIS at 48 hours 2.02

Toxicity Category IV

Irritation scores higher for abraded than intact skin.

1 hr post exposure: Data not given.

24 hr post exposure: Mean irritation abraded 3.33 vs. 

1.50 intact.

48 hr post exposure: 2.25 abraded vs. 1.00 intact.

72 hr post exposure: 2.17 abraded vs. 0.92 intact. 

Minor erythema at intact sites on Day 7, all scores at 

intact sites zero on days 10 and 14.

870.2600

Dermal Sensitization –

Guinea Pig

46917005 (1985)

Acceptable/Guideline

10M Hartley guinea pig

Buehler Protocol with 10 induction treatments.

Not a dermal sensitizer.

870.3100

Subchronic Feeding - Rat Not currently available

870.3100

Subchronic Feeding -

Not currently available
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DMDS Toxicity Profile

Guideline No./Study 

Type

MRID No. 

(year)/Classification/Exposure 

Conditions

Results

Mice 

870.3100

Subchronic Feeding -

Mice

Not currently available

870.3150

Subchronic Feeding - Dog Not currently available

870.3200

28-Day Dermal - Rabbit

46917006 (1990)

Acceptable/Guideline

New Zealand white rabbit

10 rabbits/sex/dose

10.6, 106, 1063 mg/kg/day; 

6 hours/day, 5 days/week

HDT discontinued after Day 16 due to mortality.

Irritation NOAEL not established.

Irritation LOAEL is 10.6 mg/kg/day, based on 

erythema, edema and ischemic necrosis, with 

increased severity and incrustation at mid-dose, and 

severe erythema at HDT.

Systemic NOAEL is 10.6 mg/kg/day.

Systemic LOAEL is 106 mg/kg/day, based on 

lethargy with mortality, myocarditis and myocardial 

degeneration, lung lesions, decreased body weight and 

food consumption, and hemolytic anemia at HDT.

870.3465

13-Week Inhalation - Rat

46917007 (1992)

Acceptable/Guideline

Sprague-Dawley rats

20/sex/dose of 0 (air), 10, 50, or 

250 ppm (analytical 

concentrations of 0, 0.04, 0.19, 

and 0.95 mg/L) whole body for 

6hrs/day, 7days/week, 13 weeks

Main study: 10/sex/dose after 13 

weeks

Recovery: 10/sex/dose after 4 

weeks of recovery

Interim sacrifice: 20/sex/dose at 

150 ppm (0.58 mg/L) for 6 

weeks; 10/sex/dose after 6 

weeks and 10/sex/dose after 2 

week recovery period.

Port-of-entry NOAEL was not established.

Port-of-entry LOAEL is 10 ppm (0.04 mg/L), based 

on minimal to moderate atrophy and microcavitation 

of the olfactory epithelia (8/10 rats/sex) and 

respiratory squamous metaplasia in the anterior nasal 

cavity. No effects on lung histopathology at any 

concentration. Lung wts increased only at HDT.

Systemic NOAEL is 10 ppm (0.04 mg/L).

Systemic LOAEL is 50 ppm (equivalent to 0.19 

mg/L) based on: clinical signs of toxicity (soiled fur 

and piloerection); decreased body weights (↓2-14%), 

body weight gains (↓17-36%), and food consumption 

(↓4-15%) in both sexes. 

Recovery Group: squamous cell metaplasia still 

evident in the 50 (4/10M; 6/10F) and 250 ppm (10/10 

M; 10/10F) groups. (0/10 M&F at 10 ppm)

870.3700

Inhalation Developmental 

Toxicity - Rat

46917008 (1991)

Acceptable/Guideline

30 F pregnant Sprague-Dawley 

rats/dose; whole-body to 0, 5, 

15, or 50 ppm (0.02, 0.06, 0.19 

mg/l); 6 hrs/day, GD 6-15.

Microscopic evaluation of nasal 

& respiratory tract not done.

Maternal LOAEL is 50 ppm (0.19 mg/L), based on 

rough haircoat, decreased body weights, weight gains, 

and food consumption.

Maternal NOAEL is 15 ppm (0.06 mg/L)

Developmental LOAEL 50 ppm (0.19 mg/L), based 

on decreased fetal body weights, multiple skeletal 

developmental retardations.

Developmental NOAEL is 15 ppm (0.06 mg/L).

Port-of-Entry NOAEL could not be established.

870.3700

Inhalation Developmental 

Toxicity - Rabbit

46903523 (2005)

Acceptable/Guideline

24 F New Zealand rabbits/dose; 

Maternal LOAEL was not established.

Maternal NOAEL 135 ppm (0.52 mg/L) the HDT.
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DMDS Toxicity Profile

Guideline No./Study 

Type

MRID No. 

(year)/Classification/Exposure 

Conditions

Results

whole-body to 0, 15, 45, or 135 

ppm (0, 0.06, 0.17, 0.52 mg/L); 

6 hrs/day, GD 6-28.

Developmental LOAEL was not established.

Developmental NOAEL 135 ppm (0.52 mg/L) the 

HDT.

Port-of-Entry LOAEL is 15 ppm, based on 

macroscopic lung lesions (dark red discoloration or 

areas) at all concentrations. Lung histo not evaluated. 

Lung wts not recorded.

The port-of-entry NOAEL could not be established.

870.3800

Inhalation 2-Generation 

Reproductive Toxicity -

(Main study)

Rat

47052807 (2006)

Acceptable/Guideline

30 Sprague-Dawley 

rats/sex/dose; whole-body to 0, 

5, 20 or 80 ppm (0, 0.019, 0.079, 

0.308 mg/L); 6 hrs/day, 7

days/week for 10 weeks prior to 

mating to produce F1 litters.

Parental LOAEL 20 ppm (0.079 mg/L), based on 

decreased body weight, body weight gains, and food 

consumption in F1 males.

Parental NOAEL 5 ppm (0.019 mg/L).

Offspring LOAEL was not established (>80 ppm).

Offspring NOAEL 80 ppm (0.308 mg/L) (HDT) 

Reproductive LOAEL was not established.

Reproductive NOAEL is 80 ppm (0.308 mg/L) the 

HDT.

Port-of-Entry NOAEL and LOAEL could not be 

evaluated in this study.

870.3800

Lactational/range-finding 

Inhalation phasedexposure study - Rat

47052809 (2007)

Acceptable/Non-guideline

36 pregnant Sprague-Dawley 

rats/dose; 6 hrs/day, whole-body 

to 0, 5, 20, 80 ppm (0, 0.019, 

0.078, 0.308 mg/L); 6 hrs/day.

12 dams/dose: LD5-12

12 dams/dose: LD13-20

12 dams/dose: LD5-20

All animals terminated at 

PND21

Critical period of exposure during lactation evaluated.

Evaluation on page 29 of reproductive DER (MRID 

47052807)

Maternal LOAEL is 80 ppm (0.308 mg/L), based on 

decreased body weight gains and food consumption.

Maternal NOAEL is 20 ppm (0.078 mg/L)

Offspring LOAEL was not established.

Offspring NOAEL is 80 ppm (0.308 mg/L)

Reproductive LOAEL was not established.

Reproductive NOAEL is 80 ppm (0.308 mg/L)

This study did not replicate the body weight effects 

noted in the F1 pups of the definitive study.

870.4100

Chronic Feeding 

Toxicity-Rat Currently not available

870.4100

Chronic Feeding Toxicity 

- Dog Currently not available

870.4200

Carcinogenicity 

Inhalation - Mouse Currently not available

870.4200

Carcinogenicity/gavageMouse/Rat [bioassay] Currently not available
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DMDS Toxicity Profile

Guideline No./Study 

Type

MRID No. 

(year)/Classification/Exposure 

Conditions

Results

870.4300

Chronic Inhalation 

Toxicity/CarcinogenicityRat. (2 year)

Currently not available

870.5100

Bacterial Reverse 

Mutation Test (Ames 

Assay)

46903524 (1985)

Unacceptable/guideline

Purity information not provided.

Salmonella typhimurium strains TA98, TA100, 

TA1535, TA1537, and TA1538 exposed to DMDS 

(purity not provided; Lot # 5275-164) in dimethyl 

sulfoxide (DMSO) at concentrations of 0, 50, 166, 

500, 1666, or 5000 μg/plate (+/- S9-activation).

Evidence of slight cytotoxicity (reduced number of 

revertants) was observed with strain TA100 at 5000 

μg/plate (+/- S9). There were no marked increases in 

the mean number of revertants/plate in any strain. The 

positive controls induced marked increases in 

revertant colonies compared to controls in all strains 

in the presence and absence of S9-activation. There 

was no evidence of induced mutant colonies over 

background up to the limit dose for this test 

system.

870.5100

Bacterial Reverse 

Mutation Test (Ames 

Assay)

47052811 (2007)

Acceptable/guideline

Salmonella typhimurium strains 

TA98, TA100, TA1535, and 

TA1537 and Escherichia coli

strain WP2 uvrA exposed to 

DMDS (99.2%) in DMSO at 0, 

1.5, 5.0, 15, 50, 150, 500, 1500, 

or 5000 μg/plate (+/-S9, Trial 1) 

and 0, 50, 150, 500, 1500, or 

5000 μg/plate (+/-S9, Trial 2). 

The S9 fraction was derived 

from livers of male SpragueDawley rats induced with 

Aroclor®1254. The standard 

plate incorporation method was 

used in both trials. Standard 

strain-specific mutagens served 

as positive controls.

DMDS was tested up to the limit dose (5000 

μg/plate). No evidence of compound precipitation or 

cytotoxicity was observed at any concentration in any 

strain in either trial in the presence or absence of S9-

activation. There were no marked increases in the

mean number of revertants/plate in any strain. The 

positive controls induced marked increases in 

revertant colonies compared to controls in all strains 

in the presence and absence of S9-activation. There 

was no evidence of induced mutant colonies over 

background at concentrations up to the limit dose 

for this test system.

870.5300

In Vitro Gene Mutation 

Assay- Chinese Hamster 

Ovary Cells

46917009 (1990)

Unacceptable/guideline

0, 0.46, 1.37, 4.12, 12.3, 37.0, 

111, 333, and 1000 μg/mL (Trial 

1,+/--S9), or 0, 4.12, 12.3, 37.0, 

74.1, 111, 333, 667, and 1000 

μg/mL (Trial 2, +/- S9) for 3 

hours. 

Dose formulations were analyzed for actual 

concentrations in tissue culture medium and were 

found to contain 5.4, 9.6, 15.1, 42.7 and 149.6 μg/mL 

+S9 and 5.98, 14.4, 19.0, 62.2 and 182.3 μg/mL –S9 

for nominal concentrations of 37.0, 74.1, 111, 333 and 

1000 μg/mL.

Based on the overall results, no conclusions can be 

reached because of the problems associated with 

nominal vs. actual concentrations, which precluded a 

comparative evaluation of the data from both trials. 

Since analytical determinations were only performed 

for one of the two trials, we are not able to resolve 

from which trial these values were derived. Owing to 
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DMDS Toxicity Profile

Guideline No./Study 

Type

MRID No. 

(year)/Classification/Exposure 

Conditions

Results

the problems related to test material concentrations, it 

would have been prudent for the study investigators to 

analyze actual concentrations for both trials. Despite 

these limitations, increased MFs were seen in both 

trials and under both assay conditions. However, 

there is low confidence in the findings of this study. 

Accordingly, the study is not acceptable. 

870.5375

In Vitro Chromosomal 

Aberration in Human 

Peripheral Bloody 

Lymphocytes 

46917010 (1990)

Acceptable/guideline

DMDS (99.98%) in dimethyl 

sulfoxide (DMSO) at 

concentrations of 0, 3.7, 11.1, 

33.3, 100, or 300 μg/mL (+/-S9) 

for 24 hours.

There was no evidence of chromosome aberrations 

induced over background in the presence or absence 

of S9-activation up to cytotoxic concentrations.

870.5395

Micronucleus Assaymouse

46917012 (1989)

Acceptable/guideline

5 Swiss CD-1 mice/sex/concen., 

6 hrs/day; 4 consec. Days; whole 

body inhalation; 15-L glass 

inhalation chambers of 0 or 250 

ppm (0.975 mg/L), and 10 

mice/sex for 6 hrs/day; 3 consec 

days at 500 ppm (1.95 mg/L). 

The HDT exposure time was 

reduced from 4 consec days to 3 

days due to severe toxicity. 

Bone marrow cells were 

harvested at 24 hours after the 

final exposure.

DMDS is considered negative in this test system up to 

a concentration causing overt toxicity and cytotoxicity

to the bone marrow in the treated animals. 

870.5395

Micronucleus Assay- rat

47052810 (2007)

Acceptable/guideline

DMDS (99.2%) administered 

vapor to groups of 5 or 10 CD 

rats/sex via whole-body at 0, 

217, 421, or 825 ppm for 4 

hours. Cyclophosphamide was 

administered to 5 rats/sex via i.p. 

injection at a final dose of 40 

mg/kg. Bone marrow cells were 

harvested from 5 rats/sex in all 

groups at 24 hours after 

exposure, and from an additional 

5 rats/sex in the 0 and 825-ppm 

groups at 48 hours after 

exposure. 

All animals survived to scheduled sacrifice. The 

following clinical signs of toxicity were noted in one 

or both sexes of the treated animals during exposure: 

hypoactivity, lacrimation, and clear material around 

the mouth. Decreases (not statistically significant) in 

body weights were noted in the treated groups 

compared to the negative controls. No appreciable 

reductions in the ratio of PCEs to total erythrocytes 

were observed in the dimethyl disulfide-exposed 

groups relative to the negative control group, 

suggesting that the test material was not cytotoxic to 

the bone marrow. The positive control 

(cyclophosphamide) induced increases (p≤0.05) in 

MPCEs compared to the concurrent vehicle controls. 

No treatment-related increases in the MPCE 

frequency were observed in any treatment group 

when compared to controls
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DMDS Toxicity Profile

Guideline No./Study 

Type

MRID No. 

(year)/Classification/Exposure 

Conditions

Results

870.5550

In Vitro Unscheduled 

DNA Synthesis- Primary 

Rat Hepatocytes 

46917011 (1989)

Acceptable/guideline

primary rat hepatocyte cultures 

from male Fischer rats exposed 

to DMDS (99.88%) in dimethyl 

sulfoxide (DMSO) at doses of 

either 0, 1, 5, 10, 50, 100, or 200 

μg/mL (Trial 1), or 0, 5, 10, 50, 

100, 150, 200, 250, or 300 

μg/mL (Trial 2). Hepatocytes 

were harvested at 18-20 hours 

post-dosing. 

Dimethyl disulfide was tested up to the limit of 

solubility (200 μg/mL). The mean net nuclear grain 

(NNG) counts in the treated cultures (–9.5 to –4.5) 

were well below the threshold of 0 or more NNG 

required for a positive response, and the mean percent 

of cells in repair (>3 NNG/cell) was 0-3% in both 

trials. The positive controls induced the appropriate 

response in both trials. There was no evidence that 

unscheduled DNA synthesis, as determined by 

radioactive tracer procedures [nuclear silver grain 

counts] was induced.

870.6200

Inhalation Acute 

Neurotoxicity - Rats

46903529 (2005)

Acceptable/Guideline

12/sex/concen. exposed to 

DMDS (99.7%) as vapor for a 

single, 6 hr whole-body 

inhalation exposure at 100, 200, 

or 750 ppm (0.39, 0.77, and 2.9 

mg/L). A FOB and locomotor 

activity testing were performed 

on all animals prior to the 

initiation of exposures, within 15 

minutes post-exposure for a 

duration of 1-2 hours, and on 

Days 7 and 14.

The systemic LOAEL is 100 ppm (LDT) (0.39 

mg/L), based on decreased total session locomotor 

activity in males and decreased total session motor 

activity in females. A systemic NOAEL was not 

established.

The port-of-entry LOAEL is 100 ppm (0.39 mg/L), 

based on closed eyelids at 100 ppm, red deposits on 

mouth in females at 200 ppm. A port-of-entry 

NOAEL was not established. Lung wts not recorded 

and histopathology of nose or lungs not performed.

870.6200

Inhalation Subchronic 

Neurotoxicity - Rats

46903530 (2006)

Acceptable/Guideline

12 Crl:CD(SD) rats/sex/group

DMDS (99.8%) as vapor for 

6 hrs/day, 7 days/week, 13 

weeks

0, 5, 20, or 80 ppm (0.02, 0.08, 

.31 mg/L)

FOB and motor activity assessed 

at Weeks 3, 7, 12.

Nasal lesions examined in Level 

I-IV 

6 rats/sex/group at all doses.

Lung wts and histo not 

examined.

The port-of-entry LOAEL is 20 ppm (0.08 mg/L), 

based on degeneration of the nasal olfactory 

epithelium of levels II thru IV. 

Port-of-Entry NOAEL is 5 ppm (0.02 mg/L)

Lung wts and histopathology not performed.

Systemic LOAEL is 80 ppm (0.31 mg/L) based on 

decreased total motor activity in males (↓35% Week 

12); decreases in body weight (males only, ↓11-16%), 

overall body weight gain (↓28% males, ↓15% 

females), and food consumption (↓8-21% overall 

males, ↓11% Week 1 females). 

Systemic NOAEL is 20 ppm (0.08 mg/L)

Non-guideline

Range-Finding DNT- Rat

47052812 (2007)

Acceptable/Non-guideline

10 dams/dose with 4 

pups/sex/dam

DMDS exposure began PND5:

0, 2, 20, 80 ppm (0, 0.008, 

0.078, 0.309 mg/L)

6 hrs/day PND5-PND20

Port-of-Entry NOAEL was not established.

Maternal NOAEL = 20 ppm (0.078 mg/L)

Maternal LOAEL = 80 ppm (0.309 mg/L), based on 

decreased body weight gains and food consumption.

Offspring NOAEL = 20 ppm (0.078 mg/L)

Offspring LOAEL = 80 ppm (0.309 mg/L), based on 

decreased body weights and body weight gains.

870.7485

Metabolism – Rat Not available
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DMDS Toxicity Profile

Guideline No./Study 

Type

MRID No. 

(year)/Classification/Exposure 

Conditions

Results

870.7600

Dermal Penetration - Rat Not available

870.7800

Immunotoxicity - Rat

Data were waived (TXR 0056747)
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Page 23 of 23

Attachment 3: DMDS Endpoint from the 2010 Risk Assessment.

Summary of Toxicological Dose and Endpoints for Use in DMDS Human Health Inhalation Risk 

Assessment

Risk Assessment Study NOAEL/LOAEL Endpoint HED HEC

Acute 

Inhalation

Nonoccupational

MRID 

47785501

24 hr Inhalation

NOAEL= 9 ppm

LOAEL = 12.5 ppm

Inflammation & nasal 

irritation in all 6 levels in 

male rats

HEC = 1.65 ppm

UF = 30

Occupational 24 hr Inhalation NOAEL= 9 ppm

LOAEL = 12.5 ppm

Inflammation & nasal 

irritation in all 6 levels in 

male rats

HEC = 1.65 ppm

UF = 30

Short- and 

IntermediateTerm 

Inhalation 

(1-6 months)

Nonoccupational 24 hr Inhalation NOAEL= 9 ppm

LOAEL = 12.5 ppm

Inflammation & nasal 

irritation in all 6 levels in 

male rats

HEC = 1.65 ppm

UF = 30

Occupational 24 hr Inhalation NOAEL= 9 ppm

LOAEL = 12.5 ppm

Inflammation & nasal 

irritation in all 6 levels in 

male rats

HEC = 1.65 ppm

UF = 30

Long-term 

Inhalation

(> 6 months)

Long-term exposure is not expected based on the DMDS use pattern.

Cancer Not required.

NOAEL = no observed adverse effect level; LOAEL = low observed adverse effect level; HEC = Human equivalent concentration; UF 

= uncertainty factor.

Note: Time adjusts (i.e., 8 hours/day and 5 days/week) were not applied to the occupational HECs. The duration of exposure is not the 

driving factor in the development of nasal lesions; the threshold concentration is the key factor.