Dimethyi

_ Disulfide**Regi ~~at** **ion** 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 POLLU T ION PREVENTIO N



### SUBJECT: Dimethyl disulfide. Human -Health Assessment Scoping D ocument in Support of
Re gistration Review.

PC Code : 0290R8
Decision N o .: 

## Jl7l!P.Z/
Petition No.: N / A

Ri s k Assess m e nt Type: N / A
TXR No.: N / A MRID No.: N / A DP Barcode: 0412525 Regi stra tion N o

. : N / A Regu l atory Action: Reg i stration Review Scoping
Document Case No

. : 2390 CAS No. : 624-92-0 40 CF R: N / A



### FROM: Shalu Shelat, Industrial Hygienist

# ~ llft;jn

# ~ _p Nancy McCarroll, Tox i co lo gist " 

# Yt1t-1**/ltc~ '--**  Ri s k Assessmen t Branch 6 (RABVI) · 

## 1

H ealth Effects Division (7509P)

THROUGH: J effery Dawson, Acting Branch Chief Risk Assessment Bran ch 6 (RABVI)
He a lt h Effects Division (7509P)

TO: Garland Waleko, Chemical Review Manager Risk Management and Impl ementatio n Branch II
Pe s ticide Re-Eval uation Divi s ion (750 8P)

Attached is the H ED human-health risk assessment scoping document for dimethyl di sulfide (DMDS) to support registration review.

P age I of23---··--·--**D~ethyJ Disulfi~e** **~e.gistration** Review Human

- Hea!th**Asse~s~ nt** **~~p_in~** Docu!llent

____ __ _ 

### Executive Summary



### Dimeth y l disulfide (DMDS) is a broad-spectrum fumigant used for the control or suppression of nematodes, various soil borne pathogens, and weeds. DMDS is currently registere d for us e 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 indu stria l and commercial us es of DMDS. The largest industrial use of DMDS is in the r efining
and pe trochemical indu st ries but it is also us ed 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 Effect s Division (HED) has
evaluated the status of the human-health assessments for DMDS to determine whether sufficient
data are available to support Regi strat ion Review. HED has also considered the most recen t human -health risk assessments for DMDS with respect to toxicity, exposure, and usage databases, and th e most updat e d Agency science policy and ri s k assessment methodologies to determine the scope of work necessary to support Registration Review.

The most recent Human Heal th Ri s k Assessment document for DMDS was issued in April2010

. At that time, DMDS was regis tere d as a new active in gred ie n t for agricultural use in the Un i te d S tate s to be applied to strawberry, fruiting vegetable (e.g., tomato, peppers, and egg plant),
cucurbit (e.g., cucumbers, squash, and melons), blueberry, and ornamental fields. Since that time, no new uses have been proposed for DMDS.

The re sidue chemistry and dietary-exposure databases are adequate to support current registration requirements. Although DMDS is used as an agricultural pesticide, it i s considered a non-food use chemical since i t is quickly degraded or me tabolized into non

- toxic degradates in
the soil. Furthermore, DMDS re sidues must dissipate in th e soil prior to planting or transplant damage may occur. Therefore

, th is fumigant does not r equire 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) promulga t ed under the Food Quality
Protection Act (FQP A) of 1996. As a result, a risk assessment has not been conducted for the dietary exposure scenar io

. Based on environmental fate data and modeling estimates the Agency does not expect th e 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 i s adequate for Registration Review

. Dermal irritation was observed in rat and rabbit irritation studies with severi ty of irritation varyi ng based on length of exposure. However

, the Agency does not anticipate dermal exposure resulting f rom typ ical use ofDMDS
based on the enclosed sys t ems that are required to keep DMDS as a liquid. As a re s ul t, HED has

not conducted a quan t itat ive dermal risk assessment. DMDS has a robust inhalation tox icity
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 no se with increasing concentrations.

The robust inhalation database for DMDS clearly shows that the duration of exposure does no t impact the no observed adve r se effect levels (NOAELs) or the lowest observed adverse effect
le vels ( LOA ELs)

. Therefore, the acute inhala tion and nasal irritation s tudy is adequate and hea l th protective of a ll durations of exposu re for the DMDS inhala tion risk assess me nt.

Page 2 of23Dimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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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

. T here 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 immunot oxicity 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 dr i p irrigation applications. H ED recently reviewed a protocol for this study submitted by the DMDS registrant ( Smith and Shelat; D408338; 2/22/13)

. The Agency will rev iew and incorporate the study results during Registration Review. HED may be required to update occupational and resi dential (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 follo wing risk assessment updates during Registration Review: Toxicology: None Residue Chemistry: None Dietary Exposure: None
Occ upational/Residential Exposure:

o R evised occupational handler risk assessment s 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.Dimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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### 1.0 Introduction

DMDS is a broad

- spectru m 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 45 0 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

rec ent 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 Di methyl Disulfide : Section 3 H ealth Effects Division Human Health Risk Assessment was completed in April 2010.
T he assessment focused on the new occupational uses of DMDS and utilized DMDS specific worker exposure and flux studies. No new uses of DMDS ha v e 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 Occupatio nal 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 withi n 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 ha s been incorporated into the toxicity profile

. Attachment 2 B 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.Dimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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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 a t this time. Although, d ermal irritation was observed in rat and rabbit irritation studies with severity of irritation varying based on length of exposure, t he Agency does not anticipate dermal exposure resulting from typical use of DMDS due to the enclos ed systems that are required to keep DMDS as a liquid. As a result, HED has not anticipated the need for conduct ing a quantitative dermal exposure and risk assessment for DMDS.

The inhalation route of exposure is the main exposure of concern for both wo rkers and bystanders. DMDS has a robust inhalation toxicity database with studies varying in duration from acute to repeat ed exposure s

. For example, acceptable inhalation studies in rats and rabbits are available in exposure durations ranging from sing le 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 curre nt 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 d uration.

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 di fferences) 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), de pending 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 i rritation. 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 vivoDimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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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
D MDS labels (strawberries, blueberries, fruiting vegetables, cucurbits, and ornamentals) are considered nonfood uses. Accordingly , th e 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 ; D 339675; 4/20/2010 ). However, g iven the lack of a plant metabolism study, more field trial dat a 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. B a sed 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 be en 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 ExposureDimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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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 quantif y emissions from shank injection raised bed applications using high barrier tarps (performed in Dover, FL using a metalized tarp and in Tifton, GA usin g 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 condit ionally 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 rev iew and incorporate th is study during Registration Review.

There are currently no registered residential uses of DMDS . However, there is the potential for residential bysta nder inhalation exposure to DMDS after a soil fumigation appli cation

. The Agency has specifically focus ed on assessing acute DMDS inhalation exposures resulting from applications because peak DMDS air concentrations t ypically 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 ana lyzed acute residential bystander inhalation exposure to DMDS based on numerous f ield volatility studies and PERFUM ( P robabilistic E xposure and R isk model for Fum igants) air modeling for a variety of DMDS applications ( Smith; D 339675; 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 mois ture, 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 b ystanders. 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

com pared 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 ri sks 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 :Dimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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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 th is 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 G ood A gricultural P ractice s (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 assessm ents 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 (MOE s < 30) for many occupational activities at the baseline level (no respirator). However, with the addition of a n 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 ta rps 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 workerDimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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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 P ublic 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. Dime thyl 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 Insectici de, 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 high er 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, 200 8 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 incid ents were classified as minor severity. For the Aggregate IDS, from January 1, 200 8 to February 19, 2013, there were 0 reported incident s 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 Departme nts 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 p roviding 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 deriv ed 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.

B ased 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 inf ormation and if a concern is triggered, additional analysis will be included in the risk assessment.Dimethyl Disulfide Registration Review Human

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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 Mi nority Populations and Low

Income 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 ass essments, 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 potentia l 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 me chanism 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 i nformation 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 mechani sm 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 r equired 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 4 08(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 requiredDimethyl Disulfide Registration Review Human

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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 estr ogen, 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 ef fect.

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, 2013 a 

### and 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 list s 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 scree ning of [insert chemical/case]. Before completing this Registration Review, the Agency will make an EDSP FFDCA section 408(p) determination.

1 3 .0 Human Studies

Previous assessments relied in part on data from studies in which adult human subjects were i ntentionally 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 cu rrent 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

.

1 4 .0 Risk Ass essment 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/Dimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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Page 12 of 23 

### 1 5 .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 D 339675 4/2 0/20 10 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 D 413869 8/ 20 /2013 Dimethyl disulfide (DMDS) : Tier I Review of Human IncidentsDimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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Page 13 of 23 

### Attachments: Attachment 1: Chemical Identity Table. Attachment 2: DMDS Acute, Subchronic, and Chronic Toxicity Profile Attachment 3: DMDS Endpoint Selection Tables.Dimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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Page 14 of 23 

### Attachment 1: Chemical Identity Table

.

Attachment 1A : Test Compound Nomenclature Chemical structure

Common name Dimethyl Disulfide, DMDS
Molecular formula C 2 

### H 6 

### S 2 

### 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 (pK
a ) This substance does not dissociate. 46903510Dimethyl Disulfide Registration Review Human

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Page 15 of 23 

### Attachment 2: D imethyl D isulfide 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 LD 50 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 LD 50 > 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 returne d. 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 al l lobes and surfaces of the lungs, spleen abnormalities (pale purple/cloudy discoloration, rough texture and e d ges). 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 respirat ory 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 establishedDimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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Page 16 of 23 

### DMDS Toxicity Profile Guideline No./Study Type MRID No.

(year)/Classification/Exposure

Conditions Results

rats/sex/con c . 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 (gra de 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 : D ata 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 availableDimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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Page 17 of 23 

### 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 incrusta tion 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 hemol ytic 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 histopatho logy 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 w eight 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; Materna l LOAEL was not established. Maternal NOAEL 135 ppm (0.52 mg/L) the HDT.Dimethyl Disulfide Registration Review Human

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Page 18 of 23 

### 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

- entr y 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 phased

exposure 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 gain s 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 b ody 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/gavage

Mouse/Rat [bioassay] Currently not availableDimethyl Disulfide Registration Review Human

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Page 19 of 23 

### DMDS Toxicity Profile Guideline No./Study Type MRID No.

(year)/Classification/Exposure

Conditions Results

870.4300 Chronic Inhalation Toxicity/Carcinogenicity

Rat. (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 uvr

A 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 Sprague

Dawley rats induced with Aroclor ® 1254. The standard plate incorporation method was used in bot h 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 ba ckground 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 μ g/mL (Trial 1,+/

-

- S9), or 0, 4.12, 12.3, 37.0, 74.1, 111, 333, 667, and 1000

μ g/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 μ g/mL +S9 and 5.98 , 14.4, 19.0, 62.2 and 182.3 μ g/mL

– S9 for nominal concentrations of 37.0, 74.1, 111, 333 and 1000 μ g/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 toDimethyl Disulfide Registration Review Human

- Health Assessment Scoping Document

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Page 20 of 23 

### DMDS Toxicity Profile Guideline No./Study Type MRID No.

(year)/Classification/Exposure

Conditions Results

the problems related to test material c oncentrations, 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 Assay

mouse 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 expos ure 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: hypoactivit y, 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 o bserved 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 co ncurrent vehicle controls. No treatment

- related increases in the MPCE frequency were observed in any treatment group when compared to controlsDimethyl Disulfide Registration Review Human

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Page 21 of 23 

### 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

μ g/mL (Trial 1), or 0, 5, 10, 50, 100, 150, 200, 250, or 300

μ g/mL (Trial 2). Hepatocytes were har vested at 18

- 20 hours post

- dosing. Dimethyl disulfide was tested up to the limit of solubility (200 μ g/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 pos itive 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 trace r 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 min utes 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 eyeli ds 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/se x/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 p erformed.

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, 0.30 9 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 availableDimethyl Disulfide Registration Review Human

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Page 22 of 23 

### 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)Dimethyl Disulfide Registration Review Human

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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 Non

occupational MRID

47785501 24 hr Inhalation NOAEL= 9 ppm

LOAEL = 12.5 ppm Inflammation & n asal

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 & n asal

irritation in all 6 levels in male rats HEC = 1.65 ppm UF = 30

Short

- and Intermediate

Term Inhalation (1

- 6 months) Non

occupational 24 hr Inhalation NOAEL= 9 ppm LOAEL = 12.5 ppm Inflammation & n asal

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 & n asal

irritation in all 6 levels in male rats HEC = 1.65 ppm UF = 30

Long

- term Inhalation (> 6 months) L ong

- 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.