Dazomet Registration Review Human-Health Assessment Scoping Document

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFF I CE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### MEMORANDUM

Date: September 

### 4, 2013



### SUBJECT: Dazomet. Human-Health Assessment Scoping Document in S upport of Registration Review.

PC Code: Dazom et PC Code: 035602, MITC

PC Code: 0681 03 DP Barcode: 0410391

Decision No.: 476790 Regis tration No .: N / A

Petition No.: N/A Regulatory Action: Registration Review Scoping Document

Case No.: N / A Risk Assessment Type: N/ A

TXR No.: N / A CAS No.: Dazomet: 533-74-4, MITC: 556-61 -6

40CFR : N / A MRID No.: N/A



### FROM: Shalu Shelat, Industrial Hygienis t**~~** 

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### )

Nancy McCarroll, Toxicologist 

# fll,**tft...J~.~J-1 JUJU~r~((~** **.:---o r,___t~l**  hr.!} Christopher Schlosser, Toxicologist z. 

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Risk Assessmen t Branch 1 (RAB

and

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Charles Smith, Senior Branch Chiee::=. 

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Risk Assessment Branch 1 (RAB 1)

Nathan Mottl, Biologist Health Effects Division (7509P)

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# 1~ 

# /r3

Risk Assessment and Science Support Branch

Antimicrobials Division (751 OP)



### THROUGH: Felecia Fort, Branch Chief

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Risk Assessment Branch 1 (RABV1) ()..J"0:)_ 

### ?/(;'/J3

# p~~ 

# s**.iJ ~-** **'11~1'5** 

# p**~l.** \ U-f\;-=trV'-- 

# 11**~Irs** Health Effects Division (7509P)

Steve Weiss, Branch ChiP.T--.LJ.I..NIY'

Tim Leighton, Senior Scie

Risk Assessment and Scienc upport Branch

........ j

Antimicrobials Division (751 OP)



### TO: Dana Friedman, Chemical Review Man ager Pesticide Re-Evalua tion Division (7508P)

Page 1 of29Dazomet Registration Review Human-Health Assessment Scoping Document

Attached is the combined Health Effects Division (HED) and Antimicrobia l Division (AD)

human-health risk assessment scoping document for dazomet and MITC to support registration

review.

Page 2 of29Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 3 of 29 Executive Summary

Dazomet (tetrahydro

- 3,5

- dimethyl

- 2H

- 1,3,5

- thiadiazine

- 2

- thione) is a non

- selective soil fumigant with fungicidal, herbicidal, and nematicidal properties. The primary degradate for

dazomet is methyl isothiocyanate ( MITC ). Dazomet and MITC also are active ingredient s in a variety of antimicrobial products. The MITC antimicrobial products are addressed in a separate HED scoping document. The Health Effects Division ( HED ) and the Ant imicrobial Division ( AD ) have evaluated the status of the human

- health assessments for dazomet to determine whether sufficient data are available to support Registration Review. HED and AD have also

considered the most recent human

- health risk assessments for dazomet 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. It is

noted that metam sodium and m etam potassium are other pesticide s that produces MITC upon application

, however this document does not quantify exposure to metam sodium, metam potassium, or MITC resulting from those applications , which are addressed in a separate

document

.

The Amende d Reregistration Eligibility Decision (RED) for Dazomet was issued in May 2009.

The RED addressed the major conventional and antimicrobial uses of dazome t . The

conventional uses include applications to strawberries, tomatoes, golf greens/tees, nonbearing crops, turf sites (establishing or renovating), ornamental sites (establishing or renovating), field nurseries (establishing or renovating), compost piles and potting soils. The antimicrobial uses include treatment during the production of pulp and paper ; use as a material preservative treatment for paper coatings, non

- food adhesives, epoxy flooring compounds, slurries, and high viscous suspensions; use as a biocide treatment during petroleum operations and in recirculating cooling water systems; and use as a remedial wood treatment to utility poles. No new

conventional uses of dazomet ha ve been registered since th e RED was issued

. However

, additional antimicrobial uses of dazomet in paint and finger paint were identified and will need

to be assessed duri ng Registration R eview.

The toxicity database for dazomet is adequate for Registration Review with the exception of an

MITC reproduction and fertility effects study and the chronic/carcinogenicity studies. These studies were required as part of the 2009 Amended RED and are currently being performed. The registrants have completed and submitted a number of other MITC toxicity studies required as part of the 2009 Amen ded RED including a n acute study via the inhalation route, a developmental toxicity screening test via the inhalation route

, an unscheduled DNA synthesis in

mammalian ce lls in culture study, and an i mmunotoxicity study via the inhalation route. The Agency will review and incorporate all of these studies during Registration Review. The focal points for the assessment of dazomet and MITC are occupational dermal exposure to dazomet and occupational and residential inhalation exposure to MITC. There is a rou te specific dermal study available for dazomet (NOAEL from a rabbit 21

- day dermal toxicity study was greater than 1000 mg/kg/day). There are a number of route specific MITC inhalation studies available including an acute inhalation neurotoxicity study in rats, a 28

- day inhalation study in rats, and a

13

- week inhalation study in rats. There is also an eye irritation and odor threshold study performed with human subjects that indicates the irritation properties of MITC. DuringDazomet Registration Review Human

- Health Assessment Scoping Document

Page 4 of 29 Registration Review

, the Agen cy will reevaluate the points of departure (PODs) and uncertainty

factors (UFs) for the residential and occupational exposure assessments.

The residue chemistry and dietary

- exposure databases are adequate to support current registration requirements. The current uses of dazomet have previously been determined to be

non

- food uses. In addition , based on environmental fate data, the residual contents in soils, and monitoring data, MITC is not expected to adversely impact the drinking water sources such as surface water and ground water. Dietary and drinking water assessment s are not required during Registration Review.

The occupational and residential exposure database s for the conventional uses of dazomet are adequate for Registration Review

. The registrants have completed and submitted a field volatility study measuring the breakdown products of dazomet, including MITC and formaldehyde. HED will review and incorporate this study during Registration Review.

The occupational and residential ex posure database s for the antimicrobial uses of dazomet are

not adequate for Registration Review . As part of the 2009 Amended RED , AD required occupational dermal and inhalation dazomet handler mixing/loading exposure data for open pour (liquids) and solid pour (solids) to assess the antimicrobial uses of dazomet. At this time, these data have not been submitted to the Agency. Additional product use information, handler exposure, and post

- application exposure studies are required for the antimicrobial use of dazomet in paints and finger paints during Registration Review. Additionally, AD notes that the 2009

Amended RED require d that the application rate for the antimicrobial use of dazomet in epoxy floor compounds be lowered however current labels have no t be en revised to comply with this requirement

. AD will review and incorporate all of submitted antimicrobial exposure data during Registration Review.

No data deficiencies outside those previously discussed in the 2009 Amended RED were

identified for the conventional uses of dazomet. However, the following data deficiencies were identified for the antimicrobial uses of dazomet in paints and finger paints : Occupational/Residential Exposure:

o 875.1700: Product use information 1

o 875.1200/875.1400: Occupati onal dazomet h andler dermal and inhalation

exposure for open pour mixing/loading paint 2

o 875.1200/875.1400: Occupational dazomet handler dermal and inhalation exposure applying paint (airless sprayer and brush/roller) 2

o 875.1200/875.1400: Residential dazom et handler dermal and inhalation exposure applying paint (airless sprayer and brush/roller) 2

o 875.2400: Post

- application dazomet dermal exposure for finger painting

o 875. 2 5 00 : Post

- application MITC inhalation exposure for painted rooms

1 This data will be used to identify and characterize dazomet/MITC concentrations in paint and finger paint.

2 AD notes that these data requirements may be fulfilled by completed or planned Antimicrobial Exposure

Assessment T ask Force studies.Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 5 of 29 EPA anticipates conducting the following risk assessment updates during Registration Review: Toxicology:

o Reevaluat ion of the toxicity endpoint/dose selection may be necessary based on the recently submitted toxicological data

. Residue Chemistry: None Dietary Exposure: None

Occ upational/Residential Exposure:

o R evised HED and AD occupational dazomet handler risk assessment s may be

necessary based on the most recent exposure data

, Agency policies, or if th e toxicological reevaluation results in changes to the endpoints

.

o AD anticipates the need for occupational/residential dazomet handler dermal and

inhalation risk assessment s for applying paint using an airless sprayer and brush/roller during Registration Review.

o AD anticipates the need for residential post

- application dazomet dermal risk assessments for using finger paint during Registration Review.

o AD anticipates the need for residential post

- application MITC inhalation risk

assessments for painted rooms during R egistration Review.

o Additional or revised HED residential bystander risk assessments may be necessary based on the most recent exposure data, Agency policies, or if the toxicological reevaluation of results in changes to the endpoints.

1.0 Introduction

D azomet (tetrahydro

- 3,5

- dimethyl

- 2H

- 1,3,5

- thiadiazine

- 2

- thione) is a non

- selective soil fumigant with fungicidal, herbicidal, and nematicidal properties. When dazomet is applied and mixed with moist soil or water, it quickly breaks down into several strong irritant products. One of these products is methyl isothiocyanate ( MITC), which accounts for most of the fumigant activity. Dazomet and MITC also are active ingredients in a variety of antimicrobial products. The Health Effects Division (HED) and the A ntimicrobial Division (AD) have evaluated the

status of the human

- health assessments for dazomet and MITC to determine whether sufficient data are available to support Registration Review. HED and AD have also considered the most

recent human

- health risk assessments for dazomet and MITC 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. Metam

sodium an d metam potassium are other pesticide s that produces MITC upon application however, this document does not quantify exposure to metam sodium and metam potassium or MITC resulting from dazomet applications , which are addressed in a separate document

.

The A mended Reregistration Eligibility Decision (RED) for Dazomet was issued in May 2009.

The RED addressed the major conventional and antimicrobial uses of dazomet. The

conventional uses include applications to strawberries, tomatoes, golf greens/tees, nonbearing crops, turf sites (establishing or renovating), ornamental sites (establishing or renovating), field nurseries (establishing or renovating), compost piles and potting soils. The ant i microbial uses include treatment during the production of pulp and paper; use as a material preservative treatment for paper coatings, non

- food adhesives, epoxy flooring compounds, slurries, and high viscous suspensions; use as a biocide treatmen t during petroleum operations and in re

- circulatingDazomet Registration Review Human

- Health Assessment Scoping Document

Page 6 of 29 cooling water systems; and use as a remedial wood treatment to utility poles. No new uses of

dazomet ha ve been registered since the RED was issued. However, additional antimicrobial uses

of dazomet in pa int and finger paint were identified and will need to be assessed during Registration R eview.

2.0 Hazard Identification/Toxicology

The 2009 Amended RED required a number of MITC toxicity studies, including the following : a neurotoxicity battery via the inhalation route (870.6200), a developmental toxicity screening test via the inhalation route (870.3550), a reproduction and fertility effects study via the inhalation route (870.3800), an unscheduled DNA synthesis in mamma lian cells in culture study (870.5550), an Immunotoxicity study via the inhalation route (870.7800), a chronic/carcinogenicity rat study via the inhalation route (870.4200), and a chronic/carcinogenicity mouse study via the inhalation route (870.4200).

Th e registrants have completed and submitted the neurotoxicity study, the developmental study, the unscheduled DNA synthesis, and the i mmunotoxicity study and the Agency will review and incorporate th e s e stud ies during Registration Review. The Agency has not received the reproduction and fertility effects study or the chronic/carcinogenicity studies at this time. Once these studies are completed and submitted they will be reviewed and incorporated during Registration Review

.

Attachment 2 provides a summary of the acute, subchronic, and chronic toxicity profile for

dazomet and MITC. The relevant data from the recently submitted studies ha ve been incorporated into the toxicity profile. Attachment 2 provides a summary of the relevant

toxi cological endpoints used in dazomet and MITC 2009 risk assessment. During Registration Review, the Agency will reevaluate the MITC endpoints, points of departure (PODs), and uncertainty factors (UFs) for the residential and occupational exposure assessmen ts based on current HED policy, recently submitted studies, and any other outstanding data.

No inhalation pharmacokinetic or metabolism studies are available at this time for dazomet or MITC. Dazomet is efficiently converted to MITC in vivo . Oral pharma cokinetic and

metabolism studies in rats are available for daz o met and MITC. In those studies, daz o met and

MITC were excreted mainly in urine with small amounts excreted in feces. Three different compounds (MITC, carbon dioxide [CO 2 ], carbon oxide sulfid e [COS]/carbon disulfide [CS 2 ]) were found to be excreted in the lungs over a 73 hour collection period. Although the tissue with the highest uptake for all three compounds was the thyroid gland, it is notable that tissue

retention of radioactive material was low in both sexes and at all doses. In the studies h igh uptake was also seen by the liver, kidneys, and lung, with the lowest level in testes, brain and eyes. Metabolic profiles detected in urine, liver, and the kidneys were similar for dazomet and

MITC but there were some differences, mainly quantitative in nature. The consistent results seen in the dazomet and MITC oral pharmacokinetic and metabolism studies are further supported by the similarity in the oral doses causing similar toxic effects fo r dazomet and MITC in the available oral toxicity studies. Specifically, reduced body weight gain and food consumption inDazomet Registration Review Human

- Health Assessment Scoping Document

Page 7 of 29 addition to changes in hematological parameters were observed at low doses in oral toxicity studies with rats, mice, rabbits, and dog s.

In oral developmental toxicity studies with dazomet and MITC, effects such as fetal weight decrements, reduced ossification of various skeletal structures, and increased incidence of resorptions have been noted at similar molar dose levels. There is no quantitative susceptibility

observed in the oral deve lopmental and reproductive toxicity studies with dazomet and MITC. All of the developmental NOAELs are equal to or larger than the NOAELs for maternal toxicity. There is, however, qualitative susceptibility in two rabbit developmental toxicity studies wi th

dazomet where increased incidence of resorptions were noted at a dose that resulted in maternal body weight gain decreases.

The focal points for the assessment of dazomet and MITC are occupational dermal exposure to dazomet and occupational and resid ential inhalation exposure to MITC. The dazomet short

- and

intermediate

- term dermal endpoints have previously been selected from an acute neurotoxicity study and a subchronic rat study, respectively. The dermal absorption of dazomet has been

estimated to be 4 .5%. There are a number of route specific MITC inhalation studies available including an acute inhalation neurotoxicity study in rats, a 28

- day inhalation study in rat s
, and a

13

- week inhalation study in rats. There is also an eye irritation and odo r threshold study performed with human subjects that indicates the irritation properties of MITC.

Dazomet is currently classified as Group D

- not classifiable as to h uman carcinogenicity. The

evidence of in vitro mutagenicity for dazomet is, however, not manifested in whole animal studies. Thus, the issue of mutagenicity is not a concern for dazomet. For MITC, ther e are currently insufficient data to chara cterize the cancer risk of MITC

. As mentioned above, chronic/carcinogenicity studies for MITC were required as part of the 2009 RED. HED will

reevaluate the carcinogenic potential of MITC during Registration Review after these studies are

submitted and reviewed.

Conclusions: The toxi city databases for dazomet and MITC are adequate for Registration

Review except for the outstanding toxicity studies (i.e., the reproduction and fertility effects study and the chronic/carcinogenicity studies ) required in the 2009 Amended RED

. During Regi stration Review, the Agency will reevaluate the points of departure (PODs) and uncertainty factors (UFs) for the residential and occupational exposure assessments based on current HED policy, recently submitted studies, and any other outstanding data.

3.0 Residue Chemistry

The residue chemistry database s for dazomet and MITC are adequate for Registration Review. Dazomet plant metabolism studies on strawberries and tomatoes indicate that the MITC generated from dazomet is degraded in the soil and the MIT C degradates are taken up by the plant and incorporated into the natural plant constituents such as lipids, proteins, nucleic acids, hemicellulose, pectin, lignin, and polysaccharides. Residues of MITC were below the limit of quantitation in crop field tr ials conducted on strawberries and tomatoes. Therefore, the use of

dazomet on strawberries and tomatoes are considered to be non

- food uses and tolerances are not needed (C. Olinger; D287290; 08/16/04 and C. Olinger; D 3 44375, 01/03/08).Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 8 of 29 Conclusions: The residue chemistry database for da z o met is ade quate for Registration Review.

4.0 Dietary Exposure

The dietary exposure database s for dazomet and MITC are adequate for Registration Review. As described in Section 3.0, the Agency previously decided that th e use s of dazomet on

strawberries and tomatoes are non

- food uses

.

Environmental fate data suggest that there is a low potential for the parent compound dazomet to be present in drinking water due to the rapid degradation of dazomet to MITC in the

environment. MITC from dazomet applications could potentially move to surface water through runoff under an intense rainfall and/or if continuous irrigation occurs right after dazomet application. However, the Henry’s Law Constant of 1.79 x 10

- 4 atm

- m 3 /mol for MITC suggests that it would volatilize quickly from surface water. In addition , u nder most field conditions, the potential for significant ground water contamination of MITC is unlikely due to its volatilization and fast degradation in soil. MITC was not detected in any available non

- targeted ground water monitoring samples within the USA. Based on environmental fate data, the residual contents in soils, and monitoring data, the Agency does not expect MITC to adversely impact the drinking water sources such as surface water and ground water.

Based on the discussion above, no dietary or drinking water assessments have been previously performed for dazomet or MITC.

Conclusions: The dietary exposure database for dazomet is adequate for Registration Review. Dietary and drinking water assessments are not anticipated during Registration Review.

5.0 Residential Exposure

The residential exposure database for the conventional uses of d a z o met is adequate for Registration Review. The 20 09 Amended RED required a field volatility study measuring the breakdown products of dazomet, including MITC and formaldehyde (835.8100)

. The registrants have completed and submitted this study and the Agency will review and incorporate it during Registration Review.

The residential exposure database for the antimicrobial uses of d a z o met is not adequate for Registration Review

. Product use information, residential handler dazomet dermal and inhalation exposure data for applying paint (airless spr ayer and brush/roller), post

- application MITC inhalation exposure data resulting from painted rooms, and post

- application dazomet dermal exposure data to finger paints is required for the antimicrobial use of dazomet in paints and finger paints during Regi stration Review.

There are currently no registered conventional residential uses of dazomet . However, there is the potential for residential bystander inhalation exposure to MITC after a soil fumigation application of dazomet

. The Agency has specifica lly focus ed on assessing acute MITC

inhalation exposures resulting from dazomet applications because peak MITC air concentrationsDazomet Registration Review Human

- Health Assessment Scoping Document

Page 9 of 29 typically occur in the first 24 or 48 hours after application. There is also the potential for inhalation exposure to MITC vi a ambient air however, dazomet use is minor when compared to metam sodium and metam potassium use thus it is likely that almost all MITC in ambient air would result from metam sodium/potassium applications. Ambient air exposure to MITC is

addressed in the Metam Sodium, Metam Potassium, and MITC HED scoping document. There are registered antimicrobial residential uses of dazomet in paint and finger paint. There is also the potential for residential post

- application inhalation exposure to MITC after a room is painted with using paint that contains dazomet.

Conventional Uses

There is one recent document that analyzed acute residential bystander inhalation exposure to

MITC based on numerous field volatility studies and PERFUM ( P robabilistic E xposure and R isk

model for Fum igants) air modeling for a variety of dazomet applications ( Shelat and Smith ;
D 360773 ; 4 /30/2009). The results of thi s assessment show s that bystander inhalation exposure to MITC after a soil fumigation application of dazomet can vary depending on a variety of factors such as application method, agricultural tarps, water seals, and a number of soil parameters (i.e., soil moisture, organic content, etc.). For many application scenarios, the PERFUM air modeling results showed t hat acceptable MITC air concentrations were attainable at some distance from a treated field and thus buffer zones were required to protect residential bystanders. The 2009 Amended Reregistration Eligibility Decision (RED) for Dazomet provides

more inform ation on buffer zone development.

A ntimicrobial Uses

In the most recent dazomet AD risk assessment ( C. Walls ; D 335651 ; 06/04/08 ) no residential

uses were assessed. Since that time, the Agency has identified a polymer preservative dazomet

use as an in

- can preservative in paints and finger paints that ha s potential for residential

exposure. These use s could potentially result in residential handler and post

- application

exposure s

. T he Agency will need to assess these uses during R egistration R eview. The Agency anticipates that the following residential handler and post

- application exposure scenarios are of potential concern for the dazomet paint and finger paint uses :

Painting with an airless sprayer (dermal and inhalation e xposure); Painting with a brush/roller (dermal and inhalation e xposure); Fing er painting (dermal and hand

- to

- mouth incidental ingestion exposure) ; and

MITC bystander inhalation exposure from paint ed rooms

.

D uring registration review , additional data are needed to s upport the labeled dazomet uses in paint and finger paint

. For the paint uses

, product use information (Series 875.1700) that characterizes dazomet/MITC concentrations in paint , dazomet dermal and inhalation handler exposure data (Series 875.1200/875.1400) for applicators painting (brush/roller and airless sprayer) , and MITC post

- application inhalation exposure data ( Series 875.2500 ) resulting from painted rooms is required

. For the finger paint uses, product use information (Ser ies 875.1700) that characterizes dazomet/MITC concentrations in finger paint as well as dermal (dazomet)

post

- application exposure data (Series 875.2400) for finger painting is required. The post

-Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 10 of 29 application dermal exposure data will be used to verify the actual dislodgeable dermal

dazomet/MITC residues on an adult hand and this data can be subsequently used to extrapolate children exposure while finger painting. Once th e s e data are submitted to the Agency, it will be reviewed and incorporated into the da zomet antimicrobial residential risk assessment during Registration Review.

Conclusions : The residential exposure database for the conventional uses of d a z o met is adequate for Registration Review. HED will review and incorporate the submitted field volatility study during Registration Review. Additional or updated PERFUM modeling and ambient air analyses may be required during Registration Review i f the points of departure (PODs) or uncertainty factors (UFs) for the residential exposure assessment c hange based on the toxicological data required a s part of the 2009 Amended RED.

During Registration Review, HED also plans to update the fumigant factors document (Dawson, Smith, and Shelat ; D 385314 ; 1 / 11 /20 11). The fumigant factors document provides a d iscussion of values and parameters used as the basis for buffer reduction credits (i.e., tarps) as well as for establishing GAPs (i.e., soil moisture) for the fumigants. This document impacts all of the soil fumigants including dazomet.

The residential e xposure database for the antimicrobial uses of d a z o met is not adequate for Registration Review. P roduct use information and residential handler and post

- application dermal and inhalation exposure data are required for the antimicrobial use of dazomet in p aints

and finger

- paints during Registration Review. A D will review and incorporate these data during Registration Review.

6.0 Aggregate

- Risk Assessment

Acute and chronic aggregate

- risk assessments were not previously performed for dazomet or MITC because no dietary and drinking water 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

The occupati onal exposure database for the conventional uses of dazomet is a dequate for Registration Review

. The occupational exposure database for the antimicrobial uses of d a z o met
is not adequate for Registration Review. In the 2009 Amended RED, dermal and inhalat ion

dazomet handler exposure data for the open pour (liquids) and solid pour (solids) mixing/loading scenarios was required for occupational antimicrobial uses of dazomet. At this time, these data have not been submitted to the Agency. Post

- application inhalation MITC exposure data were also required as part of the 2009 Amended RED. Since that time

, the registrants have submitted an observational MITC post

- application inhalation exposure study for the pulp/paper industry

use. AD is c urrently evaluating this study and as well as a Data Call

- In (DCI) waiver requestDazomet Registration Review Human

- Health Assessment Scoping Document

Page 11 of 29 that states that this study should be considered worst case and fulfill all the MITC post

application inhalation exposure study requirements. Product use information, open p our mixing/loading occupational handler dazomet dermal and inhalation exposure data, and occupational handler dazomet dermal and inhalation exposure data for applying paint (airless sprayer and brush/roller) are required for the antimicrobial use of dazome t in paints during Registration Review.

There is a variety of conventional and antimicrobial uses of dazomet. The conventional uses include applications to strawberries, tomatoes, golf greens/tees, nonbearing crops, turf sites (establishing or renovati ng), ornamental sites (establishing or renovating), field nurseries (establishing or renovating), compost piles and potting soils. The antimicrobial uses include treatment during the production of pulp and paper; use as a material preservative treatment f or paper coatings, non

- food adhesives, epoxy flooring compounds, slurries, and high viscous suspensions; use as a biocide treatment during petroleum operations and in re

- circulating cooling water systems; use as a remedial wood treatment to utility poles ; and use in paints

.

Occupational Handlers

Conventional Uses

There is potential for occupational handler dermal exposure to dazomet and inhalation exposure to MITC to occur based on the registered conventional uses of dazomet

. The most recent HED document that analyzed potential occupational handler risks to dazomet and MITC is the 2009

risk assessment ( Shelat and Smith ; D 360773 ; 4 /30/2009 ). HED utilized surrogate data from the Pesticide Handlers Exposure Database (PHED) and the Outdoor Residentia l Exposure Task Force (ORETF) to assess occupational handler dermal exposures to the soil fumigant uses of

dazomet in the 2009 assessment. These assessments were considered conservative because

PHED and ORETF data are based on non

- volatile chemicals while dazomet can quickly break

down to MITC. In many cases, short

- and intermediate

- term dermal risks exceed HED’s level of

concern for the soil fumigant uses of dazomet.

HED currently has no exposure data to assess handler MITC exposures during or following dazomet applications in agricultural scenarios, however a number of MITC inhalation exposure

studies are available for metam sodium. These studies examined a variety of tasks associated

with metam sodium applications such as loading and applying. In som e cases, acute as well as

short

- and intermediate

- term risks exceed HED’s level of concern for MITC at baseline (MOEs <

10 for acute and MOEs < 30 for short

- and intermediate

- term). Even with the addition of an organic vapor respirator, some acute as well as short

- and intermediate

- term risks exceed HED’s

level of concern for MITC. Based on this data, HED ha d concluded there were some concerns for MITC inhalation exposure for occupational handlers performing application tasks in the field

as we ll as worke rs performing tasks near dazomet treated areas.

Antimicrobial Uses

There is potential for occupational handler dermal and inhalation exposure to dazomet to occur based on the registered antimicrobial uses of dazomet. The most recent AD document that analyzed potential occupational handler risks to dazomet i s the 200 8 risk assessment (C. Walls;Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 12 of 29 D 335651; 06/04/08 ) . AD utilized standard assumptions, expert knowledge, and surrogate unit exposure data from the Chemical Manufacturers Associa tion (CMA) antimicrobial exposure study and the Pesticide Handlers Exposure Database (PHED) to assess occupational handler exposures to the antimicrobial uses of dazomet in the 200 8 assessment. In some cases, intermediate

- term dermal and inhalation risks exceeded AD’s level of concern (e.g., calculated MOEs were less than the target MOE of 100) for the antimicrobial uses of dazomet. The 2009 Amended RED required a number of mitigation measures to address these risk concerns . AD

notes that current dazomet antimicrobial labels do not reflect the 2009 Amended RED requirement that the application rate for the use of dazomet in epoxy floor compounds be lowered (maximum application rate of 0.35%).

In the 2009 Amended RED, dermal and inhalation dazomet handler exposure data for the open pour (liquids) and solid pour (solids) mixing/loading scenarios ( 875.1200/875.1400)

, application exposure monitoring data reporting (875.1600), product use information (875. 1700 and

875. 2700), description of human activity (875.2800), and data reporting and calculations (875.2900) were required for occupational antimicrobial uses of dazomet. At this time, these data have not been submitted to the Agency. During registration review, additional data are needed to su pport the labeled dazomet uses in paint. For the paint uses, product use information (Series 875.1700) that characterizes dazomet/MITC concentrations in paint , occupational handler

dazomet dermal and inhalation exposure data (Series 875.1200/875.1400) for open pour mixing/loading, and dazomet dermal and inhalation handler exposure data (Series 875.1200/875.1400) for applicators painting (brush/roller and airless sprayer) is required. Once

all of th e s e data are submitted to the Agency, it will be reviewed and incorporated into the

dazomet antimicrobial occupational risk assessment during Registration Review.

Occupational Post

- Application

Conventional Uses

There is potential for occupational post

- application inhalation exposure to MITC resulting from

the registered conventional uses of dazomet. HED previously determined there were inhalation risk concerns for workers reentering fumigated fields 48 hours after application. As part of the 2009 Amended RED, the Agency placed various restrictions on reentry of workers into fumigated fields. With these restrictions, HED believes that risks to reentry workers will not

exceed the HED’s level of concern.

Antimicrobial Uses

There is potential for occupational post

- application inhalation exposure to MITC result ing from the registered antimicrobial uses of dazomet. The most recent AD document that analyzed potential occupational post

- application risks to MITC is the 200 8 risk assessment (C. Walls;

D 335651; 06/04/08 ) . In that assessment, AD detailed the potentia l concerns for post

- application inhalation exposures to MITC for workers in the vicinity of dazomet applications in pulp/paper industries, as well as in coatings manufacturing, oil

- field operations, and cooling water tower facilities because MITC is a high ly volatile chemical. As a result, the 2009 Amended RED required post

- application MITC inhalation exposure data for all enclosed facilities that utilize

dazomet

. Since that time, the registrants have submitted an observational MITC post

- application

inhal ation exposure study for the pulp/paper industry use. The study measured the inhalationDazomet Registration Review Human

- Health Assessment Scoping Document

Page 13 of 29 potential exposure s to workers in indoor and outdoor settings

. The registrants have also recently

submitted a DCI waiver request that states that the pulp/paper industry MITC study should be considered worst case and fulfill all the MITC post

- application inhalation exposure study requirements. The Agency will review and incorporate the pulp and paper study during Registration Revi ew as well as determin ing if it address es all of the other indoor and outdoor antimicrobial uses of dazomet (e.g. coatings manufacturing, oil

- field operations and re

circulating cooling towers).

Conclusions: The occupational exposure database is adequat e to support the Registration Review process for the conventional uses of dazomet and MITC

. HED may be required to update the occupational handler assessments during Registration Review if the points of departure (PODs) or uncertainty factors (UFs) for th e occupational exposure assessment change based on the toxicological data required as part of the 2009 Amended RED.

The oc cupational exposure database for the antimicrobial uses of dazomet is not adequate for Registration Review . As part of the 2009 Amen ded RED, AD required occupational dermal and

inhalation dazomet handler mixing/loading exposure data for open pour (liquids) and solid pour (solids) to assess the antimicrobial uses of dazomet. At this time, these data have not been

submitted to the Agency. Additional product use information, handler exposure, and post

application exposure studies are required for the antimicrobial use of dazomet in paints and during Registration Review. Additionally, AD notes that the 2009 Amended RED requi red that the application rate for the antimicrobial use of dazomet in epoxy floor compounds be lowered

however current labels have not be en revised to comply with this requirement. AD will review and incorporate all of submitted antimicrobial exposure dat a during Registration Review.

U pdated occupational handler assessments may also be required during Registration Review if the points of departure (PODs) or uncertainty factors (UFs) for the residential exposure assessment change based on the toxicological data required as part of the 2009 Amended RED.

8.0 Public Health and Pesticide Epidemiology Data

An updated review of dazomet (and MITC from dazomet applications) incident reports was recently prepared by HED ( Recore and Evans, D 414491 , 0 8 / 29 /2013 )

. Fo r 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) databas es was consulted for pesticide incident data on the active ingredient dazomet

. Dazomet 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 agenci es 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 storesDazomet Registration Review Human

- Health Assessment Scoping Document

Page 14 of 29 incident data for death, major and moderate incidents, and it includes more details about the location, date and nature of the incident.

In A ggregate IDS , from January 1, 200 8 to February 19, 2013, there were 7 reported incident s involving dazomet

. These incidents were classified as minor severity. For the M ain IDS, from January 1, 200 8 to February 19, 2013, there was one incident reported in the database. This incident was classified as moderate severity.

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 o f 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 resp ective 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

coor dinator 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 identifies 2 cases, stemming from 2 events, involving dazomet. Both cases involve a single activ e ingredient. One case occurred in California in 1999, and was moderate in severity. No case narrative was entered. The second case occurred in California in 2005 and was low in severity. This case applied product to a telephone pole to

control for ter mites and developed a rash. Both cases were work

- related.

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

NIOSH SENSOR

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

warrant furthe r investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the Registration Review risk

assessment.

9 .0 Tolerance Assessment and International Harmonization

There are currently no tolerances for dazomet and MITC (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 dazomet human

- health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority 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 assessments, including, but not limited to, people who obtainDazomet Registration Review Human

- Health Assessment Scoping Document

Page 15 of 29 drinking water from sources near agricultural areas, the variabil ity 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 availab le 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 dazomet or MITC and any other substances. For the purposes of this assessment , therefore,

EPA has not assumed that dazomet or MITC 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 an d 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 mechani sm 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 exp osure 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 m ay 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 ass essments, 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 p art of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact with the 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.Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 16 of 29 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 iner t ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some pesticides scheduled for Registration Review and chemicals found in water

. For further information on the status of the EDSP, the pol icies and procedures, the list s of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website. 2

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

associated with the EDSP screenin g of dazomet . Before completing this Registration Review, the Agency will make an EDSP FFDCA section 408(p) determination.

1 3 .0 Human Studies

Past dazomet and MITC risk assessments rely on an intentional doing eye irritation and odor threshold study in human subjects (MRID no. 44400401) as the basis for the acute MITC endpoint. The Human Studies Review Board (HSRB) reviewed this study at a May 2

- 3, 2006

me eting . The HSRB concluded that a ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) were satisfied in the study and that there was no regulatory barrier to continued reliance on these studies.

Past d azomet and MITC risk assessments also rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pest icides, comprise generic pesticide e xposure databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF) Database . EPA has reviewed all the studies supporting these

multi

- pesticide generic exposure databases, and has found no clear and c onvincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protect ion of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

1 4 .0 Risk Assessment Updates, Data Deficiencies, and Label Revisions

No data deficiencies outside those pre viously discussed in the 2009 Amended RED were identified for the conventional uses of dazomet. However, the following data deficiencies have

been identified for the antimicrobial uses of dazomet in paints and finger paints: Occupational/Residential Exposu re:

o 875.1700: Product use information 3

o 875.1200/875.1400: Occupational dazomet handler dermal and inhalation exposure for open pour mixing/loading paint 1

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

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

2 http://www.epa.gov/endo/

3 Th e s e data will be used to identify and characterize dazomet/MITC concentrations in paint and finger paint.Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 17 of 29 o 875.1200/875.1400: Occupational dazomet handler dermal and inhalation exposure applying paint (airless sprayer and brush/roller) 2

o 875.1200/875.1400: Residential dazomet handler dermal and inhalation exposure applying paint (airless sprayer and brush/roller) 2

o 875.2400: Post

- application dazomet dermal exposure for finger painting

o 875. 2 5 00 : Post

- application MITC inhalation exposure for painted rooms

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

o Reevaluation of the toxicity endpoint/dose selection may be necessary based on the recently submitted toxicological data. Residue Chemistry: None Dietary Exposure: None Occupational/Residential Exposure:

o Revised HED and AD occupational dazomet handler risk assessments may be

necessary based on the most recent exposure data, Agency policies, or if the toxicological reevaluation results in changes to the endpoints.

o AD anticipates the need for occupational/residential dazomet handler dermal and

inhalation risk assessment s for applying pai nt using an airless sprayer and brush/roller during Registration Review.

o AD anticipates the need for residential post

- application dazomet dermal risk assessments for using finger paint during Registration Review.

o AD anticipates the need for residential pos t

- application MITC inhalation risk

assessments for painted rooms during Registration Review.

o Additional or revised HED residential bystander risk assessments may be necessary based on the most recent exposure data, Agency policies, or if the toxicological reevaluation of results in changes to the endpoints.

1 AD notes that these data requirements may be fulfilled by completed or planned Antimicrobial Exposure

Assessment Task Force studies.Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 18 of 29 1 5 .0 References

Memoranda Relevant to Registration Review.

Author Barcode Date Title
C. Olinger D287290 08/16/04 Dazomet Non

- Food Use Status
C. Olinger D344375 01/03/08 Dazomet. Non

- Food Use Status.

C. Walls D335651 06/04/08 Dazomet: Revised Occupational and Residential Exposure Assessment of Antimicrobial Uses for the Reregistration Eligibility Decision (RED) Document.

S. Shelat D360773 4/30/2009 Dazomet: Updated Final Revised HED Chapter of the Reregistration Eligibility Decision Document (RED).

J. Dawson, C. Smith, and S.

Shelat D385314 1/11/2011 Methyl Bromide ( PC Code 053201), Chloropicrin (PC Code 081501), Dazomet (PC Code 035602), Metam Sodium and Potassium (PC Codes 039003 & 039002 ), MITC (PC Code 068103), DP Barcode 385314 , Second Update To Health Effects Division Recommendations for Good Agricultural Practices and Associated Buffer Credits

S. Recore and E.

Evans D 414491 8/29 /13 Dazomet : Review of Human Incidents

Attachments:

Attachment 1: Chemical Identity Table.

Attachment 2: Dazomet and MITC Acute, Subchronic, and Chronic Toxicity Profile

Attachment 3: Dazomet and MITC Endpoint Selection Tables.Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 19 of 29 Attachment 1: Chemical Identity Table

.

Physical and Chemical Properties of Dazomet and MITC

Parameter Dazomet MITC

Mode of Pesticidal Action generates MITC The registrants have hypothesized that MITC interacts with a group of cation channels known as the transient receptor potential (TRP) family (see also Bandell, Story, Hwang, et al., 2004). In particular the report suggests that TRPA1 may be the

target.

Appearance white crystalline solid colorless crystalline solid

Melting Point 104

- 105 C 35

- 36 C

Vapor Pressure N/A 20 mm of Hg at 25 C

Partition Coefficient N/A 1.05 at 20 C

Solubility in Water < 0.1 g/100 mL at 18 C 8.94 g/L at 20 C

Toxic Impurities None 1 None 1

1 There are no major toxic impurities; however, there are several toxic degradate compounds.Dazomet Registration Review Human

- Health Assessment Scoping Document

Page 20 of 29 Attachment 2: Dazomet and MITC Acute, Subchronic, and Chronic Toxicity Profile

Acute Toxicity of Methyl Isothiocyanate (PC Code 068103 )

Guideline

No. Study Type MRID #(S). Results Toxicity Category

81

- 1 Acute Oral

- Rat 00162331 LD 50 = 82 mg/kg ~ 55 mg/kg ~ II

81

- 2 Acute Dermal

- Rat 00162330

42443501 LD 50 = 136

- 436 mg/kg ~

181 mg/kg ~ I

81

- 3 Acute Inhalation

- Rat 45919410 LC 50 = 0.54 mg/L II

81

- 4 Primary Eye Irritation 00162328 corrosion of the cornea and conjuctivae I

81

- 5 Primary Skin Irritation 00162329 all animals died within one

hour I

Acute Toxicity of Dazomet (PC Code 035602)

Guideline

No. Study Type MRID #(S). Results Toxicity Category

81

- 1 Acute Oral 00132468 LD 50 = 596 mg/kg ~

LD 50 = 415 mg/kg ~

LD 50 = 519 mg/kg (combined) II

Based on female

values

81

- 2 Acute Dermal

- Rats 42328802 LD 50 = >2000 mg/kg III

81

- 3 Acute Inhalation 41563003 LC 50 =>8.40 mg/L ~ 7.29 mg/L ~ IV

81

- 4 Primary Eye Irritation 41563002 slight to well defined conjunctival redness and

chemosis. Returned to

normal within 72 hours III

81

- 5 Primary Skin Irritation 42328801 non

- irritating to the skin of

male rabbits IV

81

- 6 Dermal Sensitization 47014505 and

44031801 Not a sensitizer N/APage 21 of 29

Subchronic, Chronic, and Other Toxicities on Dazomet and MITC
Guideline No./ Study Type Dazomet MITC

MRID No. (year)/ Classification

/Doses Results MRID No. (year)/

Classification /Doses Results

870.3100

90

- Day oral toxicity rodents (rat) 41865502 (1987)

Acceptable/guideline 0, 30, 90, 300, 600 ppm M: 0, 1.5, 4.5, 13.7, 28.0 mg/kg/day F: 0, 1.7, 5.3, 15.4, 32 mg/kg/day NOAEL = 1.5 mg/kg/day LOAEL = 4.5 mg/kg/day based on increased liver weight and liver to body weight ratio; increased incidence of pronounced foci in the liver Not available

870.3100

90

- Day oral toxicity rodents (mouse) Not available Not available

870.3150

90

- Day oral toxicity in nonrodents (dog) 41866501 (1987)

Acceptable/guideline 0, 25, 100, 400/200 ppm M: 0, 0.87, 3.5, 7.25 mg/kg/day F: 0, 0.92, 3.5, 8.09 mg/kg/day NOAEL = 3.5 mg/kg/day LOAEL = 7.25 mg/kg/day based on increase in relative liver to body weight ratio and increased hemosiderosis in the spleen of males

and females Not available

870.3200

21/28/30

- Day dermal toxicity 40299101(1987)

Acceptable/guideline 0, 10, 100, 1000 mg/kg/day Dermal and Systemic NOAEL= 1000 mg/kg/day 00132815 (1983) Unacceptable/guideline 0, 0, 120, 240, or 480 mg/kg/day NOAEL < 120 mg/kg/day LOAEL = 120 mg/kg/day based on decreased body weight gain and food

intake. Severe necrosis and corrosion of the

skin.

41221406 (1986) Unacceptable/guideline 0, 1.0, 10.0, and 100 mg/kg/day NOAEL = 1 mg/kg/day LOAEL = 10 mg/kg/day based on

decreased serum albumin and increased globulin values in addition to increased liver weights. Irritation at all doses

870.3250

90

- Day dermal toxicity Not available Not availablePage 22 of 29 Guideline No./ Study Type Dazomet MITC

MRID No. (year)/ Classification

/Doses Results MRID No. (year)/

Classification /Doses Results

870.3465

28

- Day inhalation toxicity Not available 45314802 (1987) Acceptable/guideline 0, 5.1, 19.9, 100 ug/L Systemic NOAEL = 5 mg/m 3 (1.7 ppm). LOAEL = 19.9 mg/m 3 ,(6.8 ppm), based on clinical signs consistent with irritation in both sexes and increased neutrophilic polymorphonuclear granulocytes in the

blood of males. Extrathoracic (ET) region ET NOAEL = 19.9 mg/m 3 (6.8 ppm) ET LOAEL = 100 mg/m 3 ,(34 ppm), based on observation of pathological changes of the nasal cavity (metaplasia of respiratory epithelium and atrophy of the olfactory epithelium). Tracheabronchial (TB) region TB NOAEL is 19.9 mg/m 3 (6.8 ppm) TB LOAEL = 100 mg/m 3 (34 ppm), based on observation of pathological changes (tracheal epithelial proliferation and single cell necrosis, bronchopneumonia and bronchial and bronchiolar epithelial proliferation).

870.3465

90

- Day inhalation toxicity Not available 41221407 (1978) Acceptable/guideline 0, 3.16, 30.67, and 137.13 ug/L for 4 hours/day 0, 2.1, 20.6, and 91.9 ug/L extrapolated to 6 hour exposure NOAEL = 3.16 ug/L LOAEL = 30.67 ug/L based on decreased body weight, food efficiency and blood protein values accompanied by i ncreased

water intake.

870.3465

90

- Day inhalation toxicity (rats) Not available 48869801 (2012) Acceptable/guideline 0,1, 5, or 15 ppm 0, 3, 15, or 50 ug/L for 6 hours/day Portal of Entry NOAEL = 3 ug/L LOAEL = 15 ug/L based on lesions in the larynx and the nasal cavity. Systemic NOAEL = 50 ug/L , highest dose tested (HDT)Page 23 of 29 Guideline No./ Study Type Dazomet MITC

MRID No. (year)/ Classification

/Doses Results MRID No. (year)/

Classification /Doses Results

870.3465

90

- Day inhalation toxicity (mice) 48869601 (2012) Acceptable/guideline 0,1, 5, or 20 ppm 0, 3, 15, or 60 ug/L for 6 hours/day Portal of Entry NOAEL = 3 ug/L LOAEL = 15 ug/L based on lesions in the larynx, the trachea and the nasal cavity. Systemic NOAEL = 15 ug/L LOAEL = 60 ug/L based on reduced body weights (M & F).

870.3700a

Prenatal developmental in

rodents 41483701 (1987)

Acceptable/guideline 0, 3, 10, or 30 mg/kg/day Maternal NOAEL = 10 mg/kg/day LOAEL = 30 mg/kg/day based on reduced body weight gain and decreased food consumption. Developmental NOAEL = 30 mg/kg/day 44733602 (1998) Acceptable/guideline 0, 3, 10, or 30 mg/kg/day Maternal NOAEL = 3 mg/kg/day LOAEL = 10 mg/kg/day based on salivation and decreased body weight gain. Developmental NOAEL =10 mg/kg/day LOAEL = 30 mg/kg/day based on reduced fetal weight and an increased incidence of

the skeletal variation of unossified sternebra(e).

45919417 (1987) Unacceptable/guideline 0, 3, 10, or 30 mg/kg/day Maternal NOAEL = 10 mg/kg/day LOAEL = 30 mg/kg/day based on decreased body weight gain and food consumption. Developmental NOAEL =10 mg/kg/day

LOAEL = 30 mg/kg/day based on higher number of runts and reduced placental weights.

870.3700b

Prenatal developmental in nonrodents (rabbit) 92028011 (1980)

Unacceptable/guideline 0, 25, 50, 75 mg/kg/day 0, 6.25, 12.5, 25 mg/kg/day Maternal NOAEL = 12.5 mg/kg/day LOAEL = 25mg/kg/day based on the reduced body weight gain. Developmental NOAEL = 12.5 mg/kg/day LOAEL = 25 mg/kg/day based on the increased incidence resorptions and resorptions/dam 45919418 (1986) Unacceptable/guideline 0, 1, 3 or 10 mg/kg/day Maternal tentative NOAEL = 3 mg/kg/day Tentative LOAEL = 10 mg/kg/day based on reduced body weight gain and food consumption. Developmental NOAEL =10 mg/kg/day LOAEL > 10 mg/kg/dayPage 24 of 29 Guideline No./ Study Type Dazomet MITC

MRID No. (year)/ Classification

/Doses Results MRID No. (year)/

Classification /Doses Results

870.3700a

Prenatal developmental in rodents (rats)

inhalation 48779701 (2012) Acceptable/guideline 0,1, 4, or 12 ppm 0, 3, 12, or 35 ug/L for 6 hours/day Maternal NOAEL = 12 ug/L LOAEL = 35 ug/L based on decreased body weight, body weight gain, corrected body weight gain, and food consumption.

Developmental NOAEL = ≥35 ug/L (HDT)

870.3700b

Prenatal developmental in nonrodents (rabbits)

inhalation 48779501 (2012) Acceptable/guideline 0,1, 5, or 15 ppm 0, 3, 15, or 50 ug/L for 6 hours/day Maternal NOAEL = 15 ug/L LOAEL = 50 ug/L based on mortality, clinical signs associated with the respiratory tract, unkempt appearance, blue areas on the face, gross findings in the respiratory tract and stomach, decreased body weight gain, and decreased food consumption.

Developmental NOAEL = ≥50 ug/L (HDT)

870.3800 Reproduction and fertility e ffects 41865301 (1989)

Acceptable/ guideline 0, 5, 30, 180 ppm 0, 0.5, 3, or 17

- 19 mg/kg/day Parental/Systemic NOAEL = 0.5 mg/kg/day LOAEL = 3 mg/kg/day based on increased incidence and severity of hepatic intracellular neutral lipids in male rats; decreased body weight in

F1 males. Reproductive NOAEL = 17

- 19 mg/kg/day

- 19 mg/kg/day (HDT) 40974601 (1987) Unacceptable/guideline 0, 2, 10, and 50 ppm M P: 0, 0.16, 0.76 and 3.58 mg/kg/day F P: 0, 0.21, 1.01, and 4.76 mg/kg/day M F1 0, 0.15, 0. 71, 3.4 mg/kg/day F F1: 0, 0.19, 0.87, 4.22 mg/kg/day Parental/Systemic NOAEL = 10 ppm, 0.71 mg/kg/day LOAEL = 50 ppm, 3.4 mg/kg/day based on decreased body weight gain in F1 males. Reproductive NOAEL = 50 ppm, 3.4M/ 4.22F mg/kg/day LOAEL > 50 ppm, 3.4 M/ 4.22F mg/kg/day Offspring NOAEL = 50 ppm, 3.4M/ 4.22F mg/kg/day LOAEL > 50 ppm, 3.4M/ 4.22F mg/kg/day

870.4100a Chronic toxicity

rodents 41865001 (1989)

Acceptable/guideline 0, 5, 20 or 80 ppm M: 0, 0.2, 0.9 or 3.71 mg/kg/day F: 0, 0.3, 0.84 or 4.83 mg/kg/day NOAEL = 0.84 mg/kg/day LOAEL= 4.83 mg/kg/day based on significant trend but not pair wise increased incidence of neoplastic and

non

- neoplastic pathology See combined chronic/carcinogenicityPage 25 of 29 Guideline No./ Study Type Dazomet MITC

MRID No. (year)/ Classification

/Doses Results MRID No. (year)/

Classification /Doses Results

870.4100b Chronic toxicity dogs 41967701 (1989)

Acceptable/guideline 0, 15, 50, 150 ppm M: 0, 0.028, 1.05, 3.15 mg/kg/day F: 0, 0.35, 1.12, 3.50 mg/kg/day NOAEL 0.35 mg/kg/day LOAEL = 1.15 mg/kg/day based on increased liver to body weight ratio and increased pigmentation in the

liver 41240701 (1988)

U nacceptable/guideline 0, 0.04, 0.4, 2.0 mg/kg/day NOAEL = 0.4 mg/kg/day LOAEL = 2.0 mg/kg/day based on excessive salivation, RBC measures, and increased liver weights.

870.4300

Combined Chronic/ Carcinogenicity rats 41865401 (1989)

Acceptable/guideline 0, 5, 20, 80, 320 ppm M: 0, 0.23, 0.94, 3.81, 16.36 mg/kg/day F: 0, 0.29, 1.19, 5.09, 21.5 mg/kg/day NOAEL = 0.94 mg/kg/day LOAEL= 3.81 mg/kg/day based on increased serum albumin, globulins, total protein, hemoglobulin, hematocrit, and RBC in female rats

and serum cholesterol in male rats 00150078 (1984) Unacceptable/guideline 0, 2, 10, and 50 ppm 0, 0.2, 1.0 and 5 mg/kg/day NOAEL = 50 ppm LOAEL = > 50 ppm

870.4300

Chronic/ Carcinogenicity mice 41865101 (1989)

Acceptable/guideline 0, 20, 80 or 320 ppm M: 0, 3.9, 15.6 or 69.9 mg/kg/day F: 0, 5.7, 21.4 or 95.0 mg/kg/day NOAEL = 3.9 mg/kg/day

LOAEL = 15.6 based on increased

liver masses in male mice at 78 weeks; increased liver weight in

female mice at 78 weeks 00150075 (1980) Unacceptable/guideline 0, 5, 20, 80, and 200 ppm M: 0, 0.82, 3.30, 11.83, and 25.71 mg/kg/day F: 0, 0.91, 3.66, 13.03, 29.03 mg/kg/day NOAEL = 20 ppm; 0.82 M/0.91 F mg/kg/day LOAEL = 80 ppm, 3.30 M/ 3.66 F mg/kg/day based on decreased body weight gain th roughout the majority of the study and reduced water consumption.

870.5100

Reverse Gene

Mutation

– Salmonella typhimurium 00131909 (1979)

Unacceptable/Guideline 0, 12.3

- 1000 μg/plate

- S9 0, 3.7

- 1000 μg/plate +S9 Negative

. 41221410 (1978) Acceptable/Guideline 0, 0.5, 1, 5, 10, 50, 100, 500 and 1000 μg/disc +/

- S9 Negative in S. typhimurium and

Escherichia coli WP2 uvr A up to severely cytotoxic concentrations (500 and 1000 μg/disc +/

- S9)

00131910 (1980) Acceptable/Guideline 0, 3.7

- 300 μg/plate

- S9 0, 12.3

- 1000 μg/plate +S9 (both

Aroclor 1254

- induced and phenobarbital induced) Negative up to cytotoxic doses (≥ 300 μg/plate +/

- S9.

870.5250

Sex

- linked recessive

lethal test in Drosophilia melanogastre 00131916 (1970)

Acceptable/Guideline 0, 0.025 and 0.05 mg/mL Negative Not availablePage 26 of 29 Guideline No./ Study Type Dazomet MITC

MRID No. (year)/ Classification

/Doses Results MRID No. (year)/

Classification /Doses Results

870.5300

In vitro mammalian cells gene mutation test (mouse lymphoma cells) 00131912(1980)

Acceptable/Guideline 0, 0.6, 0.8, 1.0, 2.0, 4.0, and 5.0. μg/mL +/

- S9 Positive

– S9 only at concentrations ≥0.6 μg/mL

- S9 Not available

870.5300

In vitro mammalian cells gene mutation

test

-- Chinese hamster ovary (CHO) cells at

the HGPRT locus 41497901 (1985)

Acceptable/Guideline 0, 0.1, 0.0215, 0.0464, 0.1, 0.215, and 0.464 μg/mL +/

- S9 Positive concentration

- related increases in the mutation frequency (MF) at 0.215 and 0.464 μg/mL

- S9 & 0.1, 0.215 and 0.464 μg/mL +S9 Not available

870.5375

In vitro chromosome

aberration

– mammalian cells (human lymphocytes) 41482302 (1989)

Unacceptable 0, 0.0001, 0.0004, 0.002, 0.01, and 0.05 μg/mL

- S9; 0.004, 0.02, 0.1, 0.5, 2.5, and 12 μg/mL +S9 Negative; inappropriate

concentrations tested 41221411 (1988) Acceptable/guideline 0, 3.0 & 5.0 μg

- /+S9 Negative in human lymphocytes up to a cytotoxic concentration (5.0 μg

- /+S9)

870.5375

In vitro chromosome

aberration

– mammalian cells (mouse lymphoma cells) 00131912(1980)

Acceptable/Guideline 0, 0.6, 0.8, 1.0, 2.0, 4.0, and 5.0. μg/mL +/

- S9 Positive

– S9 only at concentrations of

4 or 5 μg/mL

- S9

870.5380

Mammalian spermatogonia cytogenetic assay in

Chinese hamsters 41497902 (1985)

A cceptable 0, 10, 33, and 100 mg/kg Negative Not available

870.5395 Micronucleus Assay

– Mice 41497903 (1985)

Acceptable/Guideline 0, 45, 90 and 180 mg/kg Negative up to a toxic dose (180 mg/kg) 48631101 (2011) Acceptable/guideline 0, 20, 40, and 100 ppm (inhalation) Negative up to a toxic concentration (100 ppm)

870.5500 Bacterial DNA damage or repair tests

— Bacillus subtilis rec

assay 41482301 (1987)

Acceptable/Guideline 0, 1, 10, 100, 500, 1000, 2500, 5000 and 10,000 μg/plate +/

- S9 Negative for preferential inhibition up to a cytotoxic concentration (≥10 μg/plate +/

- S9) 41221410 (1978) Unacceptable 0, 20, 100, 200, 500, 1000, and 2000 μg/disc

– S9 NegativePage 27 of 29 Guideline No./ Study Type Dazomet MITC

MRID No. (year)/ Classification

/Doses Results MRID No. (year)/

Classification /Doses Results

Unscheduled DNA Synthesis

- Rat Hepatocytes ( in vivo ) 41482303 (1986)

A cceptable 0, 37.5, 75, 150, and 300 mg/kg Negative Not available

870.5900

In vitro sister chromatid exchange

– mammalian cells (mouse lymphoma cells) 00131912(1980)

Acceptable/Guideline 0, 0.6, 0.8, 1.0, 2.0, 4.0, and 5.0. μg/mL +/

- S9 Negative Not available

In vitro cell

transformation in

BALB 3T3 cells 00131914 (1978)

Unacceptable 0, 0.025, 0.05, 0.1, 0.2, and 0.4 μg/mL

- S9 Negative Not available

870.6200a

Acute neurotoxicity screening battery 43465302 (1994)

Acceptable/guideline 0, 50, 130, and 450 mg/kg (M) 0, 15, 50, and 150 mg/kg (F) NOAEL = 15 mg/kg (F)* LOAEL = 50 mg/kg (M & F) for neurobehavioral effects, based on FOB findings and reduced number of rearings. Not available

870.6200a Acute neurotoxicity screening battery inhalation (rats) 48675701 (2011) Acceptable/guideline 0, 20, 40, or 80 ppm (0, 0.06, 0.12, or 0.24 mg/L Portal of Entry LOAEL = 20 ppm (0.06 mg/L) based on mild to severe necrosis of the olfactory epithelium (1/6 M; 5/6 F), which was not

resolved in the 2

- week exposure time. Systemic/Neurotoxic NOAEL = 20 ppm (0.06 mg/L) LOAEL = 40 ppm (0.12 mg/L, base d on rales and gasping on study days 1 & 2 and decreased locomotor activity on study day 0 in both

sexes.
870.6200b

Subchronic neurotoxicity screening battery 43465301 (1994)

Acceptable/guideline 0, 50, 200, 400 ppm M: 0, 4, 16, 36 mg/kg/day F: 0, 4, 15, 34 mg/kg/day NOAEL = Not established LOAEL = 4 mg/kg/day based on fatty degeneration of the liver Not availablePage 28 of 29 Guideline No./ Study Type Dazomet MITC

MRID No. (year)/ Classification

/Doses Results MRID No. (year)/

Classification /Doses Results

870.6300 Developmental neurotoxicity Not available Not available

870.7600 Dermal penetration Not available Not available

870.7800 Immunotoxicity (Inhalation) Not available 1 48694901 (2011) Acceptable/guideline 0, 1, 3 or 10 ppm (0,3, 9 or 30 μg/L) 6 hours/day for 28 days Systemic: LOAEL = 10 ppm (30 μg/L), HCT

NOAEL = Not established Immunotoxicity: LOAEL = 10 ppm (30 μg/L), HCT

NOAEL = Not established

Special Study: Human Eye Irritation and Odor

Threshold Not available 44400401 (1996) Acceptable/non

- guideline 0, 0.22, 0.6, 0.8, 1.9, 3.3 ppm One

- minute exposure, the NOAEL for eye irritation is 3.3 ppm due to a lack of response in any parameter tested.

4

- 14 minutes, the NOAEL for eye irritation is 0.6 ppm based on responses on the Likert subjective scale at 1.9 ppm.

1

- 8 hours, based on the statistically significant subjective (Likert scale) responses at 0.8 ppm MITC at 1

- 4 hours and the statistically significant eyeblink responses at 2 and 3 hours, 0.22 ppm was designated as the NOAEL for this study
*= Data were submitted by Certis US A during the Phase 5 comment period, which outlined pre

- dosing motor activit y measurements in both

controls and test groups of females. Based on this information, the LOAEL of 15 mg/kg was revised to be a NOAEL (DP Barcode: 352796, 2008).

1 HED’s Hazard and Science Policy Council (HASPOC) has determined that an Immunotoxicity study is not required for dazomet ( A. Dunbar;

5/22 /13; TXR 0056663 ).Dazomet Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ _____________________________________ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ ________________________________________________________________________________________________________________________

Page 29 of 29 A ttachment 3: Dazomet and MITC Endpoint Selection

Summary of Toxicological Dose and Endpoints for Use in Dazomet

Oral and Dermal Human Health Risk Assessments

Exposure

Scenario Dose Used in Risk

Assessment Uncertainty Factors

and Level of Concern

for Risk Assessment Study and Toxicologial Effects

Dermal

Short

- Term (1

- 30 days) Occupational Oral LOAEL a,d = 15

mg/kg/day Occupational = LOC

for MOE = 1000 b,c Acute neurotoxicity study (MRID 43465302)

LOAEL f = 15 mg/kg in females (6.75 mg/kg MITC equivalents; decreased motor activity) based on neurobehavioral effects FOB findings and reduced number of rearings

. Dermal

Intermediate

- Term (1

- 6 months) Occupational Oral NOAEL a,d = 1.5 Occupational = LOC

f or MOE = 100 b,c Subchronic toxicity

- feeding rats (MRID 41865502)

LOAEL f = 4.5 mg/kg/day based on increased liver weight, liver:body weight ratio and pronounced foci of fatty degeneration in the liver

Dermal Long

- Term (> 6 Months) Occupational Long

- Term exposure via the dermal route is not expected considering the use pattern and its stability in the

environment.

Cancer Classification: Not classifiable as human carcinogen. a Use 4.5% dermal absorption to convert oral dose to dermal equivalent; b Level of Concern = LOC; c Margin of Exposure (MOE); d NOAEL = no observed adverse effect level; f LOAEL = lowest observed adverse effect level.

Summary of Toxicological Dose and Endpoints for Use in MITC Occupational and Residential

Hum an Health Inhalation Risk Assessment

Risk Assessment Study NOAEL/LOAEL Endpoints HECs c /HCs d

Acute Non

- occupational

and

Occupational Eye irritation study

(MRID 44400401) One minute NOAEL a

= 3.3 ppm

4

- 14 minutes

NOAEL a = 0.6 ppm

1

- 8 hours NOAEL a = 0.22 ppm Subjective responses to the

Likert scale and eyeblink

responses One minute HC = 3.3 ppm

UF = 10

4

- 14 minutes HC = 0.6 ppm

UF = 10

1

- 8 hours HC = 0.22 ppm

UF = 10

Short

- and

Intermediate

Term Inhalation (1 day to 6 months) Non

- occupational 28

- day inhalation study in rat (MRID 43514802) NOAEL a = 6.8 ppm

LOAEL b = 34 ppm Metaplasia of respiratory

epithelium and atrophy of the olfactory epithelium HEC = 0.16 ppm

UF = 30

Occupational Same as non

- occupational HEC = 0.68 ppm

UF = 30 e

Long

- Term

Inhalation (>6 months) Non

- occupational 28

- day inhalation study in rat (MRID 43514802) NOAEL a = 6.8 ppm

LOAEL b = 34 ppm Metaplasia of respiratory

epithelium and atrophy of the olfactory epithelium HEC = 0.16 ppm

UF = 300

Occupational Same as non

- occupational HEC = 0.68 ppm

UF = 300 e

Cancer Classification: Insufficient data to characterize cancer risk

a NOAEL = no observed adverse effect level; b LOAEL = low observed adverse effect level; c HEC = Human equivalent concentration; d HC = Human concentration.; e HECs differ between non

- occupational and occupational scenarios because the

residential HEC is based on 24

- hour exposures occurring 7 days per week, whereas the occupational HEC is based on 8

- hour

exposures oc curring 5 days per week

.