Metam S9dium/Metam**<:> tassi~m!MITC** **~~ ~istrat~on**  Review**Hun:~n-::_Health Asse~** **sment Scopi~g** **J?~~ument** UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION



### MEMORANDUM

Date: September 4, 2013

SUBJECT: Metam Sodium, Metam Potassium, and MITC. H uman-Health Assess men t Seeping Document in Support of Registration Review.

PC Code: Metam Sodium PC Code: 039003, Metam

P otass ium PC Code: 039002, MITC PC Code: 068103

Decision No.: 

### '/7Sf?lf2 DP Barcode: D409657

Registration No.: N/A
Petition No.: N / A Regulatory Action: Registration Review Scop in g
Document
Risk Assessment Type: N / A

TXR No.: N / A Case No.: 2390

CAS No .: Metam Sodium: 6734-80-1, Metam Potassium : 137-41-7, MITC: 556-61-6

MRID No.: N / A



### FROM: 40CFR: N / A



### Shalu Shelat, Indus trial Hygienist

### ~**~** "'\.[Y-l\.3

Nancy McCarroll, Toxicologi st

### jff_~f11"'£J**1 ~~~I)**  Christopher Schlosser,**Toxico logi** **st......:::;;~~:<::::----** 

### Risk Assessment Branch 6 (RABV )

# ~:aries Smith

, Branch C.hief.

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Health Effects Division (7509P) -/

Na than Mottl, Biologist

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Risk Assessment and Science Support Branch

Antimicrobials Division (751 OP)

THR O U GH: Felec ia Fort, Branch Chief :;( 

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Ri s k Assessment Branch 6 (RABV 1

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Health Effects Division (7509P) [)

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Steve Weiss, Branch · e

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Tim Leighton, Senior

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Risk Assessment and Sci e upport ranch

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Antimicrobials Di vision (751 OP)

T O: Jose Gayoso, Chemical Review Manager Risk Management and Implementation Branch II

Pesticide Re-Eval uat ion Division (7508P)

Attached is the combined HED and AD human-health risk assessment seeping document for

metam sodium ; metarn potassium, and MITC to support registration review.

Page 1 of27Metam Sodium / Metam**Potass U_!!l** **MI~~ ~e~istr~!i??** **Re~i~~}-lu!D_~_n-I:Iealth** __**~~ sessment**  Scoping Document

Executive Summary

Metam sodium (sodium N-methyldithiocarbamate) and metam potassium (potassium N

### methyldithiocarbamate) are non-selective pre-plant soil fumigants with fungicidal, herbicidal,
insecticidal, and nematicidal properties. The primary degradate for both metam sodium and

metam potassium is methyl isothiocyana te (MITC). Metam sodium, metam potassium, and

MITC also are active ingredien ts in a variety of antimicrobial products. The Health Effects

Di visio n (HED) and the Antimicrobial Division (AD) have evaluated the status of the humanhealth assessments for metam sodium, metam potassium, and MITC to determine whether

sufficient data are available to support Regis t ration Review. HED and AD have also considered

the most recent human-health risk assessments for metam sodium, metam potassium

, and MITC

with respect to toxicity, exposure, and usage databases, and the mo s t updated Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review. It is noted that dazom et is another pesticide that produces MITC upon application, however this document does not include exposure to dazomet or MITC resulting

from dazomet applications.

The Amended Metam Sodium/Potassium and MITC Reregistration E ligibility Decision (RED)

document was issued in May 2009. The Amended RED focused on fo ur basic metam sodium/potassium application categories, including: 

### (I) use as an agricultural soil fumigant for
food, feed, and fiber crops; (2) use on golf course turf and for application to small areas of turf

and soil; (3) use as a root-control agent in drains and sewers; and (4) use ofmetam potassium as

an antimicrobial for pulp and paper, recirculating cooling towers, and industrial water purification systems and use of metam sodium as an antimicrobial for remedial treatment of

wood poles and treatment of sewage sludge and animal waste (only supported by one registrant).

The Amended RED detailed a number of letters that the Agency received requesting the voluntary cancellation of several of the metam sodium and metam potassium antimicrobial uses. On August 20, 2008, the Agency published a Section 6 (f) notice in the Fe deral Register (Federal Register Notice Vol. 73, No. 162) to delete the uses specified in the RED from labels

. The Agency is i n the process of amending thes e labels to remove all of the canceled uses. Additionally, the Amended RED also included MITC us e as an antimicrobial agent for remedial

wood treatment. No new us es of these three active ingredients have been r egistered since the

Amended RED was issued.

The toxicity database for metam sodium and metam potassium is adequate for Registration

Re view 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. T he registrants have completed and submitted a number of

other MITC toxicity studies required as part of the 2009 Amended RED includ i ng an acute study

via the inhalation route, a developmental toxicity screening test via the inhalation route, an

un sc heduled DNA synthesis in mammalian cells in culture study, and an Immunotoxicity study

via the inhalation route. The Agency will review and incorporate all of these studies during Registration Re view. The focal poin ts for the assessment of metam sodium, me tam potassium

and MITC are occupational dermal exposure to metam sodium and metam potassium and occupational and residential inhalation exposure to MITC. There is no route specific dermal study available for metam sodium/potassium howev er a metam sodium rat dermal absorption

s tudy is available (dermal absorption of2.5%). There are a number of route specific MITC

inhal at ion 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 s tudy performed with human subjects that indicates the irri tat ion properties of

Page 2 of27Metam Sodium/Metam Potassium/MITC Registration Review Human

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### MITC. During Registration Review

, the Agency will reevaluate the points of departure ( PODs) and uncertainty factors (UFs) for the residential and occupational exposure assessments.

The residue chemistry and dieta ry

- exposure databases are adequate to support current registration requirements. The current uses of metam sodium and metam potassium 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

dr inking water sources such as surface water and ground water. Dietary and drinking water

assessment s are not anticipated during Registration Review.

The occupational and residential exposure database for metam sodium, metam potassium, and MITC is adequate for Registration Review with the exception of an ambient air study measuring MITC from soil fumigant applications and a number of antimicrobial occupational handler and
post

- application exposure studies required in the 2009 Amended RED

. In addition, as p art of Registration Review, the Agency requests that a shank injection tarped, bedded application flux study be completed (8 35.8100 ) . A sewer treatment occupational exposure study (MRID 48914201) required as part of the 2009 Amended RED was submitted and recently reviewed by the Agency (S. Shelat, D406497, 9/4/2013). The registrants have also completed and submitted

a field volatility study for center pivot applications (conventional soil fumigation use) required

for metam sodium as part of the 2009 Amended RED

. The Agency will review and incorporate this study during Registration Review.

The Agency 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 handler risk assessment s may be necessa ry based on the most recent exposure data

, Agency policies, or if th e toxicological

reevaluation results in changes to the endpoints

.

o Revised AD occupational post

- application risk assessments 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 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.Metam Sodium/Metam Potassium/MITC Registration Review Human

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### 1.0 Introduction

Metam sodium (sodium N

- methyldithiocarbamate) and metam potassium (potassium N

methyldithiocarbamate) are no n

- selective pre

- plant soil fumigants with fungicidal, herbicidal, insecticidal, and nematicidal properties. When metam

- sodium and metam

- potassium are applied and mixed with moist soil or water, they are quickly broken down into several strong irritant

pro ducts. One of these products is methyl isothiocyanate ( MITC), which accounts for most of the fumigant activity. Metam sodium, metam potassium, and MITC also are active ingredients in a variety of antimicrobial products. The Health Effects Division (HED) and the Antimicrobial Division (AD) have evaluated the status of the human

- health assessments for metam sodium, metam potassium, and MITC to determine whether sufficient data are available to support Registration Review. HED and AD have also considered t he most recent human

- health risk assessments for metam sodium, metam potassium, 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 ne cessary to support Registration Review. Dazomet is another pesticide that produces MITC upon application however; this document does

not include exposure to dazomet or MITC resulting from dazomet applications.

The Amended Metam Sodium/Potassium and MITC Reregistration Eligibility Decision (RED) document was issued in May 2009. The RED focused on four basic metam sodium/potassium application categories, including: (1) use as an agricultural soil fumigant for food, feed, and fiber crops; (2) use on golf co urse turf and for application to small areas of turf and soil; (3) use as a root

- control agent in drains and sewers; and (4) use for a number of

antimicrobial uses listed for metam potassium (tanning drum leather , pulp and paper, recirculating cooling towe rs, and industrial water purification systems) and metam sodium ( remedial treatment of wood poles and treatment of sewage sludge and animal waste). The RED also included MITC use as an antimicrobial agent for remedial wood treatment. No new uses of these three chemicals have been registered since the RED was issued.

The Amended RED detailed a number of letters that the Agency received requesting the voluntary cancellation of several of the metam sodium and metam potassium antimicrob ial uses.

The antimicrobial uses of metam

- sodium that were requested for voluntary cancellation included (1) treatment of process waters during the production of sugar (i.e., raw cane and beet sugars), (2) treatment of brine

- cured hides and skins (i.e., l eather) during processing, and (3) treatment of sewage sludge and animal waste (one registrant continues to support this use, while another canceled this use). The antimicrobial uses of metam potassium that were requested for voluntary

cancellation include d: (1) sugar beet and cane uses; (2) all leather uses, with the exception of the tanning drum leather use; (3) all paint uses (including the preservation of protective colloids and emulsion resins); (4) all water

- based drilling, completion, and packer flui d uses; (5) all petroleum secondary recovery operation uses; (6) all once

- through cooling water applications; and (7) all cutting fluids (metal working fluids) uses. As a result of these cancellation letters

these uses were not evaluated in the Amended RE D and will not be evaluated in Registration

Review.

Subsequently, on August 20, 2008, the Agency published a Section 6 (f) notice in the Federal Register ( Federal Register Notice Vol. 73, No. 162) to delete the uses specified in the Amended RED from labels. The Agency is in the process of amending these labels to remove all of the canceled uses. AD notes that many of the voluntarily cancelled uses of metam potassium still remain on current metam po tassium labels. These uses include the treatment of leather; petroleum secondary recovery operation uses; water based drilling, completion, and packer fluidMetam Sodium/Metam Potassium/MITC Registration Review Human

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Page 5 of 27 

### uses; and once

- through cooling water applications. AD will be following up with the registrants of metam potassium on the voluntary cancelation of these remaining uses

.

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 mammalian cells in culture study (870.5550),

an Immunotoxi city 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). The registrants have completed and submitted the neurot oxicity study, the developmental study, the unscheduled DNA synthesis, and the Immunotoxicity 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 stu dy or the chronic/carcinogenicity studies at this time. Once these studies are completed and submitted they will also be reviewed and incorporated during Registration Review

.

Attachment 2 provides a summary of the acute, subchronic, and chronic toxicity profile for metam sodium/potassium and MITC. The relevant data from the recently submitted studies ha s been incorporated into the toxicity profile

. Attachment 2 provides a summary of the relevant toxicological endpoints used in metam sodium/potassium 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 assessments based on current HED policy, recen tly submitted studies, and any other outstanding data.

No inhalation pharmacokinetic or metabolism studies are available at this time for metam sodium/potassium or MITC. Metam sodium and metam potassium are efficiently converted to

MITC in vivo . Oral ph armacokinetic and metabolism studies in rats are available for metam
sodium and MITC. In those studies, metam sodium and MITC were excreted mainly in urine with small amounts excreted in feces. Three different compounds (MITC, carbon dioxide [CO 2 

### ],

carbo n oxide sulfide [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 radioa ctive material was low in both sexes and at all doses. High uptake was also seen in the studies 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 fo r metam sodium and MITC but there were some differences, mainly quantitative in nature. The consistent results seen in the metam sodium and MITC oral pharmacokinetic and metabolism studies are further supported by the similarity in the oral doses causing similar toxic effects for metam sodium and MITC in the available oral toxicity studies. Specifically, reduced body weight gain and food consumption in addition to changes in hematological parameters were observed at low doses in oral toxicity studies with rats, mice, rabbits, and dogs.

In oral developmental toxicity studies with metam sodium 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 susceptibilityMetam Sodium/Metam Potassium/MITC Registration Review Human

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### observed in the oral developmental and reproductive toxicity studies with metam sodium and MITC. All of the developmental NOAELs are equal to or larger than the NOAELs for maternal toxicity. There is, however, qualitative s usceptibility in two rat developmental toxicity studies with metam sodium 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 metam sodium, metam pota ssium and MITC are dermal exposure to metam sodium and metam potassium and the inhalation exposure to MITC. There is no route specific dermal study available for metam sodium/potassium however a metam sodium rat dermal absorption study is available (derma l absorption of 2.5%). 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 irrit ation and odor threshold study performed with human subjects that indicates the irritation properties of MITC.

Metam sodium/potassium are classified as a probable human carcinogens based on statistically significant increases in malignant angiosarcomas in both sexes of the CD

- 1 mouse in male. F or the purpose of risk characterization, a low dose extrapolation model was applied to the animal data for the qua ntification of human risk (Q 1 

### *) , based on the total incidenc e of angiosarcomas in

male mice at all sites combined ( Q 1 

### * = 1.98x10 - 1 

### ). 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 Amended RED. HED will reevaluate the carcinogenic potential of MITC during Registration Review after these studies are submitted and

reviewed.

Conclusions: The toxicity databases for metam sodium/potassium and MITC are adequate for Registration Review except f or the outstanding toxicity studies (i.e., the reproduction and fertility effects study and the chronic/carcinogenicity studies ) required in the 2009 Amended

RED

. During Registration 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, recen tly submitted studies, and any other outstanding data

.

3.0 Residue Chemistry

The resi due chemistry database s for metam sodium/potassium and MITC are adequate for Registration Review. The Agency previously decided that there is no reasonable expectation of finite residues to be incurred in/on food and feed crops when metam sodium and metam potassium are used as preplant soil fumigants, so these uses are considered non

- food uses, an d tolerances are not needed ( Kinard; D293347; 9/30/2003). There is also no reasonable expectation of finite residues in/on food for the antimicrobial uses of met am sodium / potassium

and MITC

.

Conclusions: The residue chemistry database s for metam sodium/potassium and MITC are adequate for Registration Review.

4.0 Dietary Exposure

The dietary exposure database s for metam sodium/potassium and MITC are adequate for Registration Review. As described in Section 3.0, the Agency previously decided that there is noMetam Sodium/Metam Potassium/MITC Registration Review Human

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### reasonable expectation of finite residues to be incurred in/on food and feed crops based on the

currentl y registered uses of metam sodium and metam potassium.

Environmental fate data suggest that there is a low potential for the parent compound metam sodium or metam potassium to be present in drinking water due to the rapid degradation of metam sodium/potas sium to MITC in the environment. MITC could potentially move to surface water through runoff under an intense rainfall and/or if continuous irrigation occurs right after metam sodium application. However, the Henry’s Law Constant of 1.79 x 10

- 4 atm

- m 3 

### /mo l 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 w as 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 sou rces such as surface water and ground water.

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

Conclusions: The dietary exposure database s for metam sodium/ potassium and MITC are adequate for Registration Review. Dietary and drinking water assessments are not anticipated during Registration Review.

5.0 Residential Exposure

The 2009 Amended RED required two MITC residential exposure studies for the conventional uses of metam sodium/potassium , including the following : a field volatility study for center pivot applications of metam sodium/potassium (8 35.8100 ), and

a n ambient air monitoring study for MITC ( non

- guideline ). The registrants have completed and submitted the center pivot f ield volatility study and the Agency will review and incorporate th i s stud y during Registration Review. The Agency has not received the ambient air monitoring study at this time. Once this study is completed and

submitted

, it will also be reviewed and incorporated during Registration Review

. In addition, t he Agency requests that a shank injection tarped, bedded application flux study be completed (8 35.8100 ) . P reviously submitted tarped, bedded flux studies did not utilize a true shank injection application rig and consequently these studies may not accurately reflect potential bystander inhalation exposures . Such a study should include multiple fields and multiple tarps, one of which should be a standard LDPE tarp.

There are currently no registered residential uses of metam sodium/potassium or MITC. However, there is the potential for residential bystan der inhalation exposure to MITC after a soil fumigation application of metam sodium or metam potassium. The Agency has specifically

focus ed on assessing acute MITC inhalation exposures resulting from metam sodium /potassium applications because peak MITC a ir concentrations typically occur in the first 24 or 48 hours after application. There is also the potential for inhalation exposure to MITC via ambient air. These exposures can be acute as well as longer

- term in nature.

There are two recent document s that analyzed acute residential bystander inhalation exposure to

MITC 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 metam sodium/potassium applicationsMetam Sodium/Metam Potassium/MITC Registration Review Human

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### ( Smith ; D 357 118 ; 8 /30/200 9 and Shelat and Smith ; D 385289 ; 1 / 06 /20 11). The results of these assessments show that bystander inhalation exposure to MITC after a soil fumigation application of metam sodium/potassium can vary depending on a variety of factors such as app lication 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 that 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) Document for Methyldithiocarbamate Salts (Metam

sodium, Metam

- potassium) and Methyl Isothiocyanate (MITC) provides more information on buffer zone development.

There are two recent documents that analyzed ambient air inhalation exposure to MITC based on numerous ambient air monitoring studies from California and Washington (Smith ; D 357118 ; 8 /30/200 9 and Shelat ; D 406930 ; 2 / 2 6 /20 1 3 ). The results of these assessments show that ambient air inhalation exposures to MITC can occur for extended periods especially in areas of high use during the season of high use. In some cases, acute as w ell as short

- and intermediate

- term risk s exceed HED’s level of concern for MITC (MOEs < 10 for acute and MOEs < 30 for short

- and

intermediate

- term).

Conclusions : The residential exposure database s for metam sodium/potassium and MITC are adequate for

R egistration Review except for the outstanding exposure study (i.e., the ambient air study) required in the 2009 Amended RED . In addition, as part of Registration Review, the Agency requests that a shank injection tarped, bedded application flux study be c ompleted. HED will review and incorporate all of these studies 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 change 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 Shel at ; D 385314 ; 1 / 11 /20 11) . 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 GAPs (i.e., soil moisture) for the fumigants . This document imp acts all of the soil fumigants including metam sodium/potassium and MITC.

6.0 Aggregate

- Risk Assessment

A cute and chronic aggregate

- risk assessment s w ere not previously performed for metam sodium, metam potassiu m, or MITC because no dietary and drinking water assessments were performed (see Section 3.0 and 4.0 above)

.

Conclusions : A cute and chronic aggregate risk assessment s are not anticipated during Registration Review.

7 .0 Occupational Exposure

The 2009 Amended RED required one MITC occupational exposure study for the conventional

sewer use of metam sodium. The registrants have submitted this study (MRID 48914201) and

based on HED’s review (D406497), the updated MITC occupational handler inhala tion riskMetam Sodium/Metam Potassium/MITC Registration Review Human

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### estimates for the metam sodium sewer use are all below HED’s level of concern (i.e., MOEs ≥
10 for acute scenarios and MOEs ≥ 30 for short

- term scenarios)

.

The 2009 Amended RED required the following occupational exposure studies for the

antimicrobial uses of metam sodium and metam potassium: Metam sodium handler dermal and inhalation exposure studies for liquid pour data for the wood pole treatment use. Metam sodium product use and a post

- application inhalation exposure stud y (e.g.,

expos ure to degradate MITC) for the sew age sludge and animal waste use.

Metam Potassium product use data and a post

- application inhalation exposure stud y (e.g. exposure to degradate MITC) for th e cooling water tower and industrial water purification facilit y uses

. The Agency has not received these studies at this time. Upon receipt of the se data, AD will review and incorporate these data during Registration Review.

There are four main categories of registered occupational uses of metam sodium/potassium,

incl uding the following : (1) use as an agricultural soil fumigant for all food, feed, and fiber crops; (2) use on golf course turf and for application to small areas of turf and soil; (3) use as a

root

- control agent in drains and sewers; and (4) use of metam p otassium as an antimicrobial for pulp and paper, recirculating cooling towers, and industrial water purification systems and use of metam sodium as an antimicrobial for remedial treatment of wood poles and treatment of sewage sludge and animal waste (onl y supported by one registrant). MITC itself is registered as an antimicrobial agent for remedial wood treatment. No new uses of these three active ingredients have been registered since the Amended RED was issued.

Occupational Handlers

Conventional Uses

There is potential for occupational handler dermal exposure to metam sodium/potassium and inhalation exposure to MITC to occur based on the registered conventional use s of metam sodium/potassium. The most recent HED document that analyzed the potential oc cupational handler risks to metam sodium/potassium and MITC is the 2009 risk assessment (Smith ; D 357118 ; 8 /30/200 9 ). HED assessed the short

- and intermediate

- term dermal exposure and the cancer exposure for two major uses of metam sodium/potassium, soil f umigation and sewer fumigation. HED also assessed both acute and short

- and intermediate

- term MITC inhalation exposure for two major uses of metam sodium/potassium, soil fumigation and sewer fumigation.

For soil fumigation, HED utilized surrogate data from the Pesticide Handlers E xposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF) to assess occupational handler dermal exposures to the soil fumigant uses of metam sodium/potassium in the 2009

assessm ent. These assessments were considered conservative because PHED and ORETF data

are based on non

- volatile chemicals while metam sodium/potassium can quickly break down to MITC. In many cases, short

- and intermediate

- term and cancer risks exceed ed HED’s l evel of

concern for the soil fumigant uses of metam sodium/potassium. HED also utilized a number of

MITC specific inhalation exposure studies to assess occupational handler inhalation exposures to

MITC in the 2009 assessment . These MITC studies examined a variety of tasks associated with soil fumigation such as loading and applying. In some cases, acute as well as short

- and

intermediate

- term risks exceed ed HED’s level of concern for MITC at baseline (MOEs < 10 for

acute and MOEs < 30 for short

- and inte rmediate

- term). Even with the addition of an organicMetam Sodium/Metam Potassium/MITC Registration Review Human

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### vapor respirator, some acute as well as short

- and intermediate

- term risks exceed ed HED’s level

of concern for MITC.

For sewer fumigation, HED utilized surrogate data from the Pesticide Handlers E xposu re Database (PHED) to assess occupational handler dermal exposures to the sewer fumigant use of

metam sodium in the 2009 assessment. These assessments were considered conservative

because PHED data are based on non

- volatile chemicals while metam sodium ca n quickly break down to MITC. In many cases, short

- and intermediate

- term and cancer risks exceed HED’s

level of concern for the sewer fumigant use of metam sodium

. HED also utilized two Australian

studies that measured inhalation exposure to MITC during the application of metam sodium to

sewers to assess occupational handler inhalation exposures to MITC in the 2009 assessment. The Registrants have since submitted an observational occupational sewer application MITC inhalation exposure study. Based on t he submitted study, the updated MITC occupational
handler inhalation risk estimates for the metam sodium sewer use are all below HED’s level of concern (i.e., MOEs ≥ 10 for acute scenarios and MOEs ≥ 30 for short

- term scenarios)

.

Antimicrobial Uses

Metam Sodium There is potential for occupational handler dermal and inhalation exposure to metam sodium based on the registered antimicrobial uses of metam sodium. Because of the short loading and/or application durations (i.e., minutes), handlers are not expe cted to be exposed to MITC from the registered antimicrobial uses of metam sodium . The most recent AD document that analyzed the metam sodium potential occupational handler risks to metam sodium is the 2008 risk assessment (Leighton and Walls; D 335651; 2/ 14/2008).

The 2008 metam sodium occupational assessment assessed the potential non

- cancer and cancer

handler risks for the wood pole and sewage sludge uses . The sewage sludge use did not result in

any non

- cancer dermal and inhalation or cancer risks of concern. The wood pole use resulted in

non

- cancer dermal and inhalation risks to the handlers did not exceed AD’s level of concern (i.e., all MOEs greater than 100). The cancer risks for the handlers are in the range of 2.2E

- 5 to 3.4E

6 for treating pol es. Additional label language was required on labels to mitigate the cancer risk. The RED lists the following risk mitigation measures:

- Plug the pre

- drilled holes immediately after applications;

- Do not treat structures/beams indoors; and

- Do not drill a n application hole through seasoning checks to apply product. If the hole intersects an internal void or rot pocket, redrill the holes farther up the pole into relatively solid wood.

AD will reassess the handler wood pole uses in R egistration R eview upon receipt and review of the handler exposure data required in the Amended RED data

.

Metam Potassium There is potential for occupational handler dermal and inhalation exposure to metam potassium based on the registered antimicrobial uses of metam potassium. Because of the short loading and/or application durations (i.e., minutes), handlers are not expected to be exposed to MITC from the registered antimicrobial uses of metam potassium. The most recent AD risk assessment for the RED analyzed the metam potass ium potential occupational handler risks is the 2008 risk assessment (L eighton and Walls; 2/14/2008).Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 11 of 27 

### The 2008 metam potassium occupational assessment assessed the potential non

- cancer and

cancer handler risks for the recirculating cooling water (closed m ixing/loading scenario) and industrial water sewage use of metam potassium (closed mixing/loading scenario). These uses did not result in any non

- cancer dermal and inhalation or cancer risks of concern.

MITC Although MITC has a high vapor pressure ; based on the product formulation (solid form), product packaging (enclosed in an aluminum rod), application method (injected then capped), required PPE, and duration of handling the product the potential for MITC handler dermal or inhalation exposure is n egligible. A s a result, a quantitative risk assessment was not conducted

for the Amended RED and is not anticipated to be needed for Registration R eview.

Occupational Post

- Application

Conventional Uses

HED previously determined there were MITC inhalation risk concerns for workers reentering metam sodium/potassium 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 restrictio ns, HED believes that risks to reentry workers will not exceed the

HED ’s level of concern

.

HED does not expect occupational post

- application inhalation exposure to MITC to occur from the sewer fumigant use of metam sodium

.

Antimicrobial Uses

There is po tential for occupational post

- application inhalation exposure to MITC from the metam sodium sewage sludge use and the metam potassium industrial water purification system and recirculating cooling tower uses . No post

- application exposure is expected to result for the remedial wood treatment uses because the treated holes in the wood are capped/plugged and contact with treated poles occurs infrequently. Upon receipt of the product use data and the MITC (from met am sodium and metam potassium uses) post

- application inhalation exposure

data requested as part of the Amended RED, AD will review and incorporate these data during Registration Review

.

Conclusions: The occupational exposure database is adequate to suppo rt the Registration Review process for the conventional uses of metam sodium/potassium and MITC

. HED will review and incorporate the submitted metam sodium sewer fumigant study during Registration

Review. HED may be required to u pdate the occupational ha ndler assessments during Registration Review if the points of departure (PODs) or uncertainty factors (UFs) for the occupational exposure assessment change based on the toxicological data required as part of the

2009 Amended RED.

The occupational exposure database is adequate to support the Registration Review process for

the antimicrobial uses of metam sodium/potassium and MITC except for the outstanding product use and handler and post

- application exposure studies required in the 2009 Amended RED

. Upon receipt of the requested data, AD will review and incorporate the stud ies during Registration Review. AD may be required to u pdate the occupational handler and post

application assessments during Registration Review if the points of departure (PODs) orMetam Sodium/Metam Potassium/MITC Registration Review Human

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Page 12 of 27 

### un certainty factors (UFs) for the occupational 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 metam sodium, metam potassium and MIT C incident reports was recently prepared by HED ( Recore and Evans, D414492, 08/29/2013 )

. 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 s metam sodium, metam potassium and MITC

. Metam sodium, metam potassium and MITC are not inclu ded 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 Rodentici de 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. Rep orts 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 A ggregate IDS , from January 1, 200 8 to February 19, 2013, there were eight reported

incident s involving metam sodiu m, one reported incident involving metam potassium, and three reported incident s involving MITC

. These incidents were classified as minor severity. For the

M ain IDS, from January 1, 200 8 to February 19, 2013, there were five reported incident s involving metam sodium, one reported incident involving metam potassium, and one reported

incident involving MITC for the single chemical s only in the database. All of these incidents

w ere classified as moderate severity . There w as one additional incident for meta m sodium that

was reported as involving more than one chemical.

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 Depar tment of Labor workers’ compensation claims when reported by physicians, reports from State Departments of Agriculture, and physician reports to state Departments of Health. Although both occupational

and non

- occupational incidents are included in the data base, SENSOR

- Pesticides focuses on occupational pesticide incidents, and is of particular value in providing that information. The state coordinator at the 11 respective state Departments of Health conducts case follow

- up activities such as obtaining medi cal records to verify symptoms and severity. Using standardized protocol and case definitions derived from poison center reporting, the state SENSOR

- Pesticide

coordinator enters the incident information into the state

- based system which is sent to NIOSH

a nnually to be aggregated.

A query of SENSOR

- Pesticides 1998

- 2009 identifies 136 cases ( stemming from 60 events) for metam sodium, 3 cases (stemming from 3 events) for metam potassium, and two cases (stemming from two events) for MITC. Almost all of thes e cases were involved a single activeMetam Sodium/Metam Potassium/MITC Registration Review Human

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Page 13 of 27 

### ingredient. Most of these cases were classified as low severity, some were moderate severity, and a few were high severity.

Based on the number of incidents reported for these chemicals, the effects noted in the in cidents

, and the recently implemented safety measures put into place in 2012 f or all soil fumigant pesticides ; metam sodium, metam potassium, and MITC warrant further incident analysis during Registration R eview . This further analysis will include reviewi ng metam sodium, metam potassium, and MITC incident data from other sources as well as cases studies and a medical

literature search on human health effects of metam sodium, metam potassium, and MITC

.

9 .0 Tolerance Assessment and International Harmonizati on

There are currently no tolerances for metam sodium

, metam potassium

, 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 metam sodium/potassium and MITC 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/guida nce/justice/eo12898.pdf). The OPP typically considers the highest potential exposures from the legal use of a pesticide when conducting human

- health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricu ltural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk

estimates are based on the best available information.

11.0 Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to metam sodium, m etam potassium, or MITC and any other substances. For the purposes of this

assessment , therefore, EPA has not assumed that metam sodium, metam potassium, or MITC has a common mechanism of toxicity with other substances. For information regarding EPA’s eff orts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedur es for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

12.0 Endocrine Disruption

As required by the Federal Insecti cide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute,

subchronic and chro nic 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 or ganMetam Sodium/Metam Potassium/MITC Registration Review Human

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Page 14 of 27 

### 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, develo pmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision , 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), prometryn is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

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

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

chemical substance to interact with the est rogen, 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 whic h, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 in ert ingredients. Metam sodium, metam potassium, and MITC are not among the group of 58 pesticide active ingredients

on the initial list to be screened under the EDSP. Accordingly, as part of Registration R eview,

EPA will issue future EDSP orders/data cal l

- ins, requiring the submission of EDSP screening assays for prometryn. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please vi sit our website: http://www.epa.gov/endo/

.

1 3 .0 Human Studies

Past metam sodium/potassium and MITC risk assessments rely on an intentional do s ing 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 meeting . 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 metam sodium/potassium and MITC risk assessments also rely in part on data from studies in which adult human subjects were in tentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, 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 convincing evidence that the conduct of any of them was either fundamentally unethical or significantly defici ent relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued

reliance on these studies.Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 15 of 27 

### 1 4 .0 Risk Assessment Updates and Data Deficiencies

The occupational and residential exposure database for metam sodium, metam potassium, and MITC is adequate for Registration Review with the exception of an ambient air study measuring MITC from soil fumigant applications and a number of antimicrobial occupational handler and
post

- application exposure studies required in the 2009 Amended RED

. The registrants have completed and submitted a field volatility study for c enter pivot applications (conventional soil fumigation use) and a sewer treatment occupational exposure study required for metam sodium as part of the 2009 Amended RED. In addition, the Agency requests that a shank injection tarped, bedded application flu x study be completed. The Agency will review and incorporate all

of these studi es during Registration Review.

The Agency anticipates conducting the following risk assessment updates during Registration

Review: Toxicology:

o Reevaluation of the toxicity en dpoint/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 handler risk assessments 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 Revised AD occupational post

- application risk assessments 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 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 resul ts in changes to the endpoints.

1 5 .0 References

Memoranda Relevant to Registration Review.

Author Barcode Date Title

S. Kinard D293347 9/30/2003 Metam

- sodium. Residue Chemistry Chapter for the

Metam

- sodium Reregistration Eligibility Decision (RED) Document.

T. Leighton and

C. Walls D 335651 2/14/2008 Metam Sodium: Revised Occupational and Residential Exposure Assessment of Antimicrobial Uses for the Reregistration Eligibility Decision Document. PC Code 039003 (Metam Sodium) and 068103 (MITC).

C. Smith D357118 8/30/2009 Metam Sodium: Third Revision of the HED Human

Health Risk Assessment.

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 Practi ces and Associated Buffer

Credits

S. Shelat D406930 2/26/2013 The Health Effects Division’s Review of the Metam TaskMetam Sodium/Metam Potassium/MITC Registration Review Human

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Page 16 of 27 Memoranda Relevant to Registration Review.

Author Barcode Date Title Force Request for a Waiver for 2012 Methyl Isothiocyanate Ambient Air Monitoring Study (GDCI

039003

- 840)

S. Recore and E.

Evans D414492 08/29/2013 Metam Sodium, Metam Potassium, MITC: Review of

Human Incidents

S. Shelat D406497 9/4/ 2013 Metam Sodium: Second Addendum to the Third Revision

of the HED Human Health Risk Assessment and The

Health Effects Division’s Review of the “Observational Study to Determine Inhalation Exposure to Workers Treating Municipal Sewers Using SANAFORM VAPOROOTER II Foam Root Inhibitor” (dated 15 August 2012)



### Attachments: Attachment 1: Chemical Identity Table.

Attachment 2: Metam Sodium/Potassium and MITC Acute, Subchronic, and Chronic Toxicity Profile

Attachment 3: Metam Sodium/Potassium and MITC Endpoint Selection Tables.Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 17 of 27 

### Attachment 1: Chemical Identity Table

.

Physical and Chemical Properties of Metam Sodium, Metam Potassium, and MITC

Parameter Metam Sodium Metam Potassium MITC

Mode of Pesticidal Action generates MITC 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 yellow to light yellow

- green in solution yellow to light yellow

- green (aqueous formulation (54%) 1 ) colorless crystalline solid

Melting Point N/A N/A 35

- 36° C Vapor Pressure 4.31 x 10
- 4 mm of Hg 24 mm of Hg at 25° C (aqueous formulation (54%) 1 ) 20 mm of Hg at 25° C

Solubility in Water 578.29 g/L at 20° C yes, insoluble in mineral oil 8.94 g/L at 20° C

1 Data for the aqueous formulations MPs/EPs have been accepted because of the difficulties encountered in producing and maintaining aqueous solutions containing higher concentrations of active ingredient.Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 18 of 27 

### Attachment 2: Metam Sodium/Potassium and MITC Acute, Subchronic, and Chronic Toxicity Profile (as of May 2013)

Attachment 2A . Acute Toxicity Data on Metam Sodium/Metam Potassium

Guideline

No. Study Type MRIDs # Results Toxicity Category

81

- 1 Acute Oral

- Rat 41277002 LD 50 =7 80 mg/kg (male rats) 845 mg/kg (female rats) III

81

- 2 Acute Dermal

- Rat 41277003

41286005 LD 50 = >2020 mg/kg III

81

- 3 Acute Inhalation

- Rat 41277004 LC 50 = 2.27 mg/L III

81

- 4 Primary Eye Irritation 41277005 No corneal/iris involvement; all irritation was absent by 7 days; Slight irritation III

81

- 5 Primary Skin

Irritation

- Rabbit 41277006 non

- irritating to the skin of

male rabbits IV

81

- 6 Dermal Sensitization 43457705 Positive for sensitization in guinea pigs



### Attachment 2B . Acute Toxicity Data on MITC

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 conjunctivae I

81

- 5 Primary Skin Irritation 00162329 all animals died within one

hour I

81

- 6 Dermal Sensitization 459194101 positive for sensitization in guinea pigMetam Sodium/Metam Potassium/MITC Registration Review Human

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Page 19 of 27 

### Attachment 2C . Subchronic, Chronic, and Other Toxicities on Metam Sodium /Metam Potassium and MITC

Guideline No./ Study Type Metam Sodium /Metam Potassium MITC

MRID No. (year)/

Classification /Doses Results MRID No. (year)/ Classification

/Doses Results

870.3100

90

- Day oral toxicity rodents (rat) 42117302 (1991) Unacceptable/guideline 0, 0.018, 0.089, 0.443 mg/mL M: 0, 1.7, 8.1, 26.9 mg/kg/day F: 0, 2.5, 9.3, 30.6 mg/kg/day NOAEL = 1.7M/ 2.5F mg/kg/day LOAEL = 8.1M/9.3 F mg/kg/day based on hematology and decrease

absolute body weight. Not available

870.3100

90

- Day oral toxicity rodents (mouse) 42117301 (1991) Unacceptable/guideline 0, 0.018, 0.088, 0.35, and 0.62 mg/ml M: 0, 2.7, 11.7, 52.4, and 78.7 mg/kg/day F: 0, 3.6, 15.2, 55.4, and 83.8 mg/kg/day NOAEL = 0.018 mg/mL; 2.7M/3.6 F mg/kg/day LOAEL = 0.088 mg/mL; 11.7 M/15.2 F mg/kg/day based on urinary bladder lesions (eosinophilic granules, cystitits and mucosal hyperplasia) in both sexes and decrease in hematological parameters (hemoglobi n, RBC, hematocrit) in female Not available

870.3150

90

- Day oral toxicity in nonrodents (dog) 42600001 (1992) Unacceptable/guideline 0, 1, 5, and 10 mg/kg/day NOAEL = < 1 mg/kg/day LOAEL = 1 mg/kg/day based on increase in plasma ALT, AST, and alkaline phosphatase, as well as increase incidence of biliary duct proliferation with inflammatory

cell infiltration. Not available

870.3200

21/28/30

- Day dermal toxicity 41106204 (1979) Unacceptable/guideline Methods unacceptable 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.

870.3200

21/28/30

- Day dermal toxicity Not available 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 dosesMetam Sodium/Metam Potassium/MITC Registration Review Human

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Page 20 of 27 Guideline No./ Study Type Metam Sodium /Metam Potassium MITC

MRID No. (year)/

Classification /Doses Results MRID No. (year)/ Classification

/Doses Results

870.3250

90

- Day dermal toxicity Not available Not available

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). Systemic 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).Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 21 of 27 Guideline No./ Study Type Metam Sodium /Metam Potassium MITC

MRID No. (year)/

Classification /Doses Results MRID No. (year)/ Classification

/Doses Results

870.3465

90

- Day inhalation toxicity 00162041 (1983) Acceptable/guideline 0, 6.5, 45 and 160 mg/m 3 NOAEL = 6.5 mg/m 3 ; 1.11 mg/kg/day LOAEL = 45 mg/m 3 ; 7.71 mg/kg/day based on histopathological changes in the nasal passages (i.e., mucigenic hyperplasia) and changes in clinical chemistry. 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

increased water intake.

870.3465

90

- Day inhalation toxicity (rats) 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)

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 42983701 (1993) Acceptable/guideline 0, 5, 20, or 60 mg/kg bw/day Maternal NOAEL = 5 mg/kg/day LOAEL = 20 mg/kg/day based on reduced body weight gain and decreased food consumption. Developmental NOAEL =5 mg/kg/day LOAEL = 20 mg/kg/day based on

the increased incidence of skeletal

observat ions and the increase in total resorptions and resorptions/dam. 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).Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 22 of 27 Guideline No./ Study Type Metam Sodium /Metam Potassium MITC

MRID No. (year)/

Classification /Doses Results MRID No. (year)/ Classification

/Doses Results

870.3700a Prenatal developmental

in rodents 41577101 (1987) Acceptable/guideline 0, 4.22, 16.88, and 50.64 mg/kg/day Maternal NOAEL = 4.22 mg/kg/day LOAEL = 16.88 mg/kg/day based on reduced body weight gain and decreased food efficiency. Developmental NOAEL = 4.22 mg/kg/day LOAEL = 16.88 mg/kg/day based

on the increased incidence i n postimplantation loss and decrease

in the % of live fetuses/dam. 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. Developme ntal 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 (rabbits) 42963101 (1991)

Acceptable/guideline 0, 5, 20, and 60 mg/kg/day Maternal NOAEL = 5 mg/kg/day LOAEL = 20 mg/kg/day based on the reduced body weight gain, reduced food consumption and food efficiency. Developmental NOAEL = 5 mg/kg/day LOAEL = 20mg/kg/day based on

the increased incidence of skeletal

observations. 45919418 (19 86) 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/day

40330901 (1987) Unacceptable/guideline 0, 4.22, 12.66, 42.2 mg/kg/day Numerous deficiencies

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)Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 23 of 27 Guideline No./ Study Type Metam Sodium /Metam Potassium MITC

MRID No. (year)/

Classification /Doses Results MRID No. (year)/ Classification

/Doses Results

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 t he respiratory tract and stomach, decreased body weight gain, and decreased food consumption. Developmental NOAEL = ≥50 ug/L (HDT)

870.3800 Reproduction and fertility effects 43136101 (1993) Acceptable/ guideline 0, 0.01, 0.03, 0.1 mg/mL M: 0, 1.2, 3.2, or 11.5 mg/kg/day F: 0, 1.8, 3.9, or 13.5 mg/kg/day Parental/Systemic NOAEL = 3.2 M/ 3.9 F mg/kg/day

LOAEL = 11.5M/ 13.5F mg/kg/day based on pathology of Bowman’s gland duct and olfactory epithelium. Reproductive NOAEL = 11.5M/13.5F mg/kg/day

LOAEL =11.5M /13.5F mg/kg/day (HDT). Offspring NOAEL = 3.2M/ 3.9 F mg/kg/day

LOAEL = 11.5M/ 13.5F mg/kg/day based on decrease pup weight. 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, 3.4M/ 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 See combined chronic/carcinogenicity See combined chronic/carcinogenicity

870.4100b Chronic toxicity dogs 43275801 (1994) Acceptable/guideline 0, 0.05, 0.1, and 1.0 mg/kg/day NOAEL =1M/ 0.1F mg/kg/day LOAEL >1 M/ 1 F mg/kg/day,

based on increased ALT and microscopic changes in the liver in

females. 41240701 (1988) Unacceptable/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.Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 24 of 27 Guideline No./ Study Type Metam Sodium /Metam Potassium MITC

MRID No. (year)/

Classification /Doses Results MRID No. (year)/ Classification

/Doses Results

870.4300

Combined Chronic/ Carcinogenicity rats 43275802 (1994) Acceptable/guideline 0, 0.019, 0.056, and 0.19 mg/mL M: 0, 1.3, 3.9, and 12.0 mg/kg/day F: 0, 2.3, 6.2, and 16.2 mg/kg/day NOAEL = 0.056 mg/mL LOAEL =0.19 mg/mL based on the changes in body weight gain, food efficiency, hematologic and clinical

chemistr y alterations, and macro

and microscopic abnormalities

observed at this dose in both sexes. 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 43233501 (1994) Acceptable/guideline 0, 0.019, 0.074, and 0.23 mg/mL M: 0, 1.6, 6.5, and 27.7 mg/kg/day F: 0, 2.3, 8.7 and 29.9 mg/kg/day NOAEL = 1.6 M/ 2.3 F mg/kg/day LOAEL = 6.5 M/ 8.7F mg/kg/day based on significant increase in liver weight, and decrease body weight gain, food and water consumption in male and female

mice. Evidence of carcinogenicity 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 throughout the majority of the study and

reduced wat er consumption.

870.5100

Reverse Gene Mutation

– Salmonella typhimurium 40305602 (1987) Acceptable/guideline 0, 20, 100, 500, 1000, 1500, 2000, and 2500 μg/plate +/

- S9 (standard plate test) 0, 4, 20, 100, 200, 300, 400, 500, 1000, and 2500 μg/plate +/

- S9 (pre

- incubation test) Not mutagenic at any concentration

+/

- S9. 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

concentration s (500 and 1000 μg/disc +/

- S9)

870.5375

Chromosome Aberration

– mammalian cells 40305604 (1987) Acceptable/guideline 0, 1, 5, 10, and 20 μg/mL

- S9; 0, 10, 20 and 40 μg/mL+S9 Positive in human lymphocytes

– S9 at concentrations causing severe cytotoxicity. Positive +S9 at 20 and 40 μg/mL; predominant type of aberration =

chromatid breaks 41221411 (1988) Acceptable/guideline 0, 3.0 & 5.0 μg

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

- /+S9)

870.5385

Mammalian bone marrow cytogenetic assay in Chinese

hamsters 40305605 (1987) Acceptable/guideline 0, 150, 300, and 600 mg/kg Negative Not available

870.5395 Micronucleus Assay

– Mice Not available 48631101 (2011) Acceptable/guideline 0, 20, 40, and 100 ppm (inhalation) Negative up to a toxic concentration (100 ppm)Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 25 of 27 Guideline No./ Study Type Metam Sodium /Metam Potassium MITC

MRID No. (year)/

Classification /Doses Results MRID No. (year)/ Classification

/Doses Results

870.5500 Bacterial DNA damage or repair tests

—

Bacillus

subtilis rec assay 40305602 (1987) 0, 0.1, 1.0, 5.0, 10.0, 25.0, 50.0, 100.0, and 150.0 μL/plate +/

- S9; Preferential cytotoxicity not induced at any concentration 41221410 (1978) Unacceptable 0, 20, 100, 200, 500, 1000, and 2000 μg/disc

– S9 Negative

870.5550

Unscheduled DNA Synthesis

- Rat Hepatocytes 40305601 (1987) Acceptable/guideline 0, 0.5, 1.0, 2.5, 5.0, 10.0, 50.0, 100.0, and 250.0 nL/mL Negative up to cytotoxic concentrations (100 nL/mL) 00150072 (1985) Unacceptable Negative up to 15.2 μg/mL

870.5900

In vitro sister chromatid exchange

- Chinese hamster V79 lung fibroblasts Not available 41221412 (1988) Acceptable/guideline 0, 0.1, 2.0 or 3.5 μg/mL

– S9 0, 0.1, 2.5 or 5 μg/mL +S9 Negative up to the highest dose

tested

870.6200a Acute neurotoxicity screening battery 42977802 (1993) Acceptable/guideline 0, 22, 324, and 647 mg/kg NOAEL = < 22 mg/kg LOAEL = 22 mg/kg based on reduced ambulatory and total motor activity observed in male and female rats on day 0, 45 minutes post

- dosing. Not available

870.6200a Acute neurotoxicity screening battery inhalation (rats) Not available 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

ti me. Systemic/Neurotoxic NOAEL = 20 ppm (0.06 mg/L) LOAEL = 40 ppm (0.12 mg/L, based 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 43248801 (1994) Acceptable/guideline 0, 0.02, 0.06,and 0.20 mg/mL M: 0, 1.4, 5.0, and 12.8 mg/kg/day F: 0, 2.3,7.0 and 15.5 mg/kg/day NOAEL = 1.4 M/ 2.3F mg/kg/day

LOAEL = 5.0 M/ 7.0 F mg/kg/day based on decreased body weight gain for male and

female rats. Not availableMetam Sodium/Metam Potassium/MITC Registration Review Human

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Page 26 of 27 Guideline No./ Study Type Metam Sodium /Metam Potassium 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 42670301 (1992) Acceptable/guideline 0.1, 1, 10 mg/rat Mean absorbed at 10 hours =

2.52% Not available

870.7800 Immunotoxicity

28

- day Inhalation

mice Not required 1 48694901 (2011) Acceptable/guideline 0, 1, 3 or 10 ppm (0, 3, 9 or 30 μg/L 6 hrs/day for 28 days 10 female mice/group Systemic: NOAEL = 10 ppm (highest dose tested).

LOAEL = Not established.

Immunotoxicity: NOAEL = 10 ppm (highest dose tested). LOAEL = >10 ppm 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 th e 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

1 HED’s Hazard and Science Policy Council (HASPOC) has determined that an Immunotoxicity study is not required for metam sodium/metam potassium ( A. Dunbar ; 5 / 22 /13;

TXR 0056665 ).Metam Sodium/Metam Potassium/MITC Registration Review Human

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Page 27 of 27 

### Attachment 3: Metam Sodium/Potassium and MITC Endpoint from 2009 Risk

Assessment

.

Summary of Toxicological Dose and Endpoints for Use in Metam Sodium/Potassium

Occupational Dermal Human Health Risk Assessments

Exposure

Scenario Dose Used in Risk Assessment Uncertainty Factors and

Level of Concern for

Risk Assessment Study and Toxicological Effects

Dermal

Short

- Term (1

- 30 days) Occupational Maternal NOAEL a,d = 4.22

mg/kg/day

Dermal absorption factor = 2.5% Occupational = LOC for

MOE = 100 b,c Developmental toxicity in rat (MRID 41577101)

LOAEL e = 16.88 mg/kg/day based on reduced body weight gain and decreased food efficiency in

maternal rats

Dermal

Intermediate

- Term (1

- 6 Months) Occupational Oral NOAEL a,d = 0.1 mg/kg/day

Dermal absorption factor = 2.5% Occupational = LOC for

MOE = 100 b,c Chronic toxicity in dog (MRID 43275801)

LOAEL e = 1 mg/kg/day based on increased ALT and microscopic changes in the liver in females.

Cancer Classification: Probable human carcinogen (B2)

Q1* = 1.98x10

- 1 in human equivalents converted from animals

a Since an oral NOAEL was selected, a dermal absorption factor of 2.5% should be used in route

- to

- route extrapolation.; b Margin of Exposure (MOE) = 100 [10x for interspecies extrapolation and 10x for intraspecies variations.]; c LOC = level of concern; d NO AEL = no observed adverse effect level; e LOAEL = lowest observed adverse effect level.

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

Human 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 occurring 5 days per week

.