UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION
MEMORANDUM
DATE: 19 March2013
SUBJECT: Monsodium Methanearsonate (MSMA): REVISED Registration Review Scoping Document for Human Health Assessments.
PC Code: 013803 Decision No.: 471553 Petition No.: None DP Barcode: D410082 Registration No.: NA Regulatory Action: Registration Review Reregistration Case No.: 2395 Assessment Type: Single ChemicaV Aggregate TXRNo.: None CAS No.: 2163-80-6 MRID No.: None 40 CFR: §180.289
FROM: Donald Wilbur, Chemist

# ~ 

# W 1JJf::: 3 

# 0**1(~**\3 Nancy McCarroll, Ph.D., Senior

# Toxicologis;**--~, lite~**  .Jff 

# )l() I j Shalu Shelat, Industrial Hygienist Risk Assessment Branch VI Health Effects Division (7509P)


### THROUGH: Anna

# Lo.::::t, Ph.D., Senior Toxicologist

# 1--t2.:J-**3ft~** 1z•l3
Felecia Fort, Chief**~** _ 

# r Risk Assessment Branch VI · 

### .e-r**~(fz_ ~**  Health Effects Division (7509P)

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### U
TO: Garland Waleko, Chemical Review Manager Tom Myers, Team Leader Risk Management and Implementation Branch II Pesticide Re-Evaluation Division (7508P)

The Health Effects Division (HED) Monosodium Methanearsonate (MSMA) Registration Review Team has evaluated the status ofthe human health risk assessment for MSMA 

### to determine the scope ofwork necessary to support Registration Review. The most recent risk assessment for MSMA was completed in 2006 (C. Smith, D329694, 06/2112006) as part ofthe Reregistration Eligibility Decision (RED) which was also published in 2006. This document was revised to clarify residue chemistry data requirements.

Page 1 of22Background MSMA is a salt ofthe weak acid monomethylarsinic acid (MMA), which can also be called methanearsonic acid or methylarsonic acid (MAA). MSMA readily dissociates to MMA in water and, therefore, the majority ofthe exposure from the application of MSMA is to MMA. Dimethylarsenic acid (DMA), also known as cacodylic acid, is a major MSMA metabolite in plants. In addition, organic arsenical species can convert to inorganic arsenic (iAs) in both soil and water. HED understands that over time, and depending on the environmental conditions present, organic arsenical pesticides will biotransfonn by both methylation and demethylation. Since environmental conditions are variable, it is difficult to quantify organic versus inorganic arsenic residues at any specific point in time. Therefore, HED will evaluate exposure to MMA, DMA, and inorganic arsenic (iAs) in the MSMA risk assessment.
Based on the scientific findings in the 2006 RED, EPA concluded that all uses ofthe organic arsenical pesticides (MSMA, disodium methanearsonate (DSMA), calcium acid methanearsonate (CAMA), and dimethylarsenic acid (DMA)) were ineligible for reregistration based largely on the fact that following application, they can convert to more toxic iAs in the soil and can therefore potentially contaminate drinking water through soil runoff. It was also assumed that due to the MSMA use on cotton and its associated animal feed items, residues ofinorganic arsenic could be present in the meat and milk ofanimals that consumed these treated feed items and thus, increase the aggregate human dietary exposure and risk.

In January and February 2009, EPA reached an agreement in principle with the technical registrants ofall existing organic arsenical manufacturing-use products to eliminate, phase out, and/or modify certain uses. The result ofthis agreement was the EPA issuance ofa revised RED in April 2009 and a cancellation order in September 2009 that terminated the last remaining uses ofDSMA, CAMA, and DMA in the United States based on voluntary cancellations requested by the registrants. The order also tenninated certain MSMA product registrations and amended others (decreased rates and/or limited applications) to phase out all uses except cotton, sod farms, golfcourses, and highway rights-ofway; with the later three slated to be phased out by December 31, 2013.
The 2009 agreement in principle also provided for a scientific peer review related to the carcinogenic mode ofaction (MOA) ofiAs prior to the final cancellation ofthe remaining MSMA uses. OPP was initially considering use ofa joint review by the EPA Science Advisory Board (SAB) and the FIFRA Science Advisory Panel (SAP). However, since that time, the Agency has announced review of iAs by the National Academy ofSciences (NAS) 1 to be used 

### in lieu ofan SAB/SAP review. Therefore, EPA has agreed to postpone any decision regarding the phase out ofuses on golfcourses, sod farms, and highway rights-of-way until such time that the NAS review is complete and the Agency has analyzed and responded to the report. Additionally, in order for the MSMA use on cotton to be eligible for reregistration, the agreement required that certain mitigation measures be implemented to protect water

1 Additional information regarding the NAS review is available at: http:// www8.nationalacademies.org/cp/projectview

.aspx?key=49483 and http://dels.nas.edu/Study-ln-Progress/Review-IRJS-Toxicologicai/DELS-BEST-12-0I Page2 of22resources. These mitigation measures include: use limited to only two post-emergent applications per year of2 pounds active ingredient per acre and maintenance ofa 50·foot buffer zone around permanent water bodies. The registrants were also required to submit data indicating that residues of iAs will not enter the human food supply through the meat and milk ofanimals fed cotton by·products (undelinted seed, hulls, and/or gin trash). The Organic Arsenicals Product Task Force (OAPTF) prepared multiple submissions to the Agency in an attempt to demonstrate that no increased residues ofiAs would be present in the meat and milk ofcows. HED reviewed these data and concluded there is sufficient evidence to determine that the exposure ofcows to seeds from cotton treated with MSMA, at the rate permitted by the label, is not expected to cause an increase in the inorganic arsenic concentration in milk or tissues 

### (D. Wilbur, 0387095, 06/30/2011).
Please see http://www.epa.gov/pesticides/reregistrationlorganic arsenicals fs.html for additional details regarding the agreement in principle as well as the background ofthe organic arsenical mitigation process.
Executive Summary MSMA is a post-emergent organic arsenical herbicide which selectively controls certain weeds including Palmer amaranth. MSMA is currently registered for use on cotton, golf courses, sod farms, and highway rights-of-way. Based on these registered uses, exposures to MSMA may potentially occur via the dietary (food and drinking water), occupational (handler and post-application), and residential (post-application) exposure pathways and through the oral, dermal, and inhalation routes ofexposure.
Since MSMA readily dissociates to MMA, HED uses toxicity data for MMA to represent MSMA. The toxicity database for MMA is nearly complete with the exception ofan imrnunotoxicity study which is required in accordance with new data requirements for conventional pesticide registration ( 40 CFR Part 158). The toxicity database for DMA via the oral route is adequate. During the registration review process, HED will reevaluate the points ofdeparture (PODs), uncertainty factors (UFs), and safety factors (SFs) for the dietary, occupational and residential exposure assessments. Additionally, HED will reevaluate the carcinogenic mode ofaction (MOA) for iAs based on the findings ofthe NAS review as discussed above.
The existing residue chemistry database for MSMA is complete and adequate for risk assessment purposes with the exception oftwo outstanding residue chemistry studies: field accumulation in rotational crops (which was previously requested in 2010) and field trial (residue) data on cotton gin byproducts. The qualitative nature ofthe residue(s) of MSMA in plants and animals has been adequately identified/characterized and is understood. The residues ofconcern in plants for tolerance enforcement and risk assessment are MSMA and DMA. HED previously determined that there is no reasonable expectation of finite residues in animal commodities. The current tolerance expression as listed in the 40 CFR§180.289(a) will need to be revised during the registration review process to reflect product cancellations due to mitigation measures from the 2006 RED and subsequent agreements with the registrants.
The dietary exposure database is adequate to support the existing registrations. The only remaining food use is on cotton (via animal feed by·products). Since exposure from Page 3 of22drinking water will likely be the highest contributor to dietary risk, and iAs is the most prevalentlbioavailable species in water, new dietary exposure and risk assessments may be required during the registration review process to incorporate the findings ofthe NAS review ofiAs. No acute or chronic (noncancer) risks ofconcern were identified in the 2006 dietary assessment (S. Kinard, D329695, 06/21/2006) due to exposure to MSMA (MMA) or DMA. Cancer risks ranging from l.OE-06 to 1.0E-04 were identified when data from the FDA Total Diet Study (TDS) were aggregated with drinking water estimated concentrations. In addition to using updated drinking water estimates, any updated dietary exposure assessments will incorporate current consumption information, updated residue values, updated percent crop treated information, and any revised PoDs or uncertainty factors.
The residential exposure database is complete. A revised residential exposure assessment may be required under registration review that includes post-application exposure to adults and children entering into previously treated golfcourses. This assessment should incorporate the 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, updated human factors (e.g., body weight) assumptions, and the appropriate
uses patterns that are registered at the time ofregistration review.
The most recently completed aggregate risk assessment was conducted in connection with the 2006 RED. An updated non-occupational (residential) assessment may be

.required as use patterns have changed. It is also possible that additional data may be provided with which to update the drinking water assessment. Consequently, a revised aggregate risk assessment for MSMA may be required for registration review.
The occupational exposure database is complete. Updated occupational handler and postapplication exposure assessments may be required under registration review based upon revisions to the Agency's scenario-specific surrogate handler exposure data and changes to the use pattern.


### Introduction HED has reviewed the most recent exposure and risk assessments for MSMA, as well as toxicity data, exposure and usage databases, and the latest Agency science policy and risk assessment methodologies to determine ifsufficient data are available and ifupdates are needed to support registration review. Additionally, the team conducted a screeninglevel literature search for any information that would aid in assessing human health risks from MSMA.
MSMA is a post-emergent organic arsenical herbicide which selectively controls certain weeds including Palmer amaranth. MSMA is currently registered for use on cotton, golf courses, sod farms, and highway rights-of-way.
Information on the chemical identity and physicochemical properties of MSMA is included in Attachment 1.


### Hazard ldentificationffoxicology Since the RED was completed in 2006, no additional guideline studies have been submitted to HED for MMA or DMA. Although a data gap exists for the MMA acute Page 4 of22and subchronic neurotoxicity battery, the Agency has granted waivers to these requirements (TXR #0056514 ). The remaining requirement for MMA that has not yet been satisfied is for immunotoxicity testing. The document entitled Evaluation of the Potential Carcinogenicity Due to Exposure to Inorganic Arsenic was submitted by OAPTF in March 2012. This docwnent, which consists ofstudies in support ofthe mode ofaction (MOA) analysis ofiAs-induced skin, urinary bladder and lung tumors will be part ofthe evaluation by the NAS. Toxicological Profile o(MMA & DMA The target organ following oral exposure ofMMA is the gastrointestinal tract, particularly the large intestine. Effects such as histopathology ofthe cecum, rectum, and/or colon were noted as the most sensitive effects in chronic rat studies. MMA is classified as a "not likely" human carcinogen and is not mutagenic or genotoxic. Target organs for DMA after oral exposure are the urinary bladder and the thyroid. Bladder tumors are found in rats ofboth sexes but not in mice. Nevertheless, genetically engineered mouse strains, constructed for enhanced sensitivity to specific tumors types, showed neoplastic lesions. The mode ofaction (MOA) for the DMA-induced rat bladder tumors is cytotoxicity associated with regenerative cell proliferation.
In the last risk assessment, the default uncertainty factor of 1 OOX (IOX for intra-species; lOX for inter species) was applied to all MSMA exposure scenarios. In the case of DMA, for oral exposures ranging from short-term to chronic duration, the last risk assessment included a reduction ofthe default IOX for inter-species (animal to human) extrapolation to 3X. This reduction is based on the known pharmacokinetic differences between rats and humans which include: differences in sequestration ofDMA111 by rat hemoglobin, longer retention time in rats versus humans or mice, and the increased urinary output in rats versus humans.
There is no quantitative or qualitative evidence ofincreased susceptibility of rats or rabbit fetuses to in utero exposure in available developmental studies for MMA or DMA; therefore, the FQPA safety factor was removed.
Conclusionsfor HazardIdentification/Toxicology The endpoints, PODs, and the uncertainty factors for MMA, DMA, and iAs will be reevaluated during registration review after consideration all ofthe currently available data including the NAS report regarding

.iAs. 

### Residue Chemistry The existing residue chemistry database for MSMA is complete and adequate for risk assessment purposes with the exception oftwo studies: field accumulation in rotational crops (which was previously requested in 20IO) and field trial (residue) data on cotton gin byproducts. The qualitative nature ofthe residue(s) ofMSMA in plants and animals has been adequately identified/characterized and is understood. The residues ofconcern in plants for tolerance enforcement and risk assessment are MSMA and DMA. HED previously determined that there is no reasonable expectation offinite residues in 

### animal commodities. Adequate analytical methods exist for data collection and tolerance enforcement. Adequate storage stability data exist. Adequate magnitude ofthe residue
Page 

### 5 of22data exist for cotton with the exception ofstudies listed above. HED had previously requested residue data on undelinted cottonseed. A review ofthe existing data (MRJD 43720701) indicates that HED does indeed have these data, and thus that deficiency can be considered resolved.
Conclusionsfor Residue Chemistry The residue chemistry database for MSMA is adequate for risk assessment purposes with the exception ofthe studies listed above. Field accumulation in rotational crops data are still outstanding from a previous data call-in (DCI), while residue data on cotton gin byproducts data have not been included in a previous DCI and are required. All other residue chemistry data requirements have been adequately addressed. 

### Dietary Exposure and Risks Acute and chronic dietary exposure and risk assessments for DMA and MMA resulting from food/feed uses ofcacodylic acid and salts, DSMA, and MSMA were conducted (S. Kinard, D329695, 06/21/2006) using the Dietary Exposure Evaluation Model (DEEMFCIDTM, Version 2.03) which used food consumption data from the USDA's Continuing Surveys ofFood Intakes by Individuals (CSFII) from 1994-1996 and 1998. All species ofconcern in the assessment (MMA, DMA, and iAs) have distinct toxicities; therefore exposure to each were considered individually.
Acute Dietary Exposure andRisk Several acute dietary assessments were performed for the organic arsenic pesticides using field trial data, FDA's Total Diet Study (TDS) data, percent crop treated information, and default processing factors. Since arsenic is ubiquitous in the environment and was quantified as total arsenic in the best available data, it was not possible to detennine where the arsenic originated from (i.e., background or from pesticidal use) or to determin e speciated residue values for use in a national dietary exposure assessment. Therefore, the assessments contained assumptions that were not standard for HED dietary exposure assessments. A number ofthe assumptions that have been made 

### inthese assessments may be conservative due to the lack ofspeciated data; however, when assuming that all arsenic found in the field trials, reported in the FDA TDS, and estimated in water is either monomethylated arsenic (MMA, resulting from DSMAIMSMA use) or dimethylated arsenic (DMA or cacodylic acid), risks were below HED's level ofconcern for the U.S. population and all population subgroups at the 99.9th percentile ofexposure.
Chronic Dietary Exposure andRisk Several chronic dietary assessments were performed for the organic arsenic pesticides using field trial data, FDA's TDS data, percent crop treated information, and default processing factors. Based on
. the same assumptions used for the acute analysis, risks were below RED's level ofconcern for the U.S. population and all population subgroups.
Cancer DietaryExposure andRisk A dietary cancer assessment for inorganic arsenic (iAs) was not performed. However, based on the MMA and DMA exposure assessments, HED determined that only a small amount ofthe total arsenic exposure would be required to be from iAs to reach a cancer level ofconcern of 1 x 1 

## o-6• The 

### Q 1

## * determined by EPA's Office ofWater for cancer risks from iAs exposure used in the analysis was 3.67. For additional information on iAs Page 6of22in drinking water, please go to EPA's Office ofWater website at http://www.epa.gov/safewater/arsenic/index.html. Drinking Water A drinking water assessment (K. Moore, 0309098, 02/0 112006) was conducted by the Environmental Fate and Effects Division (EFED). To determine estimated drinking water concentrations (EDWCs) in surface water, the Pesticide Root Zone Model (PRZM 3.12; 5/7 /98), which simulates transport offthe agricultural field, is run in tandem with the Exposure Analysis Modeling System, (EXAMS 2.98

.04; 6/13/97), which simulates the fate ofchemicals in the water body. EDWCs ofMMA, DMA, and iAs were provided for each registered use. Compounds resulting from degradation/transformation were considered as well as directly applied pesticides. It is impossible to determine the exact concentration ofeach species that will be present at any one time. Each species will reach its highest level at different times, and it is concentrations from these worst-case situations which were reported and used. It was not expected that the maximum concentrations for each compound would all be present at the same time.
Conclusi onsfor Dietary Exposure andRisks The dietary exposure database is adequate to support the existing registrations. However, since FDA TDS monitoring data were used, it may be necessary for HED to conduct new dietary exposure assessments based on a review ofthe existing data for MMA, DMA, and iAs. These new exposure assessments should include incorporating new and updated information and policies and any revised points ofdeparture or uncertainty factors, including any revised cancer MoA information based on the NAS review ofiAs. The revised assessment should also include updated consumption information and utilize the newest version ofDEEM-FCID along with incorporating any revised and updated drinking water estimates from EFED.


### Residential Exposure and Risk MSMA is currently registered for use on golfcourses, sod farms, highway rights-of-way, and cotton. Based on these uses, adults and children (6< 11 years old and 11 <16 years old) may be potentially exposed to MSMA as result ofcontacting treated golfcourse turf (i.e., residential post-application exposure). As noted before, MSMA dissociates to methanearsonic acid (MMA) when mixed with water; therefore, the toxicological endpoints for MMA will be used in the risk assessment for assessing handler and postapplication exposures.
In accordance with the updated Part 158 data requirements (2007), a turftransferable residue (TTR) study is required for all occupational (e.g. , sod farms, golf courses, parks , and recreational areas) or residential turfuses. The regi s trant has submitted one TTR study in support ofMSMA, titled Determination o[Transferable Residues from Turf Treated with Monosodium Methanearsonate (MRID No. 44958901). This TTR study has previously been used to assess post-application risk estimates for MSMA.
In the last occupational and residential exposure and risk assessment (C. Smith, D329694, 06/21/2006), residential handler and post-application exposure and risks were assessed for MSMA. At that time, MSMA was registered for lawn and residential ornamental uses which are not currently registered. The handler non-cancer risk Page 7 of22estimates did not exceed HED's level ofconcern (MOEs**~** 100). Post-application dermal exposure and risk estimates were assessed for adults, youths (11-12 years old), and toddlers (3 years old) along with incidental oral post-application risk estimates for toddlers (3 years old). The post-application non-cancer risk estimates·did not exceed HED's level ofconcern (MOEs**~** 100).
Since the 2006 HED risk assessment, the RED addressed mitigation measures involving residential exposure. In 2009, an amendment to the RED outlined the deletion of residential turfuse sites. The remaining registered uses include golfcourses, sod farms, highway right ofways, and cotton and ofthose uses, golfcourse applications have the potential to result in residential exposure. As part of the mitigation, the golfcourse use was to be prohibited after 12/31/13. However, EPA has agreed to postpone any decision regarding the cancellation ofuse on golfcourses until such time that the NAS review is complete and the Agency has analyzed and responded to the report. As part ofthe mitigation, golfcourse is prohibited after December 31, 2013 pending the NAS review.
Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may occur as a result ofapplications ofMSMA. The Agency is in the process of evaluating these types ofexposures and will examine the need for spray drift and volatilization assessments for MSMA during registration review.
Conclusionsfor Residential Exposure and Risks The residential exposure database is adequate to support the registration review process for MSMA. A revised non-cancer residential exposure assessment may be required under registration review that includes post-application exposure to adults and children exposure via commercially treated golfcourses. This assessment should incorporate, as necessary, the 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, updated human factors (e.g., body weight) assumptions, and the appropriate uses patterns that are registered at the time ofregistration review. 

### Aggregate Exposure and Risk Assessment Previous aggregate assessments for the MSMA were conducted for acute, short-term, and long-term durations. Even though many uses have been cancelled, there is still a potential for short-term residential post-application exposure from the use on golf courses. Therefore, an updated aggregate risk assessment may be required to support the registration review which incorporates any new PoDs, UF/SFs, any revisions to the drinking water assessment, as well as the findings from the updated non-occupational (residential) assessment. 

### Occupational Exposure and Risks The Agency 

### has determined that there is a potential for occupational handler and postapplication exposures resulting from the registered uses ofMSMA. As noted before, MSMA dissociates to 

### :rvtMA when mixed with water; therefore, the toxicological endpoints for MMA were used in the risk assessment for assessing handler and postapplication exposures.

Page 8 of22Occupational Handlers The 2006 occupational and residential risk assessment (C. Smith, D329694, 06/21/2006) evaluated a number ofoccupational handler scenarios that represented the major MSMA occupational handler scenarios based on application equipment and formulation type. Occupational handlers can be exposed to MMA by mixing, loading, or applying MSMA. The 2006 occupational assessment indicated that occupational handler scenarios did not result in risks ofconcern for inhalation exposure from registered uses ofMSMA (MOEs**~** 100). There were dermal exposure and risk estimates ofconcern at baseline PPE, however, all risk estimates were not ofconcern with the addition ofgloves (MOEs**~** 100).
Since the 2006 assessment, there have been changes to the registered use pattern and there is new unit exposure data available to assess occupational handler scenarios. Because ofthese changes, HED will likely reevaluate the occupational handler assessment for MSMA. Occupational Post-application Occupational post-application workers can be exposed to MMA by entering an environment that has been previously treated with MSMA. The 2006 assessment addressed occupational post-application exposures using default assumptions instead of chemical specific dislodgeable foliar residue (DFR) data. All post-application scenarios assessed for MSMA did not exceed HED's level ofconcern (MOEs**~** 1 00) at day 0. The restricted-entry interval was set to 12-hours for use ofMSMA based on the technical acute toxicity category III for acute dermal toxicity, primary eye, and skin irritation. MSMA is not a dermal sensitizer.
There are currently no site- or chemical-specific DFR data for MSMA. In the 2006 assessment, HED had used standard values for DFR and dissipation in the absence of data. Based on the MOEs presented for post-application exposure from application to cotton (MOEs range from 10,000 to 36,000) and the current guidance for requiring DFR studies, a chemical-specific DFR study is not required at this time.
Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment for MSMA is not required. However, volatilization ofpesticides may be a potential source ofpost-application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization ofpesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP's fmal report on March 2, 2010 (http://www.epa.gov /scipoly/SAP/meetings/2009/120109meeting.btml)

. The Agency is in the process ofevaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. Ifnew policies or procedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for MSMA.
Conclusions (or Occupational Exposure andRisks The occupational exposure database is complete. Updated occupational handler and postPage9 of22application exposure assessments may be required under registration review based upon revisions to the Agency's scenario-specific surrogate handler exposure dati and changes in the use pattern.


### Human Studies MSMA risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemicaL Studies such as the Pesticide Handlers Exposure Database, Outdoor Residential Exposure Task Force, and Agricultural Handler Exposure·Task Force have been reviewed by the Agency and found on the basis ofavailable evidence to have been neither fundamentally unethical nor significantly deficient relative to standards ofethical research conduct prevailing when they were conducted. There is no barrier in EPA's "Protection ofHuman Subjects" Regulation to reliance on these studies.


### Endocrine Disruption Screening Program As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments ofcarcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part ofits reregistration 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), MSMA is subject to the endocrine screening part ofthe Endocrine Disrupter Screening Program (EDSP).
EPA 

### has developed 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 ofa battery of 11 screening assays to identify the potential ofa chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage ofthe EDSP where EPA will determine which, ifany, ofthe 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 of67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. MSMA is not among the group of58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part ofregistration review, EPA will issue

2

- http:/ /www.epa.gov /pesticides/sciencelhandler-exposure-data.html Page 10 of22future EDSP orders/data call-ins, requiring the submission ofEDSP screening assays for MSMA. For further information on the status ofthe EDSP, the policies and procedures, the list of67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

. 

### Public Health and Pesticide Epidemiology Data An updated review ofMSMA incident reports was recently prepared by HED (S. Recore, 0406611, 11/01/2012). Based on the low frequency and mostly low severity ofincident cases reported for metheanearsonic acid, salts in both IDS and NIOSH SENSOR, there does not appear to be a concern at this time that would warrant further investigation. However, because there were three incidents in NIOSH SENSOR-Pesticides classified as high severity, the Agency will continue to monitor the incident information and ifa concern is triggered, additional analysis will be included in the risk assessment.


### Tolerance Assessment and International Harmonization Tolerances are established under 40 CFR §180.289 for residues ofMSMA, including its metabolites and degradates, in or on a variety offood and feed crops as shown in Table Attachment 4. The Codex Alimentarius Commission, the Canadian Pest Management Regulatory Agency (PMRA) and Mexico have not established maximum residue limits (MRLs) for MSMA or any other arsenical. A summary ofthe International Residue Limits (IRLs) for MSMA are included in Attachment 4.
The current tolerance expression as listed in the 40 CFR §180.332 has been updated to reflect current HED policies. However, due to the cancellation ofDMSA, it will need to be revised. The revised tolerance expression should be as follows:
Tolerances are established for residues of the herbicide methane arsonic acid, including its metabolites anddegradates, in or on the commodities in the table in thisparagraph. Compliance with the tolerance levels specified in thisparagraph is to be determined by measuring only methanearsonic acid,from application of monosodium salts of methanearsonic acid, calculatedas the stoichiometric equivalent of As203, in or on the commodity.


### Environmental Justice Potential areas ofenvironmentaljustice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and LowIncome Populations," http://www.epa.gov/compliance/resources/policies/ej/exec order 12898.pdf. The Office ofPesticide Programs (OPP) typically considers the highest potential exposures from the legal use ofa pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability ofdiets within the U.S., and people who may be exposed when harvesting crops. Should these high exposures indicate potential risks ofconcern, OPP will further refine the risk assessments to ensure that the risk estimates are based on the best available information.

Page 11 of22

### Cumulative Risk Assessment At**thi~** time, EPA does not have available data to detennine whether MSMA has a common mechanism oftoxicity with other substances. EPA has not made a common mechanism oftoxicity finding as to MSMA and any other substances, and MSMA does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U.S. Therefore, EPA has not assumed that MSMA 

### has a common mechanism oftoxicity with other substances.


### Data Requirements HED does not anticipate that additional residue chemistry, toxicology or occupational/residential exposure data will be required for the MSMA registration review process, with the exception ofthe following studies listed below:

• Magnitude ofthe Residue (Crop Field Trials) on Cotton Gin Byproducts (GDLN 860.1500)

. • Immunotoxicity Study (GDLN 870.7800)



### References Table 1: HED Memorancbl Relevant to Regi.stratio.n Review**~** 

### Author 

### BarcodeffXR# 

### Date Title J. VanAlstine 0056514 11/08/2012 Monosodium methanearsonate (MSMA): Summary of Hazard and Science Policy Council (HASPOC) meeting C. Smith D329696 06/21/2006 Arsenic: Final Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision Docwnent for DMA, CAMA, MSMA, and DSMA C. Smith D329694 06/21/2006 Organic Arsenicals: Final HED Combined Chapter ofthe Reregistration Eligibility Decision Document (RED) S. Kinard 0329695 06/21/2006 Organic Arsenicals. Revised Acute and Chronic Dietary Exposure Assessments for the Reregistration Eligibility Decision (RED) P.Y. Barnes D309106 01/31/2006 Residue Chemistry Chapter for the Monosidiwn and Disodium Salts ofMethanearsonic Acid P.Y. Barnes 0325973 01131/2006 MAA and Salts Product Chemistry Chapter A. Lowit 014425 12/14/2000 Methanearsonic acid and its sodium and calcium salts- Report ofthe Hazard Identification Assessment Review Committee



### Attachments Attachment 1. Chemical Identity/Physicochemical Properties Attachment 2. Toxicity Profile Tables Attachment 3. Endpoint Tables Attachment 4. MSMA International Residue Limits Table

Page 12 of22

### Attachment 1. Table 

### Al.l. MSMA Nomenclature. ." ,.



# - '1J Chemical structure 

# o , /CH3 MSMA 

# As 

# HO/ 

# 'o- Na+

·Common name Monosodium methanearsonate Company experimental name N/A IUPACname Sodium hydrogen methylarsonate CAS name Sodium hydrogen methylarsonate CAS registry number 2163-80-6 Chemical structure 

# o, /CH3 MMAIMAA 

# As 

# HO/ 

# 'oH

Monomethylarsinic acid, Methanearsonic acid Chemical structure 

# o, /CH3 DMA 

# As 

# HO/ 

# 'cH3 Dimethylarsenic acid, cacodylic acid**~** 

### TableA1.2. Physicochemical Properties ofMSM.A. Parameter Value Reference Melting point/range 116-121 oc MSMA Product Chemistry pH (at2S oc) 5.5

- 5.9 Chapter (P.Y. Barnes, D Density 1.65 0325973, 0 1 /3 1/ 2006)
Water solubility 104 g/100 mL Solvent solubility gil00 mL at 20 OC methanol 16 n-hexane 0.005 Vapor pressure 1 x 10-S Pa Dissociation constant, pKa 9.02 OctanoVwater partition coefficient, <1 Log(Kow)



### Page 13 of22

### Attachment 2. Toxicity Profile Tables**--,~~** -... Th' ,. __ 

# - . -.., 

### Table A2.1. Acute Toxieity ofMSMA**~** 

### - Stu4¥· 1)-R"**oxicity** 6oidelineNQ • . MRID#s Res.ults**Ca~~f,Y, _**  81-1 Acute Oral, rat 45405601* LDso 

### = 2449 mglkg (F) III 3184 mglkg (M) 2833 m_g!!<g (Combined) 81-2 Acute Dermal, rabbit 41890001* LDso > 2000 mg!kg III 81-3 Acute Inhalation, rat 42604601* LCso 

### =2.20 m g/L III 81-4 Primary Eye Irritation, 43840901* Reversible conjunctival III rabbit irritation 81-5 Primary Skin Irritation, 41892008a Slight initant IV rabbit 81-6 Dermal Sensitization, guinea 41890002* Not a sensitizer pig 81-8 Acute Neurotoxicity N/A



## .. *Data presented m table are for formulations contammg technical MSMA.



### Page 14 of22870.3100 90-Day oral toxicity mice 4063260I (1985) Unacceptable/Nonguideline 0, 10, 100, 500, and 1250 ppm (0, 2.1, 22.5, 110.6, and 288.6 mglkgl day for males and 0, 2.8, 27.5, 137.4, and 342.5 mglkglday for females) MMA

870.3200 41872701 (1991) 21128-Day dermal toxicity Acceptable /Guideline rabbits 0, l 00, 300, or 1000 mglkglday MMA

870.3465 28/90-Day inhalation toxicity 870.3700a Prenatal developmental rats

870.3700b Prenatal developmental rabbits

870.3800 Reproduction and fertility effects rats Not available for MMA

41926401 (1990) Acceptable/Guideline 0, 10, 100, or 500 mg!kg!day MMA

15939001 (1986) Acceptable/Guideline 0, I, 3, 7, 12 mglkglday MMA

43178301 (1994) Acceptable/Guideline 0, 100, 300, or 1000 ppm. FO: 5.8, 17.8, and 63.5 mglkglday, respectively, for males and 7.5, 22.5, and 77.6 mglkglday for females. F1: 6.5, 21.1, and 75.8 mg!kglday, respectively, for males and 7.9, 25.4, and 

### Page 15 of22 Based on the data presented in this study, a LOAEL and NOAEL cannot be established. The numerous deficiencies in the conduct ofthis study preclude meaningful evaluation ofthe data.

Systemic toxicity NOAEL = 1000 Systemic toxicity LOAEL > 1000
Dermal irritation NOAEL = 1000 Dermal irritation LOAEL > 1000

Maternal toxicity NOAEL = 10 mglkglday. Maternal toxicity LOAEL = 100 mglkg!day, based on decreased body weight gain and food consumption. Developmental toxicity NOAEL= 100 mglkglday. Developmental toxicity LOAEL = 500 mglkglday, based on decreased mean fetal body weight. Maternal toxicity NOAEL 

### = 7 mg!kglday. Maternal toxicity LOAEL = 12 mglkg!day, based on decreased body weight, food consumption (during the dosing period), and abortions. Developmental toxicity NOAEL = 7 mglkglday. Developmental toxicity LOAEL = 12 mglkglday, based abortions and on an increased incidence of skeletal variations (increased numbers of 13th thoracic vertebra with ribs and gtb lumbar vertebra).

Parental NOAEL = 100 ppm for males and 300 ppm) for females. Parental LOAEL =300 ppm for male rats and 1000 ppm for female rats based on increased food consumption with decreased body weight gain along with whole litter loss. Reproductive NOAEL = 300 ppm. Reproductive LOAEL > 300 ppm.

# [ITable A2.2. Profile of Subchronic, Chrome, and Other Toxicity ofMMA 

# ., • MMA Guidelllle #-/Study Type MRID# (year) !Classification/Doses Results



### - 88.6 mglkglday for females. MMA OffspringNOAEL- 100 ppm. Offspring LOAEL = 300 ppmbased on increased pup death (day 0-21), reduced litter survival index, and decreased lactation index related to whole litter loss. 870.4200b 40546101 and41266401 (1988) NOAEL- 2 mglkg/day. Chronic toxicity Acceptable/Guideline LOAEL = 8 mglkg/day based on based on body dogs 0, 2.5, 10,40 mglkg!day (week 1 only) weight gain and kidney effects (organ weight and 0, 2, 8, and 35 mglkg/day (week 2-52) 'histopathology) in females in both sexes MMA 870.4300 41669001 (1990) NOAEL

# =50 ppm (3.2 mglkglday for males and Combined Chronic/ Acceptable 3.8 mglkg/day for females) Carcinogenicity 0, 50,400 and 800-1300 ppm (0, 3.2, 27.2, LOAEL = 400 ppm (27.2 mglkglday for males and rats and 93.1 mglkglday for males and 0, 3.8, 32.9 mglkglday for females) based on decreased 32.9, and 10 1.4 mglkg!day for females) for body weights, body weight gains, food 104 weeks. MMA consumption, histopathology ofgastrointestinal tract and thyroid. Dosing was considered adequate.

870.4300 42173201 (1991) NOAEL = 50 ppm (9

.3 and 12 mglkg/day) for Carcinogenicity Acceptable males and females. mice 0, 10, 50, 200, and 400 ppm (0, 1.8, 9.3, LOAEL = 200 ppm (38 and 46 mglkg/day) for 38, and 83 mglkglday for males and 0, 2.2, males and females based on decrease inbody 12, 46, and 104 mglkg/day for females) weight gain, increased water consumption, and MMA histopathology ofthe kidney. Dosing was considered adequate. 870 .5100 41651902 (1989) There was no evidence ofinduced mutant colonies Gene mutation Acceptable/Guideline over background. Salmone/la typhimurium In deionized distilled water at reverse gene mutation concentrations ofO, 667, 1000. 3333, 6667 and 10,000 IJ.g/plate +/-S9 870.5300 41651904 (1989) MMA was tested up to cytotoxic concentrations. Gene mutation Acceptable/Guideline There was no evidence ofinduced mutant colonies Mouse lymphoma assay In deionized water at 0, 300, 400, 534, over background. 712,949, 1266, 1688,2250, 3000 and 4000**~J.g/mL** -S9 and at 0, 7 1, 95, 127, 169,225,300,400,534,712,949,1266 and 1688 ug/mL +S9



### Page 16 of22-cc**T•ble.Al~.** 

### Profile ofSubchronic, Chronic., and .Other Toxicity**of ~**  j MMA**GuideliDe--~**/Study Type 

### .**~** MRID# (year}**/~eatioDIDoses** Results

- 870.5375 41651903 (1989) MMA was tested up to a slightly cytotoxic Chromosomal aberration Acceptable/Guideline concentration, limited by solubility in the solvent, Mouse micronucleus assay In distilled water in two independent distilled water. There was no evidence of assays. Concentrations tested in the initial chromosomal aberrations induced over background. assay were 0, 625, 1250, 2500, 5000 J.!g/mL, with and without metabolic activation (S9-mix) 870.5550 4 [651905 (1989) There was no evidence that unscheduled DNA Unscheduled DNA Acceptable/Guideline synthesis, as determined byradioactive tracer Synthesis In deionized distilled water at procedures [nuclear silver grain counts} was concentrations ofO, 10, 50, 100, 500, 750 induced. and 1000 p.glmL for 18 to 20 hours in an initial and a confrrmatory assay. 870.6200a Not available for MMA Acute neurotoxicity rat 870.6200b Not available for MMA Subchronic (13 weeks) neurotoxicity screening battery rat 870.7485 42010501 (1991) Analysis offecal and urinary samples by HPLC and Metabolism and Acceptable/Guideline TLC revealed that the radioactivity ofall pharmacokinetics In water at concentrations ofO, 5.0, or preparative fractions was associated with parent dogs 200.0 mglkg according to the following compound and two unknown metabolites. The five different dose groups: I) In the major product excreted in both urine and feces was vehicle control group, dosed with water by unchanged parent, accounting for 80-97% ofthe gavage; 2) a single radiolabeled gavage administered dose. dose of5.0 mg/kg; 3) a single radiolabeled gavage dose of200 mg/kg; 4) dosed by gavage for 14 consecutive days with unlabelled MSMA at 5.0 rnglkglday followed by a single radiolabeled dose of MSMA at MSMA; 5) a single radiolabeled i.v. dose of5.0 mglkg. MSMA in rats 870.7600 Not available for MMA Dermal penetration
870.7800 Not available for MMA Immunotoxicity NOAEL = no observed adverse effect level; LOAEL = lowest observed adverse effect level; FQPA SF = FQPA Safety Factor; PAD = population adjusted dose (c = chronic); LOC = level ofconcern; MOE = Margin ofexposure.



### Page 17 of22

### Att h a

c men 

# . D lPOID 

### a 

### t3 E d ' t T bles 

### TableA3.1. Summary ofToxie

. oJogical Doses and 

### Endpoints for 

### MMA for 

### Use in 

### Dietary and NonOccupational Human Rbk Assessments• kposure Poiotof Uaeert.inty/ RID, PAD, Level of FQPASafety Coocera. for Stady and Toxieological E.tleets Sceoario Departure Fa¢or Risk Assessment
NOAEL = UF,.. = 10 Chronic Toxicity in Dog, MMA study (MRID# Acute Dietary 10 mglkg UFH= 10 Acute RID = 0. 1 mglkg 40546101) (general (week 1 only) FQPASF= IX aPAD = 0.1 mglkg LOAEL = 40 mglkg/day based on clinical signs of population) diarrhea and vomiting observed in the first ofweek ofdosing with 2-5 hours ofeach days dosing. UFA

### = 10 Chronic Toxicity Rat, MMA study (MRID# UFH = 10 41669001) NOAEL = Chronic RID 

### = Rat LOAEL 

### = 27.2 mglkglday for males and 32.9 Chronic Dietary 3.2 mglkg/ d ay FQPA SF= IX 0

. 1 mglkg mglkg/day for females based on decreased body (all populations) c PAD = 0

.03 mglkg weights, diarrhea, body weight gains, food consumption, histopathology ofgastrointestinal tract and thyroid. UFA = 10 Rabbit developmental toxici ty, M:MA study (MRID# Incidental Oral NOAEL= UFH = 10 15939001) Short

-Term 7 mg/kg/day FQPAS F= IX Residential LOC = 100 LOAEL = 12 mglkglday, based on decreased body (1

- 30 days) weight, food consumption (during the dosing period), and abortions. Inciden t al Oral UFA= 10 Chronic Rat, MMA study (MRID# 41669001 ) Intermediate
- NOAEL= UFH = 10 Resident ial LOC 

### = 100 LOAEL = 27.2 mglkg/day for males and 32.9 Term 3

.2 mglkglday FQPA S F= IX mglkglday for females based on decreased body (1

- 6 months) weights, diarrhea. Dermal UFA = 10 Short

-Term UFH = 10 21

-Day D ennal Toxicity in Rabbit, M:MA study (1- 30 days) Dennal NOAEL= FQPA SF= IX Residential LOC = 100 (MRJD# 41872701) Intermediate- 1000 mglkglday LOAEL > 1000 mglkg/day. Term (1- 6 months) Dermal Long-Term Not applicable (> 6 months) Inhalation**A** = 10 90-Day Inhalation with DMA • Ra t (MRID# Short

-Term Inhalation NOAEL= UFH = 10 4470030I)b (1- 30 days) 0.01 mg/L FQPA SF = IX Residential LOC "" 100 LOAEL = 0

.034 mglkg/L (14.9 5 mglkglday) based Intermediate- (4

.38 mglkg/day, on presence ofmode rate and marked Term adjusted) intracytoplasmic eosinophilic granules (lEG) in the ( 1 - 6 months) nasal turbinate cells ofmale and f emale rats. C ancer Classification: " not likely human carcinogen"



### . . •Abbreviations: Point ofDeparture (POD) A data point or an estimat ed point that is derived from observed dose-response dataand used to mark the beginning ofextrapolation to determine risk associated with lower environm entally relevant human exposures. NOAEL = no observed adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extr apolation from animal to human (interspecies). UFH = po ten tial variation in sensitivity among members of the human population (intraspecies). MOE = margin ofexposure. LOC =level ofconcern. N/A = not applicable. UF =uncertainty factor

. FQPA SF =Special FQPA safety factor. PAD = population adjusted dose (a= acute, c = chro.nic). RID = reference dose. MOE= margin of

. exposure. bUsed as surrogate for MMS 

### Page 18 of 22

### Table 

### .A3.2. Summary of

### Toxicological Doses and Endpoinu for MMA Use in**o~~upational** 

### Human Risk Assessments•**w·~intyt ~**  Exposure Poiatof RfD, PAD, Level of FQPASafety Coacern for Study
· aad ToxicologkalEffects Seeuario Departure Factor RbkAssessmeat
Dermal UFA = 10 Short

-Term UFH = 10 21·Day Dermal Toxicity in Rabbit, MMA study (1-30 days) Derma l NOAEL= FQPASF= IX Occupational LOC = (MRID# 41872701) Intermediate- 1000 mglkglday 100 LOAEL > 1000 mglkglday. Term (I - 6 months) Dermal Not applicable Long-Term (> 6 months) Inhalation UFA = 10 90-Day Inhalation with DMA

- Rat {MRlD# Short

-Term Inhalation NOAEL= UFH= 10 4470030l)b (1- 30 days) 0.01 mg!L FQPA SF= IX Occupational LOC = LOAEL = 0

.034 mglkg/L (14.95 mglkglday) based Intermediate- (4 .38 mglkglday, 100 on presence ofmoderate and marked Term adjusted) intracytoplasmic eosinophiJic granules (lEG) in the (1 - 6 months) nasal turbinate cells of male and female rats. Cancer Classification: "not likely human carcinogen"

•Abbreviations: Point ofDeparture (POD)= A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning ofextrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). · UFH = potential variation in sensitivity among members of the human population (intraspecies). MOE= margin ofexposure. LOC =level ofconcern. N/A = not applicable. UF =uncertainty factor. FQPA SF
= Special FQPA safety factor. PAD = population adjusted dose (a= acute, c =chronic). RID referen ce dose. MOE = margin of exposure. bUsed as surrogate for MMA



### Page 19 of22

### TableA3.3. Summary ofToxicological Doses and Endpoints for DMA for Use iD 

### Dietary and Non

-Occupational Human Risk Assessments • EXPQSUre Point of Uneertaiaty/**~Um),PAJ>,~dof** &eurio FQPA.Safdy Concera fOJ' Study and**Toiicol~** Effects**Depa~** Faetot Risk ·Asiessmeot Rat Developmental Toxicity study (MRID# 40625701) LOAEL = 36 mglkglday based on decreased fetal UFA = IO weights, sh orter crown-rump length, the suggestion Acute Dietary NOAEL = ofdiaphragmatic hernias and delayed/lack of (general 12 mglkg UFH= IO Acute RID = 0.1 2 mglkg ossification o numerous bones. population) FQPA SF= IX aPAD = 0

. 12 mglkg Rabbit Developmental Toxicity study (MRID# 40663301) LOAEL = 48 mglkglday based on mortality, abortions, body weight loss and reduced food
consumption. BMDLIO = UFA=3 Chronic RID = Chronic Dietary 0

.43 mglkglday UFH = 10 O.l4mglkg BMD10 of0

.92 mglkglday for BrdU labeling from (all populations) FQPA SF= IX cPAD = 0.14 mglkg Arnold et al (1999)
Rat Developmental Toxicity study (MRID# 4062570 1) LOAEL = 3 6 mglkglday based on decreased fetal
UFA= IO weights, shorter crown-rump length, the sugges tion Incidental Oral ofdiaphragmatic he rnias and delayed/lack of Short

-Term NOAEL = UFH = 10 LOC = 100 ossification o numerous bones. {I- 30 days) 12 mglkglday FQPA SF= IX Rabbit Developmental Toxicity study (MRID# 40663301) LOAEL = 48 mglkglday based on mortality, abortions, body weight loss and reduced food consumption. Incidental O r al UFA =3 Intermediate- BMDLto = UFH = IO LOC = 30 BMD 10 of0.92 mglkglday for BrdU labeling from Term 0

.43 mglkglday FQPA SF = IX Arnold et a! ( 1999) (I- 6 months) Dermal UFA = 10 21-Day Dermal Toxicity in Rabbit, MMA study Short-Term UFH= 10 (MRID# 41872801) (1- 30 days) Dermal NOAEL= FQPA SF= IX LOC = 100 LOAEL = I000 mglkglday based on decreased body Intermediate- 300 mglkglday weights gain in females, and decreased testicular Term weights, hypospermia, and tubular hypoplasis in (1 - 6 months) males. Dermal Long-Term Not required (> 6 months) Inhalation UFA = 10 90-Day Inhalation with DMA

- Rat (MRID# Short

-Term Inhalation NOAEL= UF8 = 10 44700301) (1

- 30 days) 0.01 mg!L FQPA SF = IX LOC = 100 LOAEL = 0.034 mglkg!L (I4.95 mglkglday) based Intermediate- (4.38 mglkglday, on presence ofmoderate and marked Term adjusted) intracytoplasmic eosinophilic granules (IEG) in the (1 - 6 months) nasal turbinate cells ofmale and female rats. Cancer Classification: No carcinogenic at doses that do not result I enhanced cell proliferation.

.. a Abbreviations: 

### Page 20 of22Point ofDeparture (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning ofextrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies ). UFH = potential variation in sensitivity among members of the human population (intraspecies). MOE= margin of exposure
. LOC = level of concern. N /A = not applicable. U P = uncertainty factor. FQPA SF

= Special FQPA safety factor. PAD= population adjusted dose (a= acute, c =chronic). RID = reference dose. MOE= margin of exposure. BMD =Benchmark Dose. BMDL =Lower 95% confidence on the BMD.



### Table

. A3.4. Summary ofToxicological Doses and Endpoints for DMA Use in Occupational Human Risk**.Assessme~ts·**

__ o Exposure Point of Uncertainty/ RID, PAD, Le:vel of FQPASafety**Con~ru** for Study and Toxicological E«ects Scenario Departure j Factor Risk Assessment Dermal UFA = 10**~Day** Dermal Toxicity in Rabbits study (MRID# Short-Term UFH = 10 41872801) (1-30 days) Dermal NOAEL= FQPA SF= IX LOC = 100 LOAEL = 1000 mglkglday based on decreased body Intermediate- 300 mglkglday weights gain in females, and decreased testicular Term weights, hypospennia, and tubular hypoplasis in (1

- 6 months) males. Dermal Not applicable Long-Term (> 6 months) Inhalation UFA = 10 90-Day Inhala tion with DMA

- Rat (MRID# Short-Term Inhalation NOAEL= UFH = 10 44700301) (1

- 30 days) 0.01 mg!L FQPASF= 1X LOC = 100 LOAEL = 0.034 mglkg/L (14.95 mglkglda y) based Intermediate- (4.38 mglkglday, on presence ofmoderate and marked Term adjusted) intracytoplasmic eosinophilic granules (lEG) in the (1 - 6 months) nasal turbinate cells ofmale and female rats. Cancer Classification: Not carcinogenic at doses that do not result in enhanced cell proliferation.

.. • AbbreVIations: Point ofDeparture (POD}= A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning ofextrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin ofexposure. LOC =level of concern. N/A =not applicable

. UF = uncertainty factor. FQPA SF =Special FQPA safety factor. PAD= population adjusted dose {a= acute, c = chronic). RID = reference dose. MOE= margin of exposure.



### Page 21 of22

### Attachment 4. MSMA International Residue Limits Table 

### Monosodium methanearsonate (MSMA) (013803; 10/15/2012) Summazy ofUS and International Tolerances and Maximum Residue Limits Residue De finition : 

## us Canada Mexicoz Codex 3 40 CFR 180.289: None None Plant: methanearsonic acid (calculated 

### as**A~** 

### 0 3 ) from application ofthe disodium and monosodium salts ofmethanearsonic acid Commodity 1 Tolerance (ppm) !Maximum Residue Limit (mg/kg) 

# us Canada Mexico.t Codex.) Cotton undelinted seed 

### 0.7 Cotton, hulls 

### 0.9

Completed: M. Negussie; 10/18/2012

1 Includes only commodities ofinterest for this action

. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Me xico adopts US tolerances and/or Codex MRLs for its export purposes
.
3 • 

### =absent at the limit ofquantitation; Po = postharvest treatment, such as treatment ofstored grains. PoP

= processed postharvest treated commodity, such as processing oftreated stored wheat

. (fat)= to be measured on the fat portion ofthe sample. MRLs indicated .as proposed have not been finalized by the CCPR and the CAC.

Page 22 of22