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


                                                 OFFICE OF CHEMICAL SAFETY AND 
                                                           POLLUTION PREVENTION

MEMORANDUM

DATE:  	August 30, 2011

SUBJECT:	Metsulfuron-Methyl: Registration Review Scoping Document for Human Health Assessments.

PC Code:  122010
DP Barcode: D389257
MRID No.:  NA
Registration No.: NA
Petition No.: NA
Regulatory Action: Registration Review
Assessment Type: Single Chemical/ Aggregate
Reregistration Case No.: 7205
TXR No.:  NA
CAS No.: 74223-64-6


FROM:	Charles Smith, Senior Environmental Scientist/Risk Assessor
		Sheila Piper, Senior Chemist 
		Monica Hawkins, Ph.D., M.P.H., Environmental Health Scientist
		Steven Dapson, PhD, Senior Toxicologist
		Risk Assessment Branch VI
            Health Effects Division (7509P)

THROUGH:	Felecia Fort, Branch Chief
		Risk Assessment Branch VI
		Health Effects Division (7509P)
            
TO:		Jill Bloom, Chemical Review Manager
		Risk Management and Implementation Branch II
		Pesticide Re-Evaluation Division (7508P)

Executive Summary
The Health Effects Division (HED) Metsulfuron-Methyl Registration Review Team has evaluated the status of the human health assessment for the herbicide metsulfuron-methyl to determine the scope of work necessary to support Registration Review.  Metsulfuron-methyl is registered for use on a number of food and feed crops, on conifers and hardwoods, on industrial sites, and on turf.  It is also the principal degradate of iodosulfuron-methyl (currently registered only on corn) in water.  The Codex Alimentarius Commission and Mexico have not established maximum residue limits (MRLs) for metsulfuron-methyl.  Canada has established MRLs for some plant and livestock commodities.  The most recent exposure and risk assessments for metsulfuron-methyl were completed in 2002 (M. Collantes, D282214, 6/19/02 and W. Cutchin, D281907, 6/26/2002).  Based on the current use profile, exposures can be expected to occur via the dietary (food and drinking water), residential (handler and post-application), and occupational (handler and post-application) routes for metsulfuron-methyl.

The toxicity database for metsulfuron-methyl is nearly complete at the present time with the exception of a neurotoxicity battery (i.e., acute and subchronic neurotoxicity) and an immunotoxicity study.  A 28-day inhalation study was previously required as a condition of registration for the use of metsulfuron-methyl on sorghum (W. Cutchin, D281907, 6/26/2002).  This study has not been submitted to the Agency as this time.  The Agency has classified metsulfuron-methyl as "not likely to be carcinogenic to humans" based on the results of carcinogenicity studies in rats and mice.  Metsulfuron-methyl has low acute toxicity by oral, dermal, and inhalation routes of exposure but it is classified as a severe eye irritant.  No reproductive or developmental effects were observed in metsulfuron-methyl toxicity studies using rats and rabbits.  Upon receipt of the required toxicity studies, HED will reevaluate the points of departure and uncertainty factors for the dietary and occupational exposure assessments.

The existing residue chemistry database for metsulfuron-methyl is adequate for risk assessment purposes.  The qualitative nature of the residue(s) of metsulfuron-methyl in plants and animals has been adequately identified/characterized and is understood.  The current tolerance expression as listed in the 40 CFR§180.428(a) has not been updated to reflect current HED policies and thus will need to be revised during the registration review process.

The dietary exposure database is adequate to support the existing registrations.  New chronic dietary exposure and risk assessments will be required during registration review, which incorporate current consumption information, updated residue values and percent crop treated information while directly incorporating drinking water values into the assessment.  Further, an acute dietary assessment may need to be completed if new toxicity data are identified that indicate the need for an acute dietary risk assessment.

The residential exposure database is adequate to support the registration review process for metsulfuron-methyl.  In the 2002 exposure assessment, all of the non-cancer residential handler and postapplication risk estimates were below the Agency's level of concern.  No new residential handler or postapplication worker studies are needed at this time.  An updated residential exposure assessment may be required under registration review based upon revisions to HED's Residential SOPs which was reviewed by the Scientific Advisory Panel (SAP) in October 2009.  An updated assessment may also be required if new data are identified which impact exposure estimates, new points of departure, a revised FQPA SF, or revisions to exposure policies and procedures are made.

The occupational exposure database is adequate to support the registration review process for metsulfuron-methyl.  In the 2002 exposure assessment, all of the non-cancer occupational handler and postapplication risk estimates were below the Agency's level of concern.  No new occupational handler or postapplication worker studies are needed at this time.  Revised occupational handler and postapplication assessments may be needed if toxicological endpoints change, other new data are received by EPA, or other parameters are modified, such as changes to Standard Operating Procedures or default exposure assessment assumptions.  Determination of the appropriate REI for metsulfuron-methyl should be performed during registration review.

Introduction
Metsulfuron-methyl is a herbicide used to control a variety of annual grasses and broadleaf weeds.  It is also the principal degradate of iodosulfuron-methyl (currently registered only on corn) in water.  HED has reviewed the most recent exposure and risk assessments for metsulfuron-methyl, as well as toxicity data, exposure and usage databases, and the latest Agency science policy and risk assessment methodologies to determine if sufficient data are available and if updates are needed to support registration review.  Additionally, the team conducted a screening-level literature search for any information that would aid in assessing human health risks to metsulfuron-methyl.

Chemical Identity
Metsulfuron-methyl is a sulfonylurea herbicide registered on a number of food and feed crops, on conifers and hardwoods, on industrial sites, and on turf.  Sulfonylurea compounds inhibit acetolactate synthase (ALS) which is involved in cell division at the root tip.  Registered products containing metsulfuron-methyl include water dispersable granule (WDG)/dry flowable (DF) formulations. These formulations may be applied pre- or post-emergence using aerial and ground equipment.  

The current tolerance expression as listed in the 40 CFR §180.416 has not been updated to reflect current HED polices.  The revised tolerance expression should be as follows:  
Tolerances are established for the residues of the herbicide metsulfuron-methyl, including its metabolites and degradates, in or on plant commodities.  Compliance with the tolerance levels is to be determined by measuring only the sum of metsulfuron-methyl (methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl] benzoate) and its metabolite, methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-4-(beta-D-glycopyranosyl)benzoate (Metabolite A) and methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-4-hydroxybenzoate (Metabolite A1), calculated as the stoichiometric equivalent of metsulfuron-methyl, in or on the commodity.
Tolerances are established for the residues of the herbicide metsulfuron-methyl, including its metabolites and degradates, in or on livestock commodities.  Compliance with the tolerance levels is to be determined by measuring only metsulfuron-methyl (methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl] benzoate), in or on the commodity.

The chemical structure and nomenclature of metsulfuron-methyl and the physicochemical properties of technical grade metsulfuron-methyl are presented in Tables 1 and 2.

Hazard Identification/Toxicology
The toxicity database for metsulfuron-methyl is nearly complete at the present time with the exception of a neurotoxicity battery (i.e., acute and subchronic neurotoxicity) and an immunotoxicity study (see Table 3A).  The acute database indicates that metsulfuron-methyl has low acute toxicity by oral, dermal, and inhalation routes of exposure (see Table 3B).  It is a severe eye irritant (Category 1) but does not cause primary dermal irritation.  Metsulfuron-methyl is not a skin sensitizer.

For a summary of the subchronic and chronic toxicity profile, see Table 3C.  In mammals, metsulfuron methyl exhibited generalized, nonspecific toxicity and did not appear to have specific target organ toxicity.  Rats appear to be the most sensitive species tested.  The HED Hazard Identification Assessment Review Committee (HIARC), in accordance with the 1999 Draft Guidance for Carcinogenic Risk Assessment, classified metsulfuron methyl as "not likely to be carcinogenic to humans."  This is based on the lack of evidence of carcinogenicity in mice and rats, no evidence of mutagenicity in several acceptable studies, and the non-carcinogenic potential of structurally related compounds.

Metsulfuron-methyl is well absorbed regardless of dose or treatment regimen
(single gavage dose alone or after repeated dietary feeding).  The primary route of excretion is via the urine (71-95%) followed by fecal elimination (4.8-13.3%) and levels remaining in the tissues are negligible.

HED has fully evaluated the toxicity database of metsulfuron methyl with respect to the potential for special sensitivity of infants and children, and concludes that there is no concern for pre- and postnatal susceptibility for infants and children.  The FQPA safety factor has been reduced to 1X because (1) the toxicity database is complete and adequate to characterize potential pre- and postnatal risk for infants and children; and (2) no reproductive or developmental effects were observed in rats and rabbits.    

In accordance with the revised 40 CFR Part 158 data requirements, a neurotoxicity battery (i.e., acute and subchronic neurotoxicity) is required for all food and non-food use chemicals. Although the available metsulfuron-methyl toxicity studies showed no neurotoxicity, these studies do not use optimal methods to evaluate the nervous tissue structure and function. Consequently, the neurotoxicity studies are required to detect and more fully characterize the potential neurotoxic effects of metsulfuron-methyl.  

An immunotoxicity study is also required as a part of the new data requirements in 40 CFR Part 158 for conventional pesticide registration.  Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide's potential immunotoxicity.  While data from hematology, lymphoid organ weights, and histopathology in routine chronic or sub-chronic toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immunotoxicity.  Consequently, the immunotoxicity study is required to detect and more fully characterize the potential immunotoxic effects of metsulfuron-methyl.  

Once these studies are made available to the Agency, they will be reviewed and HED will reevaluate the points of departure and uncertainty factors used in risk assessment. In the absence of the required studies, EPA may use a database uncertainty factor of up to 10X.
 
For a summary of the relevant toxicological endpoints used in risk assessment, please see Tables 3D (dietary endpoints) and 3E (occupational endpoints).


Endocrine Disruption
As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals.  Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring.  For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups.  As part of registration review, EPA will review these data and select the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database.  However, as required by FFDCA section 408(p), metsulfuron-methyl 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 estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals.  Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  Metsulfuron-methyl is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP.  Accordingly, as part of registration review, EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP screening assays for metsulfuron-methyl.  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 visit our website:  http://www.epa.gov/endo/.

Conclusions for Hazard Identification/Toxicology
The toxicity database for metsulfuron-methyl is nearly complete at the present time with the exception of a neurotoxicity battery (i.e., acute and subchronic neurotoxicity) and an immunotoxicity study.  A 28-day inhalation study was previously required as a condition of registration for the use of metsulfuron-methyl on sorghum (W. Cutchin, D281907, 6/26/2002).  This study has not been submitted to the Agency as this time.

Residue Chemistry
The HED Metabolism Assessment Review Committee (MARC) determined that the residue of concern for plants is metsulfuron-methyl and its metabolite, methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-4-(beta-D-glycopyranosyl)benzoate (Metabolite A) and methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-4-hydroxybenzoate (Metabolite A1) (MARC, D279786, 12/17/01).  The residue of concern for livestock is metsulfuron methyl.  The current tolerance expression as listed in the 40 CFR§180.428(a) has not been updated to reflect current HED policies.

Adequate analytical methods (HPLC/UV) exist for data collection and tolerance enforcement.  PAM Vol. II lists Methods I and III which are respectively capable of determining residues of metsulfuron-methyl and the combined residues Metabolites A and A1 in/on wheat RACs.  Method II determines metsulfuron methyl in ruminant tissues and milk.  No additional residue chemistry data are required to support the existing uses of metsulfuron-methyl.

Dietary Exposure and Risks
An unrefined chronic dietary (food only) risk assessment was completed for a Section 3 use on grain sorghum (W.Cutchin, D281906, 4/3/02).  HED concluded that there is a reasonable certainty that no harm will result to the general population, infants and children from chronic dietary exposure to metsulfuron-methyl.  Acute and cancer dietary exposure estimates are not required for metsulfuron-methyl.

Drinking Water
Metsulfuron-methyl appears not to be persistent and has high mobility in soils. The MARC concluded that only the parent compound needs to be included in the drinking water assessment.  The Environmental Fate and Effects Division (EFED) provided drinking water numbers for use in dietary risk assessments (S.Termes, D279400, 1/9/02) in association with the use on sorghum.  The FIFRA Index Reservoir Screening Tool (FIRST) was used for estimating the concentration of metsulfuron-methyl as a metabolite of iodosulfuron-methyl, since FIRST has been used in estimating the drinking water values for the corn use with the proposed label for iodosulfuron-methyl.  The Screening Concentration in Groundwater (SCI-GROW) model was utilized to estimate the concentration of metsulfuron in ground water as a result of application on turf.  

In the 2002 HED risk assessment, risks from potential exposure to metsulfuron-methyl in drinking water from all sources were evaluated by comparing these modeled surface and ground water estimates against calculated drinking water levels of comparison (DWLOCs).  This assessment indicated that the estimated drinking water concentration (EDWC) estimates for metsulfuron-methyl residues in surface and ground water did not exceed the Agency's estimated chronic DWLOC value. 

Acute Dietary Exposure and Risk (Food and Drinking Water) 
In the 2002 HED risk assessment, an acute dietary assessment was not required for metsulfuron methyl because an appropriate acute dietary endpoint was not available.

Chronic Exposure and Risk (Food and Drinking Water)
In the 2002 HED risk assessment, an unrefined, chronic dietary exposure assessment was performed using tolerance level residues, default DEEM processing factors, and assuming 100% crop treated.  This assessment concluded that the chronic dietary exposure estimates did not exceed HED's level of concern (<100% cPAD) for any population subgroup.

Conclusions for Dietary Exposure and Risk
The dietary exposure database is adequate to support the existing registrations. However, it will be necessary for HED to conduct a new dietary exposure assessment for metsulfuron-methyl including new and updated information and policies, which includes directly incorporating drinking water estimates into the dietary assessment.  The revised assessment should include updated consumption information and utilize the newest version of DEEM-FCID.  Further, an acute dietary assessment may need to be completed if new toxicity data are identified that indicate the need for an acute dietary risk assessment.

Residential Exposure and Risks
Metsulfuron-methyl is registered for use on residential lawns, recreational areas (i.e., parks and sports fields), and on golf courses.  Due to this use profile, adult residential homeowners may experience exposure to metsulfuron-methyl during application of the chemical (i.e., residential handler exposures).  Adults and children may experience exposure to metsulfuron-methyl when contacting previously treated areas (i.e., residential postapplication exposure).

The most recent metsulfuron occupational and residential exposure assessment (M. Collantes, D282214, 6/19/02) addressed the potential residential handler exposures to adults and the potential residential postapplication exposures to adults and children.

Residential Handler
The Agency has determined that there is potential for residential handlers to be exposed to metsulfuron-methyl during the following activities: 
   *	mixing/loading/applying water dispersable granules/dry flowables with low pressure handwand equipment;
   *	mixing/loading/applying water dispersable granules/dry flowables with backpack sprayer equipment;
   *	mixing/loading/applying water dispersable granules/dry flowables with hose end sprayer equipment; and
   *	mixing/loading/applying water dispersable granules/dry flowables with sprinkler can equipment.

The 2002 exposure assessment assessed two residential handler scenarios (i.e., low pressure handwand sprayer and hose end sprayer).  Residential handler exposures were estimated using exposure data from the Pesticide Handler Exposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF).

The non-cancer handler risk estimates presented in the 2002 exposure assessment indicate that all of the residential handler scenarios resulted in risks that did not exceed HED's level of concern (i.e., MOEs > 100).  

Residential Post-Application 
The Agency has determined that there is potential for residential postapplication exposure to children from use of metsulfuron-methyl on residential lawns and to adults from use of metsulfuron-methyl on residential lawns and golf courses.

In the 2002 exposure assessment, a number of postapplication residential exposure scenarios were assessed for adults and children.  These scenarios included playing on a treated lawn (adults and children) and golfing on treated turf (adults only).  For adults, dermal exposures were assessed for all scenarios while for children, dermal and non-dietary ingestion exposures were assessed for all scenarios.  Post-application exposures were calculated using the HED Draft SOP's for Residential Exposure Assessments (12/18/97).  All scenarios for both adults and children had MOEs that did not exceed HED's level of concern (MOE >=100).

Residential bystander inhalation exposures resulting from off-site transport (e.g., spray drift or volatilization) may occur as a result of applications of metsulfuron-methyl.  The Agency is in the process of evaluating these types of exposures and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  The need for a bystander inhalation risk assessment for metsulfuron-methyl should be examined during registration review.

Conclusions for Residential Exposure and Risk Assessment
The residential exposure database is adequate to support the registration review process for metsulfuron-methyl.  An updated residential exposure assessment may be required under registration review based upon revisions to HED's Residential SOPs which were reviewed by the Scientific Advisory Panel (SAP) in October 2009.  An updated assessment may also be required if new data are identified which impact exposure estimates, new points of departure, a revised FQPA SF, or revisions to exposure policies and procedures are made.

Aggregate Risk Assessment
In the 2002 metsulfuron-methyl risk assessment, HED determined that short-term, intermediate-term, and chronic aggregate risk assessments were appropriate.  The chronic aggregate assessment was equivalent to the chronic dietary risk assessment.  The chronic dietary risk estimates for the general population and all population subgroups were not of concern to HED.

For the short- and intermediate-term aggregate assessment, HED combined residential exposures from turf with the chronic dietary exposures.  HED concluded that the combined residues of metsulfuron-methyl from food and other potential residential exposures do not result in short- and intermediate-term aggregate risks of concern.  

As noted above in the dietary section, the 2002 risk assessment did not directly incorporate drinking water into the dietary assessment and thus a new chronic dietary assessment is required during registration review.  As a result, during registration review, new short-term, intermediate-term, and chronic aggregate risk assessments are required.

Conclusions for Aggregate Exposure and Risk Assessment
Updated aggregate exposure and risk assessments will be required under registration review based on the need for directly incorporating drinking water into the dietary exposure estimates.

Occupational Exposure and Risks
Metsulfuron-methyl is registered as a water dispersable granule (WDG)/dry flowable (DF) for occupational use on a number of agricultural field crops, on conifers and hardwoods, on industrial sites, and on turf.  It may be applied pre- or post-emergence using aerial and ground equipment.  

Occupational Handlers
The Agency has determined that there is potential for occupational handlers to be exposed to metsulfuron-methyl during the following activities: 
   *	mixing and loading of water dispersable granule (WDG)/dry flowable (DF) to support groundboom and aerial equipment;
   *	applying sprays with groundboom and aerial equipment;
   *	mixing/loading/applying water dispersable granules/dryflowables with low pressure handwand equipment, backpack sprayer equipment, and turfgun equipment; and 
   *	flagging for aerial sprays.
   
The 2002 exposure assessment assessed a number of occupational handler scenarios.  Occupational handler exposures were estimated using exposure data from PHED and ORETF.

The non-cancer handler risk estimates presented in the 2002 exposure assessment indicate that all of the occupational handler scenarios resulted in risks that did not exceed HED's level of concern (i.e., MOEs > 100) at some level of risk mitigation.  

Occupational Postapplication
The Agency has determined that there is the potential for occupational postapplication exposures to individuals entering areas treated with metsulfuron-methyl including, agricultural fields, conifers and hardwood forests, industrial sites, and turf.

The 2002 exposure assessment assessed the occupational postapplication exposure resulting from applications of metsulfuron-methyl to sorghum, conifer and hardwoods, industrial sites, and turf.   It did not assess all of the potential postapplication exposures that could result from the other agricultural uses of metsulfuron-methyl (e.g., barley, sugarcane, and wheat).  The 2002 assessment utilized surrogate transfer coefficient data from the Agricultural Reentry Task Force (ARTF) database.  For all postapplication exposure scenarios, non-cancer risks do not exceed HED's level of concern (i.e., MOEs > 100) on the day of application.  

Metsulfuron-methyl is classified as Toxicity Category I for primary eye irritation and thus should have a Restricted Entry Interval (REI) of 48 hours based on the Worker Protection Standard.  Current metsulfuron-methyl labels appear to carry either a 4 or 12 hour REI so this issue should be revisited during registration review.

Conclusions
The occupational exposure database is adequate to support the registration review process for metsulfuron-methyl.  No new handler or postapplication worker studies are needed at this time.  Revised occupational handler and postapplication assessments may be needed if toxicological endpoints change, other new data are received by EPA, or other parameters are modified, such as changes to Standard Operating Procedures or default exposure assessment assumptions.  Determination of the appropriate REI for metsulfuron-methyl should be performed during registration review.

Human Studies
Metsulfuron-methyl 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 PHED, ORETF, and ARTF have been reviewed by the Agency and found on the basis of available evidence to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted.  There is no barrier in EPA's "Protection of Human Subjects" regulation to reliance on these studies.

Public Health and Pesticide Epidemiology Data
An updated review of metsulfuron-methyl incident reports was recently prepared by HED (K. Oo, D389637, 05/25/2011).  For this evaluation, the OPP Incident Data System (IDS) was consulted for pesticide incident data on the active ingredient metsulfuron-methyl. 

The IDS includes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports from registrants, other federal and state health and environmental agencies and individual consumers.  IDS contain reports from across the U.S. and most incidents have all relevant product information recorded.  Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report.  IDS records incidents resulting in higher severity outcomes in more detail, in a module called the Main IDS module.  This system stores incident data for death, major and moderate incidents, and it includes more details about the location, date and nature of the incident.

For IDS aggregate summaries, from January 1, 2006 to March 31, 2011, there are 37 cases reported for metsulfuron-methyl.  Because it falls within the categories reported as counts (which includes minor, unknown or no effects), there is no unique report that provides details about the incident and single chemical incidents are not distinguished from multiple chemical incidents; however, a high frequency of incidents indicates there is a high potential for exposure and vice versa.  For the Main IDS, from January 1, 2006 to March 31, 2011, there are 12 cases reported that involve the active ingredient metsulfuron-methyl.  However, there are no incidents reported for single chemical metsulfuron-methyl only in the database.  

Based on the low frequency and severity of incident cases, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included during registration review.

Tolerance Assessment and International Harmonization
Tolerances are established under 40 CFR§180.428(a) for residues of the herbicide metsulfuron-methyl, including its metabolites and degradates, in or on a variety of plant commodities as well as in or on livestock commodities (see Table 4).  The Codex Alimentarius Commission and Mexico have not established maximum residue limits (MRLs) for metsulfuron-methyl.  Canada has established MRLs for some plant and livestock commodities.  Any metsulfruon-methyl tolerances reassessed during the registration review process will be considered for possible harmonization with international MRLs should they be established.

Environmental Justice
Potential areas of environmental justice concerns, to the extent possible, will be considered in the registration review 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.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf.  The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops.  Should these high exposures indicate potential risks of concern, OPP will further refine the risk assessments to ensure that the risk estimates are based on the best available information.

Cumulative Risk Assessment
At this time, EPA does not have available data to determine whether metsulfuron-methyl has a common mechanism of toxicity with other substances.  EPA has not made a common mechanism of toxicity finding as to metsulfuron-methyl and any other substances, and metsulfuron-methyl 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 metsulfuron-methyl has a common mechanism of toxicity with other substances.

Data Requirements
HED does not anticipate that additional residue chemistry, toxicology or occupational/residential exposure data will be required for the metsulfuron-methyl registration review process, with the exception of the following studies listed below:
   * Immunotoxicity Study (OPPTS 870.7800)
   * Neurotoxicity Battery (Acute and Subchronic Studies) (OPPTS 870.6200)
The following study was previously required as a condition of registration for the use of metsulfuron-methyl on sorghum.  To date, the Agency has not received this study.
   * 28-Day Inhalation Study (OPPTS 870.3465) - The 90-day study protocol should be followed using an exposure duration of 28 days.
Table 1.  Metsulfuron-methyl Nomenclature
Compound
Chemical Structure



Common name
AE F075736; metsulfuron-methyl
IUPAC name
Methyl 2-[3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)ureidosulphonyl]benzoate
CAS name
Methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)amino]carbonyl]amino]sulfonyl]-benzoate
CAS registry number
74223-64-6
Molecular formula
C14H15N5O6S

Table 2.  Physicochemical Properties of the Technical Grade Metsulfuron-methyl
Parameter
Value
Reference
Melting point/range
158 °C

Water solubility (mg/L at 25°C)
109 at unbuffered, pH 4.1
270 at buffered pH 4.6
1750 at buffered pH 5.4
9500 at buffered pH 6.7

Solvent solubility (mg/L at 20°C)
0.79 in n-hexane 0.79
580 in xylene
2300 in ethanol
7300 in methanol
36000 in acetone
121000 in methylene chloride

Vapor pressure (@ 25°C)
2.5 X 10 -12 mm Hg

Octanol/water partition coefficient Log(KOW)
0.018













Table 3A.  Metsulfuron-methyl Toxicology Data Requirements
Test 
Technical

Required
Satisfied
870.1100	Acute Oral Toxicity	
870.1200	Acute Dermal Toxicity	
870.1300	Acute Inhalation Toxicity	
870.2400	Primary Eye Irritation	
870.2500	Primary Dermal Irritation	
870.2600	Dermal Sensitization	
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100	Oral Subchronic (rodent)	
870.3150	Oral Subchronic (nonrodent)	
870.3200	21/28-Day Dermal	
870.3250	90-Day Dermal	
870.3465	90-Day Inhalation	
yes
yes
yes
no
yes[1]
yes
yes
yes
---
no
870.3700	Developmental Toxicity (rodent)	
870.3700	Developmental Toxicity (nonrodent)	
870.3800	Reproduction	
yes
yes
yes
yes
yes
yes
870.4100	Chronic Toxicity (rodent)	
870.4100	Chronic Toxicity (nonrodent)	
870.4200	Oncogenicity (rat)	
870.4200	Oncogenicity (mouse)	
870.4300	Chronic/Oncogenicity (mouse)	
870.4500	Chronic/Oncogenicity (rat)	
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100	Mutagenicity -- Gene Mutation - bacterial	
870.5300	Mutagenicity -- Gene Mutation - mammalian	
870.5375	Mutagenicity -- Structural Chromosomal Aberrations	
870.5385	Mutagenicity -- Structural Chromosomal Aberrations	
870.5395	Mutagenicity -- Other Genotoxic Effects	
870.5550	Mutagenicity -- Other Genotoxic Effects	
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.6100	Acute Delayed Neurotox. (hen)	
870.6100	90-Day Neurotoxicity (hen)	
870.6200	Acute Neurotox. Screening Battery (rat)	
870.6200	Chronic Neurotox. Screening Battery (rat)	
870.6300	Develop. Neuro	
no
no
yes
yes
no
---
---
no
no
---
870.7485	General Metabolism	
870.7600	Dermal Penetration	
870.7800    Immunotoxity
yes
no
yes
yes
---
no

[1]	A 28-day inhalation study was previously required as a condition of registration for the use of metsulfuron-methyl on sorghum.  At this time, the Agency has not received this study.
Table 3B.  Metsulfuron-methyl Acute Toxicity Profile
Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral  -  rat
94.9% a.i.
                                   42545901
LD50 > 3000 mg/kg (HDT)
                                      III
870.1200
Acute dermal  - rabbit
92.9% a.i.
                                   00125828
LD50 > 2000 mg/kg (ODT)
                                      III
870.1300
Acute inhalation  - rat
92.9% a.i.
                                   00125830
LC50 > 5.3 mg/L/4hr (dust inhalation)
                                      IV
870.2400
Acute eye irritation  - rabbit
95% a.i.
                                   40357801
Moderate to severe irritation
                                       I
870.2500
Acute dermal irritation  -  rabbit  95.8% a.i.
                                   40858802
                                   42559604
Non-irritating
                                      IV
870.2600
Skin sensitization  -  guinea pig  95.8% a.i.
                                   40858803
                                   42559600
Negative dermal sensitizer
                                      N/A

Table 3C.  Metsulfuron-methyl Subchronic, Chronic and Other Toxicity Profile
                                Guideline No. 
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3100

13-Week feeding  -  rat
125834 (1982)
Acceptable
NOAEL: 68/64 mg/kg/day (M/F)
LOAEL: 52 1/659 mg/kg/day (M/F) based on transient decreases in body weight gain
870.3200

21/28-Day dermal toxicity - rabbit
40357803 (1987) 
41247801 (1989)
Acceptable
Dermal NOAEL: 125 mg/kg/day
Dermal LOAEL: 500 mg/kg/day (skin lesions characterized by diffuse/multifocal dermatitis
Systemic NOAEL: 125 mg/kg/day
Systemic LOAEL: 500 mg/kg/day based on increased incidence of diarrhea.
870.3700

Prenatal developmental in the rat
125835 (1982)  
153318 (1985) 
Acceptable
Maternal NOAEL: 250 mg/kg/day
Maternal LOAEL: 1000 mg/kg/day based on salivation and decreased body weight gain - compensatory increase after dosing stopped.
Developmental NOAEL: 1000 mg/kg/day (HDT) Developmental LOAEL: >1000 mg/kg/day (HDT)
870.3700

Prenatal developmental in the rabbit
125836 (1982)
153319 (1985)
Acceptable
Maternal NOAEL: 25 mg/kg/day
Maternal LOAEL: 100 mg/kg/day based on increased mortality, decreased body weight gains, and clinical signs of anorexia, red/orange urine and/or exudate.
Developmental NOAEL: > 700 mg/kg/day (HDT) Developmental LOAEL: >700 mg/kg/day (HDT)
870.3800

Reproduction and fertility effects in the rat

151028 (1985)
Acceptable
Parental systemic NOAEL: 34/43 mg/kg/day (M/F) Parental systemic LOAEL: 342/475 mg/kg/day (M/F) (decreased premating body weight gains by FO males and females).
Offspring/Reproductive NOAEL: > 342/475 mg/kg/day (M/F) Offspring/Reproductive LOAEL: > 342/475 mg/kg/day (M/F)
870.4100

Chronic oral toxicity in the dog

141821 (1984)
Acceptable
NOAEL: >125 mg/kg/day (M/F) at the HDT 
LOAEL: not determined
870.4300

Carcinogenicity in the mouse by the oral route

151135 (1985)
Acceptable
NOAEL: 666/836 mg/kg/day (M/F) at the HDT 
LOAEL: not determined.
No evidence of carcinogenic potential of the test material.
870.4500
Combined Chronic/Carcin-ogenicity in the rat by the oral route
154477 (1985)
Acceptable
NOAEL: 25 mg/kg/day in M/F
LOAEL: 250 mg/kg/day in M/F (decreased body weight and body weight gain)
No evidence of carcinogenic potential of the test material.
870.5100

Salmonella typhimurium, Ames assay
125837 (1980)
Acceptable
Not mutagenic under the conditions of the study.
870.5375
In vitro mammalian chromosomal
aberrations - CHO cells (2 studies)
125838 (1982)   125839 (1983)
Acceptable
Metsulfuron methyl is not a clastogen under the conditions of the study.
870.5385

In vivo mammalian chromosome aberrations - rat bone marrow
125840 (1983)
Acceptable
Metsulfuron methyl did not induce a significant increase in chromosome aberrations in bone marrow cells when compared to the vehicle control group.
870.5395

In vivo mammalian cytogenetics -
micronucleus assay in mice
41118002 (1989)
Acceptable
Metsulfuron methyl was negative at the limit dose for clastogenic activity in the micronucleus assay in bone marrow cells.
870.5550

UDS assay in primary rat hepatocytes/
mammalian cell culture
41773901 (1990)
42545801 (1990)
43035601 (1993)
Acceptable
Metsulfuron methyl was negative for UDS in mammalian hepatocytes in vivo.
870.7485

Metabolism and pharmaco-kinetics in the rat
141828 (1984)
Acceptable
The primary route of excretion was via the urine which accounted for approx. 7 1-95% (78-96% if cage wash radioactivity is considered) among the various treatment groups. Fecal elimination was 4.8-13.3%. 
Tissue burdens were minimal (generally <0.1% to 1%) regardless of exposure protocol; the gastrointestinal tract, carcass, and skin had the highest concentrations of radioactivity. No evidence for sequestration of the test article or its biotransformation products.
Four metabolites and parent were recovered in both urine and feces in all treatment groups. Parent compound accounted for most of the urinary and fecal radioactivity (77-90% and 1.8-6.2% of the administered dose, respectively). Metab. I was consistent with (methyl 2-[(amino)sulfonyl] benzoate); Metab. II - (2-[(amino)sulfonyl]-benzoic acid); and Metab. III was consistent with (methyl 2-[[{(amino)carbonyl]aminoj sulfonyl] benzoate). Metab. I and II appeared to result from sequential hydrolysis reactions terminating in the formation of saccharin while Metab. III was formed by cleavage of the two ring structures. Total metabolites (in urine + feces of each group) accounted for approximately 5.4-8.2% of the administered dose. The metabolite profiles were qualitatively similar for urine and feces in that parent compound and the four metabolites (saccharin, Metabolites I, II, and III) were found in both matrices.












Table 3D.  Metsulfuron-methyl Summary of Toxicological Doses and Endpoints for Use in Dietary Human Health Risk Assessments.
Exposure Scenario
                              Point of Departure
                             Uncertainty/FQPA SFs
                 Population Adjusted Dose for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary All Populations
A single dose effect relevant to the general US population including infants and children was not identified in the toxicity studies conducted with metsulfuron-methyl.
Chronic Dietary (All Populations)
NOAEL = 25 mg/kg/day
UFA = 10x
UFH =10x
FQPA SF= 1x
cPAD = 0.25 mg/kg/day
Rat, Oral Chronic/Carcinogenicity  Toxicity Study
LOAEL = 250 mg/kg/day based on decreased body weight and body weight gain.
Incidental oral (short- & intermediate-term)
NOAEL = 34 mg/kg/day (parental)
UFA = 10x
UFH =10x
FQPA SF= 1x
Residential LOC for MOE = 100
Rat, 2 Generation Reproduction Study
LOAEL = 342 mg/kg/day based on decreased premating (FO) body weights.
Dermal exposure (all durations)
NOAEL = 125 mg/kg/day
UFA = 10x
UFH =10x
FQPA SF= 1x
Residential LOC for MOE = 100
Rabbit, 21 Day Dermal Exposure Study
LOAEL = 500 mg/kg/day based on increased incidences of diarrhea.

Inhalation exposure (short- & intermediate term)
NOAEL = 34 mg/kg/day (parental)
Oral study
UFA = 10x
UFH =10x
FQPA SF= 1x
IA = 100%
Residential LOC for MOE = 100
Rat, 2 Generation Reproduction Study
LOAEL = 342 mg/kg/day based on decreased premating (FO) body weights.
Inhalation exposure (long term)
NOAEL = 25 mg/kg/day
Oral study
UFA = 10x
UFH =10x
FQPA SF= 1x
IA = 100%
Residential LOC for MOE = 100
Rat, Oral Chronic/Carcinogenicity  Toxicity Study
LOAEL = 250 mg/kg/day based on decreased body weight and body weight gain.
Cancer (oral, dermal, inhalation)
Metsulfuron methyl is classified as "not likely to be carcinogenic to humans." This is based on the lack of evidence of carcinogenicity in mice and rats, no evidence of mutagenicity in acceptable studies, and the non-carcinogenic potential of structurally related compounds.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation 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).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).


Table 3E.  Metsulfuron-methyl Summary of Toxicological Doses and Endpoints for Metsulfuron methyl for Use in Occupational Human Health Risk Assessments
Exposure/
Scenario
Point of Departure
Uncertainty Factors
Level of Concern for Risk Assessment
Study and Toxicological Effects
Dermal exposure (all durations)
NOAEL = 125 mg/kg/day
UFA = 10x
UFH =10x
Occupational LOC for MOE = 100
Rabbit, 21 Day Dermal Exposure Study
LOAEL = 500 mg/kg/day based on increased incidences of diarrhea.
Inhalation exposure (Short- & intermediate term)
NOAEL = 34 mg/kg/day (parental)
Oral study
UFA = 10x
UFH =10x
IA = 100%
Occupational LOC for MOE = 100
Rat, 2 Generation Reproduction Study
LOAEL = 342 mg/kg/day based on decreased premating (FO) body weights.
Inhalation exposure (long term)
NOAEL = 25 mg/kg/day
Oral study
UFA = 10x
UFH =10x
IA = 100%
Occupational LOC for MOE = 100
Rat, Oral Chronic/Carcinogenicity  Toxicity Study
LOAEL = 250 mg/kg/day based on decreased body weight and body weight gain.
Cancer (oral, dermal, inhalation)
Metsulfuron methyl is classified as "not likely to be carcinogenic to humans." This is based on the lack of evidence of carcinogenicity in mice and rats, no evidence of mutagenicity in acceptable studies, and the non-carcinogenic potential of structurally related compounds.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation 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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key date (i.e., lack of a critical study).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.  IA = inhalation absorption factor




















Table 4.  Metsulfuron-methyl International Residue Limits 
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US 
Canada
Mexico[2]
Codex[3]
40 CFR 180.428(a)1: 
Plants: combined residues of the herbicide metsulfuron methyl (methyl 2-[[[[(4-methoxy-6-methyl-1,3,5- triazin- 2-yl)amino]carbonyl]amino] sulfonyl] benzoate) and its metabolite methyl 2-[[[[(4-methoxy-6-methyl-1-,3,5- triazin-2-yl)amino]carbonyl]amino] sulfonyl]-4-hydroxybenzoate 

methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)
amino]carbonyl]amino]sulfonyl]benzoate, including the
metabolite methyl 2-[[[[(4-methoxy-6-methyl-1,3,5-
triazin-2-yl)amino]carbonyl]amino]sulfonyl] 4-
hydroxybenzoate


None
Commodity[1]
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US
Canada
Mexico[2]
Codex[3]
Barley, grain
0.1
0.1


Barley, hay
20.0



Barley, straw
0.3



Grass, forage
15.0



Grass, hay
15.0



Grass, straw
15.0



Sorghum, grain, forage
0.2



Sorghum, grain, grain
0.1



Sorghum, grain, stover
0.2



Sugarcane, cane
0.05



Wheat, forage
5.0



Wheat, grain
0.1
0.1


Wheat, hay
20.0



Wheat, straw
0.3



2
Canada
Mexico[2]
Codex[3]
 metsulfuron methyl (methyl-2[[[[(4-methoxy- 6-methyl-1,3,5-triazin-2- yl)amino]carbonyl]amino] sulfonyl] benzoate)
Same as above


None
Commodity[1]
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US
Canada
Mexico[2]
Codex[3]
Cattle, fat
0.1
0.1


Cattle, kidney
0.5
0.5


Cattle, meat
0.1
0.1


Cattle, meat byproducts
0.1
0.1


Goat, fat
0.1
0.1


Goat, kidney
0.5
0.5


Goat, meat
0.1
0.1


Goat, meat byproducts
0.1
0.1


Hog, fat
0.1
0.1


Hog, kidney
0.5
0.5


Hog, meat
0.1
0.1


Hog, meat byproducts
0.1
0.1


Horse, fat
0.1



Horse, kidney
0.5



Horse, meat
0.1



Horse, meat byproducts
0.1



Milk
0.05
0.05


Sheep, fat
0.1



Sheep, kidney
0.5



Sheep, meat
0.1



Sheep, meat byproducts
0.1



[1] Includes only commodities of interest for this action.  Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains.  PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.













Table 5: HED Memoranda Relevant to Registration Review 
Author
Barcode/TXR #
Date
Title
M. Collantes	

                                    D282214
                                       
6/19/2002	
                                       
Occupational and Residential Exposure and Risk for the Proposed Use of Metsulfuron-Methyl on Sorghum. 

W. Cutchin, S. Williams-Foy, M. Collantes

                                    D281907
                                       
6/26/2002
                                       
Human Health Risk Assessment for the Section 3 Registration of Metsulfuron Methyl on Grain Sorghum.


