**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**MEMORANDUM** DATE: August 30 , 2011 SUBJECT: **Metsulfuron**  

Human Health Assessments ** PC Code:** 122010 **MRID No.:** NA **Petition No.:** NA **Assessment Type:** Single Chemical/ Aggregate T **XR No.:** NA FROM : Charles Smith

Sheila Piper, Senior Chemist Monica Hawkins, Ph.D., M.P.H., Environmental Health Scientist Steven Dapson Risk Assessment Health Effects Division (7509P) THROUGH: Felecia Fort , Branch Chief

Risk Assessment Health Effects Division (7509P) TO: Jill Bloom , Chemical Review Manager

Risk Management and Pesticide Re - E **Executive Summary** The Health Effects Division (HED) evaluated the status of the human health assessment for the to determine the scope of work necessary to support Registration Review. methyl is registered for use on a hardwoods, on industrial sites, and on turf iodosulfuron - methyl (currently registered only

on corn) in water. Alimentarius Commission and Mexico have not established maximum residue limits (MRL s) for metsulfuron - methyl. Canada has established MRL s for some plant a livestock commodities. The most recent methyl w ere completed in 200

**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND** 

**POLLUTION PREVENTION** 2011

**- Methyl**  **:** R egistration Review Scoping Document for Health Assessments . **DP Barcode:** D 389257

**Registration No. :**  NA **Regulatory Action:** Registration Review Single Chemical/ **Reregistration Case No.:** 7205

**CAS No.:** 74223 - 64 - 6 Charles Smith , Senior Environmental Scientist /Risk Assessor Sheila Piper, Senior Chemist Monica Hawkins, Ph.D., M.P.H., Environmental Health Scientist Steven Dapson , P hD , Senior Toxicologist Risk Assessment Branch V I Health Effects Division (7509P)

Branch Chief Risk Assessment Branch V I Health Effects Division (7509P)

Chemical Review Manager Risk Management and Implementation Branch I I

E valuation Division (7508 P ) The Health Effects Division (HED) Metsulfuron - Methyl Registration Review Team has evaluated the status of the human health assessment for the herbicide metsulfuron to determine the scope of work necessary to support Registration Review. Metsulfuron 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

methyl (currently

registered only

on corn) in water. The Codex Alimentarius Commission and Mexico have not established maximum residue limits methyl. Canada has established MRL s for some plant a The most recent exposure and risk assessment s for metsulfuron 200 2 ( M. Collantes, D282214, 6/19/02 and W . Cutchin **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**OFFICE OF CHEMICAL SAFETY AND**

**POLLUTION PREVENTION**

egistration Review Scoping Document for Registration Review

Monica Hawkins, Ph.D., M.P.H., Environmental Health Scientist

Registration Review Team has

metsulfuron - methyl Metsulfuron - , on conifers and principal degradate of The Codex Alimentarius Commission and Mexico have not established maximum residue limits methyl. Canada has established MRL s for some plant a nd metsulfuron Cutchin ,Page 2 of 21

D 281907 , 6 /2 6 /200 2 ) . Based on the current use profile, exposures can be exp ected 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 previousl y required as a condition of registration for the use o f metsulfuron - methyl on sorghum ( W. Cutchin, D281907, 6/26/2002) . This study

has not been submitted to the Agency as this time. T he Agency has classified metsulfuron - methyl as “not likely to be carcinogenic to humans” based on the results of carcinogenic ity 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 ey e 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 uncertaint y 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 adequatel y identifie d/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 data

base 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 infor

mation while directl y 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, a ll of the non - cancer residential handler and postapplication risk estimates we re below the Agency ’s level of concern. No ne w 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 Advis ory

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 occupationa l exposure database is adequate to support the registration review process for metsulfuron - methyl . In the 2002 exposure assessment, a ll 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 b y EPA, or other parameters are modified, such as changes to Standard Operating Procedures or defaultPage 3 of 21

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 variet y of annual grasses and broadleaf weeds. It is also the principal degradate of iodosulfuron - methyl (currentl y registered onl y on corn) in water. HED has reviewed the most recent exposure and risk assessments for me tsulfuron - 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. Additi onall y, the t eam 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 fe ed crops, on conifers and hardwoods, on industrial sites, and on turf . Sulfonylurea compounds inhibi t acetolactate s ynthase (ALS) which is involved in cell division at the root tip. Registered products containing metsulfuron - methyl include water dispersa ble granule ( WD G) / 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 commodi ties. Compliance with the tolerance levels is to be determined b y measuring only the sum of metsulfuron - methyl (methyl 2 - [[[[(4 - methox y - 6 - methyl - 1,3,5 - triazin - 2 - yl )amino]carbonyl]amino]sulfonyl] benzoate) and its metabolite, methyl 2 - [[[[(4 - methoxy- 6 - meth yl - 1,3,5 - triazin - 2 - yl )amino]carbon yl ]amino]sulfonyl] - 4 - (beta - D - gl yc opy ranos yl )benzoate (Metabolite A) and methyl 2 - [[[[(4 - methox y- 6 - methyl - 1,3,5 - triazin - 2 - yl )amino]carbon yl ]amino]sulfonyl] - 4 - hydrox yb enzoate (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 t o be determined b y 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 phy sicochemic al properties of technical grad e 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 s evere ey e irritant (Category 1) but does not cause primary dermal irritation . Metsulfuron - methyl is not a skin sensitizer.Page 4 of 21

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 H ED Hazard I dentification Assessment Review Committee (HIARC), in accordance with the 1999 Draft Guidance for Carcino genic 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 - carcinogen ic potential of structurally related compounds. Metsulfuron - methyl i s well absorbed regardless of dose or treatment regimen (single gavage dose alone or after repeated dietary feeding). The primary

route of excretion i s via the urine (71 - 95%) followed b y fecal elimination (4.8 - 13.3%) and levels remaining in the tissues are negligible. HED has full y 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 childr en; 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 n on - 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 i mmunotoxicity

study is also required as a part of the new data requirements in 40 CFR Part 158 for conventional pesticide registration. Because the immune sy stem is highl y complex, studies not specificall y conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity . While data from hematology , l ymphoid 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 stud y is required to detect and more full y characterize the p otential immuno toxic 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 uncertaint y factors used in risk assessment . Inthe absence of the require d studies, EPA may use a database uncertaint y 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).Page 5 of 21

Endocrine Disruption As required b y 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 carcinogenicit y, neurotoxici ty , developmental, reproductive, and general or s ys temic toxicity . These studies include endpoints which may

be susceptible to endocrine influence, including effects on endocrine target organ histopathology , organ weights, estrus cy clicity , sexual maturati on, 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 b y FFDCA section 408(p), metsulfuron - methyl is subject to the en docrine 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 effec t produced by

a “naturally

occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employ s a two - tiered approach to making the statutorily

required determinations. Tier 1 consists of a battery of 11 screening assa ys to identify

the potential of a chemical substance to interact with the estrogen, androgen, or thy roid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal s ys tems 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 an y 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 gr oup 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. Accordingl y, as part of registrat ion review, EPA will issue future EDSP orders/data call - ins, requiring the submission of EDSP screening assay s 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 p reviousl y 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 Committe e (MARC) determined that the residue of concern for plants is metsulfuron - methyl and its metabolite, methyl 2 - [[[[(4 -Page 6 of 21

methoxy- 6 - methyl - 1,3,5 - triazin - 2 - yl )amino]carbonyl]amino]sulfonyl] - 4 - (beta - D gl ycop yr anos yl )benzoate (Metabolite A) and methyl 2 - [[[[(4 - methoxy- 6 - methyl - 1,3,5 - triazin - 2 - yl )amino]carbonyl]amino]sulfonyl] - 4 - hy drox yb enzoate (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) h as not been updated to reflect current HED policies. Adequate anal yt ical methods (HPL C/UV) exist for data collection and tolerance enforcement. PAM Vo l . II lists Methods I and III which are respectivel y capable of determining residues of metsulfuron - meth yl 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 Expos ure and Risks**  An unrefined chronic dietary (food onl y) 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 W

ater 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 a ssociation with the use on sorghum. The FIFRA Index Reservoir Screening Tool (FIRST) was used for estimating the concentration of metsul furon - 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 b y comparing these modeled surface and ground water estimates against calculated drinking water levels of comparison (DWL OCs). This asse ssment 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 Wa ter ) 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 dietaryPage 7 of 21

exposure e stimates did not exceed HED’s level of concern (<100% cPAD) for an y population subgroup. Conclusions for Dietary Exposure and Risk The dietary

exposure database is adequate to support the existing registrations. However, i t will be necessary

for HED to co nduct 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 c o nsumption 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 Ris ks**  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/appl yi ng water dispersable granules/dry flowables with low pressure handwand equipment;  mixing/loading/appl yi ng water dispersable granules/dry flowables with backpack spray er equipment;  mixing/loading/appl yi ng water dispersable granules/dry flowables with hose end spray er equipment; and  mixing/loading/appl yi ng 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 spray er). Residential handler exposures were estimated using exposure data from the Pesticide Handler Expos ure 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).Page 8 of 21

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 mets ulfuron - 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 childr en) and golfing on treated turf (adults onl y). 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 by stander 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 t yp es of exposures and may , as appropriate, develop policies and procedures to identify the need for and, subsequentl y, the way to incorporate post - application inhalation exposure into the Agency ’s risk assessments. The need for a b ys tander 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 w ere reviewed b y the Scientific Advisory Panel (SAP) in October 2009. An updated assessment may

also be required if n ew 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 sh ort - 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 an d 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.Page 9 of 21

Conclusions for Aggregate Exposure and Risk Assessment Updated aggregate exposure and risk assessment s will be required under registration review based on the need for directl y incorporating drinking water into the dietary exposure estimates . **Occupational Exposure and Risks** Metsulfuron - methyl is regi stered 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 spray s with groundboom and aerial equipment;  mixing/loading/appl yi ng wat er dispersable granules/dry flowables with low pressure handwand equipment, backpack spray er equipment, and turfgun equipment; and  flagging for aerial spray s . 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 indic ate 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 o ccupational postapplication exposures to individuals entering areas treated with metsulfuron - methyl including, agricultural fields, conifers and hardwood forests, industrial sites, and turf. T he 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 exc eed HED’s level of concern (i.e., MOEs > 100) on the day

of application. Metsulfuron - methyl is classified as Toxicity Category Ifor primary

ey e irritation and thus should have a Restricted Entry Interval (REI) of 48 hours based on the WorkerPage 10 of 21

Protection Standard. Current metsulfuron - methyl labels appear to carry either a 4 or 12 hour REIso this issue should be revisited during registration review. Conclusions The occupational exposure database is adequate to support the registration review p rocess 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 b y 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 rel y 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 avail able 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 relianc e on these studies. **P ublic Health and Pesticide Epidemiology Data**  An updated review of metsulfuron - methyl incident reports was recently prepared by

HED ( K. Oo, D 389637 , 05 / 25 /2011 ) . For this evaluation, the OPP Incident Data Sy stem (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 high er severit y outcomes in more detail, in a module called the Main IDS module. This sy stem 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, 200 6 to March 31, 2011, there are 37 case s reported for metsulfuron - methyl . Because it falls within th e 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 frequenc y of incidents indicates there is a high potential for exposure and vice versa . For the M ain IDS, from January 1, 200 6 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 onl y in the database. Based on the low frequency and severity

of incident cases, there does not appear to be a conce rn at this time that would warrant further investigation. The Agency will continue toPage 11 of 21

monitor the incident information and if a concern is triggered, additional a naly sis 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 ) . T he Codex Alimentarius Commission and Mexico have not established maximum residue limits ( MRL s ) for metsulfuron - methyl . Canada has established MRL s for some plant and livestock commodities. Any metsulfruon - methyl tolerances reassessed during the registration review process will be considered for possible harmonization with international MRL s should they be established . **Environmental Justice** Potential areas of environmental justice concerns, to the extent possible, will be considered in th e registration review human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) ty pically considers the highest potential exposures from the legal use of a pesticide when conducting human health ri sk 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 poten tial 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 - m eth yl has a common mechanism of toxicity with other substances. EPA has not made a common mechanism of toxicity finding as to metsulfuron - methyl and an y other substances, and metsulfuron - methyl does not appear to produce a toxic metabolite produced b y 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 stud ies listed below :  Immunotoxicity

Study (OPPT S 870.7800 )  Neurotoxicity

Battery (Acute and Subchronic Studies) (OPPTS 870.6200) The following stud y 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 day s.Page 12 of 21

**T able**  **1. Metsulfuron**  **- methyl**  **Nomenclature**

Compound Chemical Structure

S N H N H O O O O C H 3 N

N C H 3

O C H 3 O

N

Common name AE F075736; mets ul furon - 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 **T able**  **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 s olubility (mg/L at 2 0 °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) 0.018Page 13 of 21

**Table 3A**  **. Metsulfuron**  **- methyl**  **Toxicology Data Requirements Test**  **Technical Required**  **Satisfied** 870.1100 Ac ute Oral Toxicity ................................ ...................... 870.1200 Ac ute Dermal Toxicity ................................ ................. 870.1300 Ac ute Inhalation Toxicity ................................ ............. 870.2400 Primary Eye Irritation ................................ ................... 870.2500 Primary Dermal Irritation ................................ ............. 870.2600 Derm al Sensitization ................................ .................... yes yes yes yes yes yes y es

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) ................................ .... 870.4 5 00 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 .. 870.53 8 5 Mutagenicity

— Structural Chromosomal Aberrations .. 870.5395 Mutagenicity

— Other Genotoxic Effects ...................... 870.5 550 Mutagenicity

— Other Genotoxic Effect s ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.6100 Ac ute Delayed Neurotox. (hen) ................................ .... 870.6100 90 - Day

Neurotoxicity (hen) ................................ ......... 870.6200 Ac ute 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 Derm al Penetration ................................ ....................... 870.7800 Immunotoxity yes no yes y es

--- **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.Page 14 of 21

**Table 3B**  **. Metsulfuron**  **- methyl**  **Acute Toxicity Profile** Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute oral

– rat

94.9% a.i. 42545901 LD 50 > 3000 mg/kg (HDT) III 870.1200 Ac ute dermal - rabbit

92.9% a.i. 00125828 LD 50 > 2000 mg/kg (ODT) III 870.1300 Ac ute inhalation - rat

92.9% a.i. 00125830 LC 50 > 5.3 mg/L/4hr (dust inhalation) IV 870.2400 Ac ute eye irritation

–rabbit

95% a.i. 40357801 Moderate to severe irritation I 870.2500 Ac ute 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 3**  **C. 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 Derm al NOAEL: 125 mg/kg/day Derm al LOAEL: 500 mg/kg/day (skin lesions characterized by diffuse/multifocal derm atitis Sy stemic NOAEL: 125 mg/kg/day Sy stemic 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)Page 15 of 21

**Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  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 Com

bined 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

ty phimurium, 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 com

pared to the vehicle control group. 870.5395 In vivo mammalian

cy togenetics - 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.Page 16 of 21

**Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  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 w as consistent with (m ethyl 2 - [(amino)sulfonyl] benzoate); Metab. II - (2 - [(amino)sulfonyl] - benzoic acid); and Metab. III w as consistent with (methyl 2 - [[{(amino)carbonyl]aminoj sulfonyl] benzoate). Metab. I and II appeared to result from sequential hydrolysis reactions terminati ng in the formation of saccharin while Metab. III w as 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 qualitativel y similar for urine and feces in that parent compound and the four metabolites (saccharin, Metabolites I, II, and III) w ere found in both matrices.Page 17 of 21

**Table 3D. Metsulfuron -**  **methyl Summary of Toxicological Doses and Endpoints for**  **Use in Dietary Hum**  **an Health Risk Assessments.** Exposure Scenario Point of

Departure Uncertainty/

FQPA SFs Population Adjusted

Dose for Risk Assessment Study and Toxicological Effects Ac ute Dietary All Populations A single dose effect relevant to the general US population including infants and children

wa s not identified in the toxicity studies conducted with metsulfuron - methyl. Chronic Dietary (All Populations) NOAEL = 25

mg/kg/day UF A = 10x

UF H =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) UF A = 10x

UF H =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. Derm al exposure (all durations) NOAEL = 125

mg/kg/day UF A = 10x

UF H =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 UF A = 10x

UF H =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 UF A = 10x

UF H =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 an d 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. UF A = extrapolation f rom animal to human (interspecies). UF H = potential variation in sensitivity am ong members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic).Page 18 of 21

**Table 3 E**  **. Metsulfuron -**  **methyl Su**  **mmary 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 Derm al exposure (all durations) NOAEL = 125

mg/kg/day UF A = 10x

UF H =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 UF A = 10x

UF H =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 UF A = 10x

UF H =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. Po int 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 obse rved adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity am ong members of the human population (intraspecies). U F L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term risk assessment. UF DB = 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 appl icable. IA = inhalation absorption factorPage 19 of 21



### 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]benzo ate, 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) Sam e 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 by

products 0.1 0.1 Goat, fat 0.1 0.1 Goat, kidney 0.5 0.5 Goat, meat 0.1 0.1 Goat, meat b yproducts 0.1 0.1 Hog, fat 0.1 0.1 Hog, kidney 0.5 0.5Page 20 of 21

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3 Hog, meat 0.1 0.1 Hog, meat b yproducts 0.1 0.1 Horse, fat 0.1 Horse, kidney 0.5 Horse, meat 0.1 Horse, meat b yp roducts 0.1 Milk 0.05 0.05 Sheep, fat 0.1 Sheep, kidney 0.5 Sheep, meat 0.1 Sheep, meat b yproducts 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 w heat. (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.Page 21 of 21

**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.