UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 16-APR-2013 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Mesosulfuron-methyl. Human Health Assessment Seeping Document in Support of 

Registration Review. 

PC Code: 122009 

Decision No.: 471309 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.:NA 

MRIDNo.:NA 

FROM: Nancy Dodd, Chemist/ .v-... ....,...£-od' 

Whang Phang, Toxicologist 

Kristin Rury, Biologist V: 

Risk Assessment Branch III (RA 

Health Effects Division (7509P) 

Office of Pesticide Programs 

DP Barcode: D406414 

Registration No.: NA 

Regulatory Action: Registration Review 

Case No.: 7263 

CAS No.: 208465-21-8 

40 CFR: 180.597 

THRU: Christine Olinger, Branch Chief fJ ( Risk Assessment Branch Ill (RAB3 f 

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Jolene Trujillo, Chemical Review Manager 

Risk Management and Implementation Branch V (RMIB5) 

Pesticide Re-Evaluation Division (PRD) (7508P) 

Office of Pesticide Programs 

Page 1 of 19 
Executive Summary 

The HED Registration Review Team has evaluated the human health assessment for the 

herbicide mesosulfuron-methyl to determine whether sufficient data are available and whether 

any updates are needed to support Registration Review. Mesosulfuron-methyl is only registered 

for use on wheat and triticale. To evaluate the scope of work necessary to support Registration 

Review, HED has considered the previous human-health risk assessment conducted for this 

chemical as well any updates to the toxicity, exposure, and usage databases, and current Agency 

science policy and risk assessment methodologies. In addition, HED conducted an open 

literature search of the scientific databases for any potential data relevant to the human health 

risk assessment and found no relevant toxicity or exposure information. 

The toxicology database for mesosulfuron-methyl is essentially complete except for an 

immunotoxicity study. HED's Hazard Science Policy Council (HASPOC) has granted waivers 

· for the acute neurotoxicity battery and the subchronic dermal and subchronic inhalation toxicity 

studies. 

The acute toxicity data indicate thatmesosulfuron-methyl has low acute oral, dermal, and 

inhalation toxicity (Toxicity Category IV). It was not found to be a skin irritant, and irritation 

that occurred in the eye was cleared up 48 hours after exposure. Mesosulfuro:n-methyl was not a 

dermal sensitizer. The data on repeated oral dosing with mesosulfuron-methyl demonstrated very 

low toxicity in rats, mice, rabbits, and dogs. There was no evidence of quantitative or qualitative 

susceptibility following in utero exposures to rats and rabbits and following pre- and post-natal 

exposure to rats. The FQPA safety factor was reduced (IX) due to lack of residual uncertainty 

for pre- and post-natal toxicity. Mesosulfuron is classified as "not likely to be carcinogenic to 

humans" based on the lack of evidence of carcinogenicity in mice and rats and an acceptable 

battery of genotoxicity studies showed no mutagenicity potential. 

A new dietary exposure and aggregate risk assessment may be needed in the registration review 

process if drinking water residues of concern or estimated residue levels in drinking water are 

revised. Some additional data regarding the livestock enforcement method are required. 

A residential handler assessment will not be needed for Registration Review because there are no 

residential uses of mesosulfuron-methyl. The Agency will examine the need for a spray drift and 

volatilization assessment for mesosulfuron-methyl during Registration Review based on the 

potential for exposure to bystanders from agricultural applications. 

Occupational exposure to mesosulfuron-methyl may need to be reassessed based on current 

Occupational and Residential Exposure (ORE) policies and to consider the results of the required 

immunotoxicity study. 

Page 2 of 19 
Page 3 of 19

Introduction

Mesosulfuron-methyl is a systemic herbicide belonging to the pyrimidinylsulfonylurea group of 

herbicides. It inhibits the action of the plant enzyme acetolactate synthase (ALS)/acetohydroxy 

acid synthase (AHAS). 

The only human health risk assessment for mesosulfuron-methyl was conducted in 2004

(D298764, K. O’Rourke, 3/4/04). The only registered uses are on wheat and triticale. Refer to 

Attachment 1 (Table 1) for the chemical identity of mesosulfuron-methyl. 

Hazard Identification/Toxicology

The toxicology database for mesosulfuron-methyl is essentially complete with exception of an 

immunotoxicity study. On January 17, 2013, HED’s HASPOC ( J. Van Alstine, 2/21/13, TXR # 

0056562) concluded, based on a weight of evidence approach that considered all of the available 

hazard and exposure information, that subchronic inhalation and dermal toxicity studies as well 

as the acute and subchronic neurotoxicity studies are not needed for mesosulfuron-methyl at this 

time. The acute and subchronic neurotoxicity studies are not needed because of the lack of target 

organ toxicity and/or the potential for low toxicity observed in multiple species and observance 

of neurotoxicity only at high doses (near the limit dose, 1000 mg/kg/day, or above) for chemicals 

structurally related to mesosulfuron-methyl. The use of an oral Point of Departure (POD) for 

assessing risk via the inhalation and dermal routes results in risks below the Agency’s Level of 

Concern (LOC). The Council concluded that an immunotoxicity study is required.

OPP has published the findings of an independent retrospective analysis of 170 immunotoxicity 

studies submitted to the Agency. The retrospective analysis showed that the submitted 

immunotoxicity studies have not yet resulted in PODs that are lower than the PODs selected 

from other available guideline experimental toxicology studies. Since the currently available 

immunotoxicity studies have not impacted the Agency’s risk assessments, HED does not believe 

that the immunotoxicity study for mesosulfuron-methyl will provide a more sensitive endpoint or 

a lower POD than that which is currently used. Additionally, results of the retrospective analysis 

provide strong support for not applying a database uncertainty factor, or UFDB, as no 

immunotoxicity study available thus far provided a more sensitive endpoint than conventional 

toxicity studies. The anticipated completion date of OPP’s retrospective analysis is early 2013. 

In the interim, HED recommends that immunotoxicity studies continue to be required for 

registration and registration review chemicals.

 

The acute toxicity data indicate that mesosulfuron-methyl has low acute oral, dermal, and 

inhalation toxicity. It was not found to be a skin irritant, and irritation that occurred in the eye 

was cleared up 48 hours after exposure. Mesosulfuron-methyl was not a dermal sensitizer.
Page 4 of 19

The existing data showed that, with repeated oral dosing, mesosulfuron-methyl produced very 

low toxicity in rats, mice, rabbits, and dogs. No target organ toxicity was demonstrated in any of 

the studies; generalized toxicity manifested as decreased body weight and body weight gain 

following subchronic and chronic exposures. For example, in the 90-day oral toxicity studies in 

rats, mice, and dogs, no toxicity was seen at the highest tested dose levels, which ranged from 

648 to 1603 mg/kg/day. In the developmental toxicity studies in rats and rabbits, no maternal or 

developmental effects were found at the limit dose (1000 mg/kg/day). The two generation 

reproduction study in rats showed no parental, reproductive, or offspring effects at the highest 

tested dose (1387 mg/kg/day), which exceeded the limit dose for a reproductive toxicity study. 

The FQPA safety factor is reduced (1X) since there are no residual uncertainties for pre- and 

post- natal toxicity. No increase in tumor incidence was seen in rats and mice, which received 

doses up to 952 mg/kg/day and 1356 mg/kg/day, respectively; in addition, no systemic toxicity 

was seen at the highest tested dose levels for rats and mice. In the one year toxicity study in 

dogs, increased mucus secretion in the cardiac and fundic sections of the stomach was seen in 

male dogs at 574 mg/kg/day. Mesosulfuron-methyl is classified as “not likely to be carcinogenic 

to humans.” An acceptable battery of genotoxicity studies showed no mutagenicity potential. 

The low or no toxicity seen in the test animals with oral dosing appeared to be consistent with 

the results of the oral metabolism study which demonstrated low absorption. At 12 hours post 

dosing, greater than 60% of the applied dose was found in the stomach and small intestinal 

contents. Refer to Attachment 3 for a summary of toxicological endpoints and points of 

departure for mesosulfuron-methyl.

Conclusions: The toxicology database is currently considered to be adequate, with the exception 

of data from an immunotoxicity study. The registrant should submit an immunotoxicity study or 

provide justification for a waiver. Although an immunotoxicity study is not available, the PODs 

and endpoints of concern, and the safety/uncertainty factors are unlikely to change. 

Dietary Exposure

Pending submission of some additional data regarding the livestock enforcement method and the 

review of submitted storage stability data on wheat, the residue chemistry database is sufficient 

to support current registrations. The nature of the residue in plants and livestock has been 

adequately defined. The residue of concern to be measured by the enforcement method is the

parent. An adequate plant enforcement method is available. Some additional data regarding the 

livestock enforcement method are required. Adequate field trial and rotational crop data are 

available. 

 

The most recent dietary exposure assessment (D298762, N. Dodd, 2/17/04) was conducted using 

the Dietary Exposure Evaluation Model (DEEM-FCID , Version 1.30) and the Lifeline

Model Version 2.0, which use food consumption data from the USDA’s Continuing Surveys of 

Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. An acute dietary assessment 

was not conducted because an endpoint attributable to a single dose was not identified; an acute 

reference dose was not established. The chronic dietary exposure and risk assessment conducted 

in 2004 was not conducted according to current models and procedures. The chronic dietary 

(food only) assessment was an unrefined assessment using tolerance-level residues, DEEM ver 

7.81 default processing factors, and 100% crop treated. Exposures from food only were <1% of 
Page 5 of 19

the chronic population adjusted dose (cPAD) for the general US population and all population 

subgroups.

The chronic risk from exposure to food and drinking water was determined. Surface and ground 

water estimated drinking water concentrations (EDWCs) were used to compare against backcalculated Drinking Water Levels of Comparison (DWLOCs) for the aggregate assessment. For 

the chronic scenario, the DWLOCs are 54,000 μg/L for the general US population and 16,000 

μg/L for the most highly exposed subpopulation (all Children subgroups). The chronic EDWCs 

(highest 0.2 μg/L) are less than the Agency’s DWLOCs for mesosulfuron-methyl residues in 

drinking water as a contribution to chronic aggregate exposure. Therefore, the chronic aggregate 

exposure from mesosulfuron-methyl residues in food and drinking water does not exceed the 

Agency’s level of concern (100% of the chronic PAD) for chronic dietary aggregate exposure by 

any population subgroup. 

 

Conclusions: A new chronic dietary (food and drinking water) exposure and risk assessment 

may be needed in the registration review process if drinking water residues of concern or 

estimated residue levels in drinking water are revised. 

Some additional data regarding the livestock enforcement method were previously required in 

connection with registration actions and remain outstanding. The petitioner must modify the 

livestock enforcement method (EM F07/00-0) to be confirmatory, preferably by using three-ion 

monitoring or total ion chromatogram full scan. The petitioner must provide evidence that 

weathered and aged residues are extracted by the enforcement procedure (radiovalidation).

 

Residential Exposure

Residential Handlers

A residential handler exposure assessment will not be needed for Registration Review because 

there are no registered residential uses of mesosulfuron-methyl. 

Residential Post-Application 

The Agency has not considered residential post-application exposure for mesosulfuron-methyl 

since there are no registered residential uses at this time. Residential exposures from off-site 

transport (e.g., spray drift or volatilization) may occur as a result of mesosulfuron-methyl

applications to wheat or triticale fields. The Agency is in the process of evaluating these types of 

exposures and will examine the need for spray drift and volatilization assessments for 

mesosulfuron-methyl during Registration Review.

Conclusions: Residential handler and conventional residential post-application assessments will 

not be conducted during Registration Review; however, the Agency will examine the need for a 

spray drift and volatilization assessment for mesosulfuron-methyl during Registration Review. 

 

Aggregate Risk Assessment

In the most recent human health risk assessment (D298764, K. O’Rourke, 3/4/04), an acute 

aggregate risk assessment was not conducted because an endpoint attributable to a single dose 
Page 6 of 19

was not identified. Short- and intermediate-term aggregate risk assessments were not performed 

because residential exposure, which is combined with the dietary exposure for aggregate 

assessments, is not expected. The chronic aggregate assessment consists of the food and 

drinking water dietary assessment (refer to the Dietary Exposure section). A cancer aggregate 

risk assessment was not performed because mesosulfuron-methyl is not likely to be carcinogenic 

to humans.

Conclusions: A new aggregate exposure assessment may be needed in the registration review 

process if drinking water residues of concern or estimated residue levels in drinking water are 

revised.

 

Occupational Exposure

Mesosulfuron-methyl is currently registered for use on wheat and triticale. There is potential for 

short- and intermediate-term occupational exposure to mesosulfuron-methyl during handling 

(mixing, loading, and applying) and post-application activities.

Occupational Handlers

Occupational handler inhalation exposure and risk assessments (D298763, S. Winfield, 3/3/04)

were conducted for a water dispersible granular (WDG) mesosulfuron-methyl formulation used

on wheat. A dermal POD has not been selected for mesosulfuron-methyl based on the lack of 

dermal, systemic, neurological, and developmental toxicity following mesosulfuron-methyl 

exposure. Therefore, dermal occupational handler and post-application exposure assessments

were not conducted. 

Occupational exposure is expected to be short- and intermediate-term in duration. The registered 

mesosulfuron-methyl labels require occupational handlers to wear long-sleeved shirts, long 

pants, shoes, socks, chemical resistant gloves, and protective eyewear. Applications can be made 

with ground and chemigation equipment.

The occupational inhalation margins of exposure (MOEs) range from 900,000 to 10,000,000 and 

were not of concern (target MOE of 100) with the personal protective equipment (PPE) required 

by the labels (no respirator). 

Although an occupational exposure assessment has been conducted to estimate exposure risk for 

all existing uses of mesosulfuron-methyl, the assessment was not conducted based on current 

occupational exposure policies. Therefore, a new occupational handler risk assessment may be 

needed during Registration Review. 

Occupational Post-Application

Occupational post-application exposure was not quantitatively assessed because a dermal 

endpoint was not selected for mesosulfuron-methyl based on the lack of dermal, systemic, 

neurological, and developmental toxicity.

 
Page 7 of 19

Labels of registered mesosulfuron-methyl products require restricted entry intervals (REIs) of 12 

and 24 hours, except for Osprey Herbicide (EPA Reg. No. 264-802) which allows a reduced REI 

of 4 hours. 

Chemical-specific residue data were not submitted for mesosulfuron-methyl; however, based on 

the lack of route-specific dermal toxicity, a dislodgeable foliar residue (DFR) study is not 

required at this time.

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment has not been performed for mesosulfuron-methyl at this time. 

Conclusions: There is sufficient information available to assess occupational handler and postapplication exposures. However, the occupational handler exposure scenarios were not assessed 

based on current ORE policies. An up-to-date handler occupational assessment may be needed 

during Registration Review to account for the changes in these policies.

Endocrine Disruptor Screening Program (EDSP)

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic and 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 its most recent registration decision, EPA reviewed these 

data and selected the most sensitive endpoints for relevant risk assessment scenarios from the 

existing hazard database. However, as required by FFDCA section 408(p), mesosulfuron-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 
Page 8 of 19

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Mesosulfuronmethyl 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 mesosulfuronmethyl. 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/.

Public Health and Pesticide Epidemiology Data

Both the OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event 

Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for 

pesticide incident data on the active ingredient mesosulfuron-methyl. In addition, findings from 

the Agricultural Health Study (AHS) were reviewed. Mesosulfuron-methyl is not included in the 

AHS, and therefore this study does not provide information for this report. No incidents were 

identified for mesosulfuron-methyl in either the IDS or NIOSH SENSOR databases. 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 in the risk assessment.

Tolerance Assessment and International Harmonization

Permanent US tolerances are established under 40 CFR §180.597(a) for residues of the

herbicide mesosulfuron-methyl (methyl 2-[[[[(4,6-dimethoxy-2-

pyrimidinyl)amino]carbonyl]amino]sulfonyl]-4-[[(methylsulfonyl)amino]methyl]benzoate]) on 

meat byproducts of cattle, goat, horse, and sheep at 0.01 ppm; aspirated grain fractions and 

wheat forage at 0.60 ppm; wheat germ at 0.10 ppm; wheat grain at 0.03 ppm; wheat hay at 0.06 

ppm, and wheat straw at 0.30 ppm.

As shown in Attachment 2, there are Canadian maximum residue limits (MRLs) but no Codex

MRLs established for residues of mesosulfuron-methyl in crop or livestock commodities. The 

tolerance expression is the same for Canada and the US. For commodities with both US and 

Canadian tolerances, the tolerance levels are the same. However, in accordance with the policies 

regarding the use of pesticides on livestock feed items and potential transfer to livestock 

commodities, the US has tolerances on some wheat commodities for which Canada did not 

establish tolerances, and Canada has some tolerances on livestock commodities for which the US 

did not establish tolerances.

In accordance with HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the 

tolerance expression for mesosulfuron-methyl in 40 CFR §180.597 should be revised as follows:

“Tolerances are established for residues of mesosulfuron-methyl, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring only mesosulfuron-methyl (methyl 2-[[[[(4,6-
Page 9 of 19

dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-4-

[[(methylsulfonyl)amino]methyl]benzoate]).”

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, will be considered in the 

registration review, in accordance with US Executive Order 12898, "Federal Actions to Address 

Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

under the National Health and Nutrition Examination Survey, What We Eat in America 

(NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Cumulative 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to mesosulfuron-methyl and any other substances and mesosulfuron-methyl does not appear to 

produce a toxic metabolite produced by other substances. For information regarding EPA’s 

efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the 

cumulative effects of such chemicals, see the policy statements released by EPA’s Office of 

Pesticide Programs concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.
Page 10 of 19

Human Studies

The risk assessment which has been previously conducted for mesosulfuron-methyl relied in part 

on data from studies in which adult human subjects were intentionally exposed to a pesticide to 

determine their dermal and inhalation exposure. Many such studies, involving exposure to many 

different pesticides, comprise generic pesticide exposure databases such as the Pesticide 

Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF), 

and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies 

supporting these multi-pesticide generic exposure databases, and has found no clear and 

convincing evidence that the conduct of any of them was either fundamentally unethical or 

significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of 

Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued 

reliance on these studies.

Data Requirements

The following data are needed for conducting a comprehensive registration review human health 

risk assessment. 

Toxicology

870.7800 Immunotoxicity

An immunotoxicity study is required under 40 CFR §158.500.

Residue Chemistry

860.1340 Residue Analytical Method

Additional information for the livestock enforcement method (EM F07/00-0) is required. 

The petitioner must modify the method to be confirmatory, preferably by using three-ion 

monitoring or total ion chromatogram full scan. The petitioner must provide evidence 

that weathered and aged residues are extracted by the enforcement procedure 

(radiovalidation).

Occupational and Residential Exposure

None.
Page 11 of 19

References

Memoranda Relevant to Registration Review of Mesosulfuron-methyl

Author Barcode 

(DP#)

Date Title

Risk Assessment

K. O’Rourke D298764 3/4/04 Human Health Risk Assessment for Mesosulfuron-methyl to Support 

Request for New Active Ingredient Uses on Wheat

Residue Chemistry

N. Dodd D284051 2/18/04 Mesosulfuron-methyl. Petition for the Establishment of Permanent 

Tolerances on Wheat. Summary of Analytical Chemistry and 

Residue Data. PP#1F06298 

N. Dodd D307723 12/1/04 Mesosulfuron-methyl. Petition for the Establishment of Permanent 

Tolerances on Wheat. Review of Livestock Enforcement Method. 

PP#1F06298.

Dietary Exposure Assessment

N. Dodd D298762 2/17/04 Mesosulfuron-methyl Chronic Dietary Exposure Assessment for the 

Section 3Registration Action on Wheat

Occupational Residential Exposure

S. Winfield D298763 3/3/04 Occupational and Residential Risk Assessment to Support Request for 

a Section 3 Registration of Mesosulfuron-methyl on Wheat

Toxicology

S. Recore D409035 2/7/13 Mesosulfuron-methyl: Review of Human Incidents

J. Van 

Alstine

TXR # 

0056562

2/21/13 Mesosulfuron-Methyl: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of January 17, 2013: Recommendations 

on the Need for a Subchronic Inhalation Toxicity, a Subchronic 

Dermal Toxicity, Neurotoxicity Battery (Acute and Subchronic), and 

Immunotoxicity Studies. 

Attachments

1. Chemical Identity Table

2. Tolerance/MRL Summary Table

3. Endpoint Selection Table

4. Toxicity Profile Tables
Page 12 of 19

Attachment 1

Chemical Identity Table

Table 1. Chemical Identity – Mesosulfuron-methyl

Common Name mesosulfuron-methyl

Chemical Name (CAS) methyl 2-[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-4-

[[(methylsulfonyl)amino]methyl]benzoate

PC Code 122009

Chemical Abstracts No. 208465-21-8

Registration Review Case No. 7263

Chemical Class pyrimidinylsulfonylurea herbicide

Chemical Structure 
Page 13 of 19

Attachment 2

Tolerance/MRL Table

As shown in the table below, there are Canadian maximum residue limits (MRLs) but no Codex

MRLs established for residues of mesosulfuron-methyl in crop or livestock commodities. The 

tolerance expression is the same for Canada and the US. For commodities with both US and 

Canadian tolerances, the tolerance levels are the same. However, in accordance with the policies 

regarding the use of pesticides on livestock feed items and potential transfer to livestock 

commodities, the US has tolerances on some wheat commodities for which Canada did not 

establish tolerances, and Canada has some tolerances on livestock commodities for which the US 

did not establish tolerances.

Mesosulfuron-methyl (122009; 2/07/13)

Table 2. Summary of US and International Tolerances and Maximum Residue Limits1

Residue Definition:

US Canada Codex

40 CFR §180.597(a): Tolerances are established 

for residues of the herbicide mesosulfuron-methyl 

(methyl 2-[[[[(4,6-dimethoxy-2-

pyrimidinyl)amino]carbonyl]amino]sulfonyl]-4-

[[(methylsulfonyl)amino]methyl]benzoate])

methyl 2-[[[[(4,6-

dimethoxy-2-

pyrimidinyl)amino]carbo

nyl]amino]sulfonyl]-4-

[[(methylsulfonyl)amino]

methyl]benzoate]

None

Commodity1Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada2 Codex

Cattle, meat byproducts 0.01 0.01

Goat, meat byproducts 0.01 0.01

Grain, aspirated fractions 0.60

Horse, meat byproducts 0.01 0.01

Sheep, meat byproducts 0.01 0.01

Wheat, forage 0.60

Wheat, germ 0.10 0.1

Wheat, grain 0.03 0.03

Wheat, hay 0.06

Wheat, straw 0.30

MRLs with No US Equivalent

Eggs 0.01

Fat of cattle 0.01

Fat of goats 0.01

Fat of hogs 0.01

Fat of horses 0.01

Fat of poultry 0.01

Fat of sheep 0.01

Meat byproducts of hogs 0.01

Meat byproducts of poultry 0.01

Meat of cattle 0.01

Meat of goats 0.01

Meat of hogs 0.01

Meat of horses 0.01

Meat of poultry 0.01

Meat of sheep 0.01

Milk 0.01
Page 14 of 19

Table 2. Summary of US and International Tolerances and Maximum Residue Limits1

Residue Definition:

US Canada Codex

Completed by: M. Negussie; 2/07/2013

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 Canada does not establish MRLs for livestock feed commodities.
Page 15 of 19

Attachment 3

Summary of Toxicity Endpoints and Points of Departure of Mesosulfuron-methyl

Table 3. Summary of Toxicological Doses and Endpoints for Mesosulfuron-methyl for Use in 

Human Risk Assessment

Exposure

Scenario

Dose Used in 

Risk 

Assessment, UF

FQPA SF and Level of 

Concern for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary:

All populations

An endpoint attributable to a single dose was not identified in the database.

Chronic Dietary:

All populations

NOAEL= 155

mg/kg/day

UF = 100

Chronic RfD = 

1.55 mg/kg/day

FQPA SF = 1X

cPAD = 

chronic RfD

FQPA SF

= 1.55 mg/kg/day

Chronic oral toxicity study in dogs.

LOAEL = 574 mg/kg/day [M] based on 

increased mucus secretion in the cardiac 

and fundic sections of the stomach, and 

chronic superficial gastritis (1/6) of male 

dogs.

Incidental Oral: 

Short- and 

Intermediate-Term)

No Residential Uses are registered for Mesosulfuron-methyl.

Dermal Exposure: 

Short-, Intermediateand Long-Term

Quantification of dermal risk is not required for this route of exposure due to the lack of 

dermal, systemic, neurological, and developmental toxicity concerns. 

Inhalation Exposure: 

Short-, Intermediateand 

Long-Term

Oral NOAEL= 

155 mg/kg/day

(Inhalation 

toxicity assumed 

to be equivalent 

to oral)

Residential LOC for 

MOE = NA

Occupational LOC for 

MOE = 100

Chronic oral toxicity study in dogs.

LOAEL = 574 mg/kg/day [M] based on 

increased mucus secretion in the cardiac 

and fundic sections of the stomach, and 

chronic superficial gastritis (1/6) of male 

dogs.

Cancer (oral, dermal, 

inhalation)

“Not likely to be carcinogenic to humans” based on the lack of evidence of 

carcinogenicity in the rats and mice. 

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, 

LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = 

reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable
Page 16 of 19

ATTACHMENT 4

Toxicity Profile for Mesosulfuron-methyl 

Acute Toxicity of Mesosulfuron-methyl - Technical

Guideline 

No. Study Type MRID No. Results

Toxicity 

Category

870.1100 Acute oral toxicity 45386321 LD50 > 5000 mg/kg [M/F] IV

870.1200 Acute dermal 

toxicity

45386322 LD50 > 5000 mg/kg [M/F] IV

870.1300 Acute inhalation 

toxicity

45386323 LC50 > 1.33 mg/kg [M/F] III

870.2400 Acute eye irritation 45386324 Conjunctival irritation at 24 hrs in 1/3 which 

cleared by 48 hrs.

III

870.2500 Acute dermal irritation 45386325 Non Irritant IV

870.2600 Skin sensitization 45386326 Unacceptable Negative 1

1 There was no indication that the material is a dermal sensitizer; however, the study is unacceptable because the 

submitted positive control study was not conducted within 6 months (i.e., they were approximately 9 months apart).

Toxicity Profile of Mesosulfuron-methyl Technical with Repeated Dosing 

Guideline No./ 

Study Type

MRID No. (year)/ Classification 

/Doses

Results

870.3100

90-Day oral toxicity 

in rats

45386327 (1999)

Acceptable/guideline

0, 240, 1200, 6000, 12000 ppm

M: 0, 17.5, 88.6, 435, 908mg/kg/day

F: 0,19.1, 96.1, 475, 977 mg/kg/day

NOAEL = 908/977 [M/F] mg/kg/day

LOAEL = not observed.

870.3100

90-Day oral toxicity 

in mice

45386328 (1999)

Acceptable/guideline

0, 140, 1000, 7000 ppm

M: 0, 25.5, 176.1, 1238.3 mg/kg/day

F:0, 32.3, 206.1, 1603.4 mg/kg/day

NOAEL = 1238.3/ 1603.4 [M/F] mg/kg/day

LOAEL = not observed.

870.3150

90-Day oral toxicity 

in dogs

45386329 (2000)

Acceptable/guideline

0, 750, 3750, 7500 ppm

M: 0, 63, 348, 648 mg/kg/day

F:0, 75, 348, 734 mg/kg/day

NOAEL = 648/ 734 [M/F] mg/kg/day

LOAEL = not observed.

870.3200

21/28-Day dermal 

toxicity

Waived+
Page 17 of 19

Toxicity Profile of Mesosulfuron-methyl Technical with Repeated Dosing 

Guideline No./ 

Study Type

MRID No. (year)/ Classification 

/Doses

Results

870.3465

90-Day inhalation 

toxicity

Waived+

870.3700a

Prenatal 

developmental in 

rats

45430404 (1999)

Acceptable/guideline

0, 100, 315, 1000 mg/kg/day

Maternal NOAEL = 1000 mg/kg/day

LOAEL = not observed

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not observed

870.3700b

Prenatal 

developmental in 

rabbits

45386401 (1998)

Acceptable/guideline

0, 100, 315, 1000 mg/kg/day

Maternal NOAEL = 1000 mg/kg/day

LOAEL = not observed

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not observed

870.3800

Reproduction and 

fertility effects in 

rats

45430405 (2000)

Acceptable/guideline

0,160, 1600, 16000 ppm

M: 0, 11.7, 115.3, 1175.2 mg/kg/day

F: 0, 13.5, 132.6, 1387.6 mg/kg/day

Parental/Systemic NOAEL = 1175.2/ 1387.6 

[M/F] mg/kg/day

LOAEL = not observed

Reproductive NOAEL = 1175.2/ 1387.6 [M/F] 

mg/kg/day

LOAEL = not observed

Offspring NOAEL = 1175.2/ 1387.6 [M/F] 

mg/kg/day

LOAEL = not observed

870.4100a

Chronic toxicity in 

rats

45430402 (2000)

Acceptable/guideline

0, 160, 1600, 16000 ppm

M: 0, 7.46, 73.8, 764 mg/kg/day

F: 0, 9.39, 94.7, 952 mg/kg/day

NOAEL = 764/ 952 [M/F] mg/kg/day

LOAEL = not observed.

870.4100b

Chronic toxicity in 

dogs

45386330 (2000)

Acceptable/guideline

0, 400, 4000, 16000 ppm

M: 0, 14.7, 155, 574, mg/kg/day

F: 0, 15.3, 169, 646 mg/kg/day

NOAEL = 155 [M] mg/kg/day

LOAEL = 574 [M] mg/kg/day based on increased 

mucus secretion in the cardiac and fundic sections 

of the stomach of the males dogs (HDT) and 

chronic superficial gastritis (1/6).

870.4200

Carcinogenicity rats

45430402 (2000)

Acceptable/guideline

0, 160, 1600, 16000 ppm

M: 0, 7.46, 73.8, 764 mg/kg/day

F: 0, 9.39, 94.7, 952 mg/kg/day

NOAEL = 764/ 952 [M/F] mg/kg/day

LOAEL = not observed.

(no) evidence of carcinogenicity

870.4300

Carcinogenicity 

mice

45430403 (2000)

Acceptable/guideline

0, 80, 800, 8000 ppm

M: 0, 10.6, 102.8, 1069.4 mg/kg/day

F: 0, 13.9, 129.8, 1355.6 mg/kg/day

NOAEL = 1069.4/ 1355.6 [M/F] mg/kg/day

LOAEL = not observed.

(no) evidence of carcinogenicity

Gene Mutation

870.5100

Bacterial reverse 

mutation assay

45386402 (1996)

Acceptable/ guideline

(a.i.)

Negative ± S9 up to cytotoxic 5000 μg/ml plate 
Page 18 of 19

Toxicity Profile of Mesosulfuron-methyl Technical with Repeated Dosing 

Guideline No./ 

Study Type

MRID No. (year)/ Classification 

/Doses

Results

Gene Mutation

870.5300

Mammalian cell 

culture

45386404 (1998)

Acceptable/ guideline

(a.i.)

Negative ± S9 up to cytotoxic 2500 μg/ml and 

precipitation 250 μg/ml

Cytogenetics 

870.5375 

Chromosomal 

aberrations

45386403 (1998)

Acceptable/ guideline

(a.i.)

Negative ± S9 precipitation 100 μg/ml 

Cytogenetics 

870.5395

Micronucleus test 

on mouse

45386406 (1998)

Acceptable/ guideline

(a.i.)

Negative at the highest dose tested (limit dose) 

2000 mg/kg.

Other Effects 

870.5550

Unscheduled DNA

45386405 (1998)

Acceptable/ guideline

(a.i.)

Negative ± S9 precipitation 100 μg/mL 

870.6200a

Acute neurotoxicity 

screening battery

Waived+.

870.6200b

Subchronic 

neurotoxicity 

screening battery

Waived+.

870.6300

Developmental 

neurotoxicity

Study not required

870.7485

Metabolism and 

pharmacokinetics

45386407- 45386415 (1997- 2000)

Acceptable/guideline

Dose:10 or 1000 mg/kg [phenyl- U14C]- AE F130060

Overall recovery of the radioactive dose was 98-

103%, predominantly recovered in the feces within 

24 hours (80-97% dose). The onset of absorption 

was quick (detected in the blood 15 minutes postdose), but the quantity absorbed was low. At 72 

hours post-dose (or 168 hours following the final 

dose of the repeated study), urinary excretion 

accounted for 1-4% (except 13-14% in the 10 

mg/kg animals), and radioactivity in the bile of the 

10 mg/kg animals was only 7-9% of the dose by 12 

hours post-dose. The 10 mg/kg rats had slightly 

more radioactivity in urine and slightly less 

radioactivity in feces compared to the 1000 mg/kg 

rats. Bioaccumulation was not observed, and 

radioactivity in tissues was <0.1% of the dose in all 

animals at each study termination. 

870.7600

Dermal penetration

45386416 (2000)

Unacceptable/ guideline

Doses: 0.0075 cm ai/cm2 or 0.3 mg 

ai/cm2
Page 19 of 19

Toxicity Profile of Mesosulfuron-methyl Technical with Repeated Dosing 

Guideline No./ 

Study Type

MRID No. (year)/ Classification 

/Doses

Results

870.7800

Immunno toxicity 

study

Not available Required

+

HASPOC, 2/21/2013; TXR: 0056562