UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D

. C. 20460

MEMORANDUM

Date: 16

- APR-2013 OFFICE OF CHEMICAL SAFETY
AND POLLUTION PRE V ENTION

SUBJECT: Mesosulfuron-methyl. Human Health Assessment Seeping Document in Support o f Registration Review.

PC Code: 122009

D eci sion No.: 471309

Petition No.: NA

Risk Assessment Type: NA

TXRNo

. :NA

MRIDNo.:NA

FROM: Nancy Dodd

, Chem i st/ .v-

...

....,...£-od' Whang Phan g, T oxicologist

Kristin Rury, Biologist 

## V:

Risk Assessment Branch III (RA

Hea l th Effects Division (7509P)

Office of P est i c id e P rograms DP Barcode: D406414 Registration No

. : NA Regulatory Action : Regi stration Review

Case No. : 7263

CAS N o. : 2084 65 -21-8

40 CFR: 180.597

THRU: Christine O lin ger , Branch C hi ef 

# fJ (

Risk Assessment Branch Ill (RA B3 

# f

H ealth Effects Division (7509P)

Office of Pesticide Pro grams

TO: Jolene Trujillo

, Chemical R eview Manager
Risk Management and I mplementation Branch V (RM I B5)

Pesticide Re- Eval uation Divi sion (PRD) (7508P)

Office of Pesticide Programs

Page 1 of 1 9Executive 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 t riticale. 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 li te ratu re search of the scientific databases for any po te ntial data rele vant 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 th e 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
inhala tion toxicity (Toxicity Category IV)

. It was not found to be a skin irritant, and irrita t ion
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

expos ure to rats. The FQPA safety factor was reduced (IX) due to l ack of residual uncertainty
for pre- and post-natal toxici ty

. Mesosulfuron is classifi e d 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 s tudies showed no mutagenicity potential.

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

process if drinking water r es idu es of concern or estimated residue levels in drinking water are revised. Some additional data regarding the livestock enforcemen t method are required.

A residential handler assessment will not be needed for Registration Review because there are no residential us es 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 bys tanders 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

I ntroduction

Mesosulfuron

- methyl is a systemic herbicide belonging to the pyrimidinyl sulfon ylurea 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 ( D 298764, 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 excepti on of an immunotoxicity study. On January 17

, 2013

, HED’s HASPOC ( J. Van Alstine, 2/21/13, TXR #
0056562 ) concluded , b ased on a weight of evidence approach that consider ed all of the available hazard and exposure information, that subchronic inhalation a nd 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 mesosul furon

- 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 publi shed 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 select ed 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 provid e 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 UF DB 

### , 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 i mmunotoxicity studies continue to be required for registration and registration review chemicals.

The acute toxicity data indicate that mesosulfuron

- methyl ha s 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; g eneralized 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 dos e 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 t wo generation reproduction study in rats showed no pare ntal, 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 yea r 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 genotox icity 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 hour s 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 databa se 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

. Al t hough an i mmunotoxicity study is not available, the PODs

an d 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, t he 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 en forcement 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 (D2 98762 , N. Dodd, 2/1 7/04 ) 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. T he chronic dietary exposure and risk assessment conducted
in 2004 was not conducted accordin g 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 p opulation 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 com pare against back

calculated 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 Child ren 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 previousl y 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 pet itioner 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 need ed for Registration Review becaus e there are no registered residential uses of mesosulfuron

- me t h yl.

Residential Post

- Application The Agency has not considered residential post

- application exposure for mesosulfuron

- methyl since there are no registered residential uses at this tim e. 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 ex amine the need for spray drift and volatilization assessments for
mesosulfuron

- methyl during Registration Review.

Conclusions: R esidential handler and conventional residential post

- application assessment s 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), a n 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 d ietary 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 oc cupational 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 use d
on wheat. A dermal POD has not been selected for mesosulfuron

- methyl based on the lack of dermal, systemic, neurological, and developmental toxicity following mesosulfu ron

- methyl exposure. Therefore, dermal occupational handler and post

- application exposure assessment s

w ere not conducted.

Occupational exposure is expected to be short

- and intermediate

- term in duration. The registered
mesosulfuron

- methyl labels requi re 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.

Th e occupational inhalation margins of exposure (MOEs) rang e 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 r egistered mesosulfuron

- methyl products require restricted entry intervals ( REI s ) of 12
and 24 hours, except for Osprey Herbicide (EPA Reg. No. 264

- 802) which allows a reduced REI
of 4 hour s.

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 post

application exposure s. 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 po licies.

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 che micals. 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 assessmen ts, 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 Administr ator 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, o r 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 FFDC A 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. Me sosulfuron

methyl is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP
orders/data call

- ins, requiring the submission of EDSP s creening assays for mesosulfuron

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/

.

Public Health and Pesticide Epidemiology Data

B oth 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

pe sticide 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 th is 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 in formation and if a concern is triggered, additional analysis
will be included in the risk assessment.

Tolerance Assessment and International Harmonization

P ermanent US tolerances are established under 40 CFR §180.597(a) for residues of the
herbicide meso sulfuron

- 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

w heat 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

.

A s shown in Attachment 2, t here are Canadian maximum residue limits (MRLs) but no Codex

MRLs established for residues of mesosulfuron

- methyl in crop or li vestock 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. Kni zner), the tolerance expression for mesosulfuron

- methyl in 40 CFR §180. 597 should be revised as follow s :

“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 meas uring 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 , w ill be considered in th e 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 bas ed 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 appro priate, 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 rel ied in part on data from studies in which adult human subjects were intentionally exposed to a p esticide 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

Ha ndlers 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 t hem was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was
conducted. A ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and t here 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 Im munotoxicity

A n immunotoxicity study is required under 40 CFR §158.500.

Residue Chemistry

860.1340 Residue Analytical Method

A dditional information for the livestock enforcement method (EM F07/00

- 0) is required. The petitioner must modify the method to be confirma tory, 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 Reside ntial 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 D 284051 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 D 298763 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

Immu notoxicity Studies.



### Attachment s 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) m ethyl 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. 7 263
Chemical Class pyrimidinyl sulfonylurea herbicide

Chemical Structure

### Page 13 of 19 Attachment 2
Tolerance /MRL Table

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

MRLs established for residues of mesosulfuron

- methy l in crop or livestock commodities. The tolerance expression is the same for Canad a 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 pestici des on livestock feed items and potential transfer to livestock commodities, t he 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 est ablish tolerances.

Mesosulfuron

- methyl (12 2009 ; 2/07/13 )

Table 2 . Summary of US and International Tolerances and Maximum Residue Limits 1
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 ] N one

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada 2 Codex Cattle, meat byproducts 0. 0 1 0. 0 1 Goat, meat byproducts 0. 0 1 0. 0 1 Grain, aspirated fractions 0.60 Horse, meat byproducts 0. 0 1 0. 0 1 Sheep, meat byproducts 0. 0 1 0. 0 1 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

M eat byproducts of hogs 0.01

M eat 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 Limits 1
Residue Definition : US Canada Codex Completed by: M. Negussie; 2 / 07 /201 3

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

- , Intermediate

and 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

- , Intermediate

and 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 LD 50 > 5000 mg/kg [M/F] IV

870.1200 Acute dermal

toxicity 45386322 LD 50 > 5000 mg/kg [M/F] IV

870.1300 Acute inhalation

toxicity 45386323 LC 50 > 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 Meso sulfuron

- 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 Meso sulfuron

- methyl Technical with Repeated Dosing

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

870.3465
90

- Day inhalation toxicity W aived+

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 Meso sulfuron

- 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

- U

14 C]

- 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 post

dose), 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. Bioac cumulation 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 Meso sulfuron

- 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