Mesosulfuron-Methyl Human H ea lth Risk Assessment 04270 39



### UNITED STATES ENV I RONMENTAL PROTECT I ON AGENCY

WAS HI NGTON, D.C. 20460

MEMORANDUM

DATE: Sept e mber 9, 2015 OFFICE OF
CHEMICAL SAFETY ANO
POLLUTION PREVENTION



### SUBJECT: Mesos ul furon-Met h y l

. Hum an Health Dr aft Ri s k Ass ess m e nt for Registration

Re v i ew

.

PC Code: 1 2200 9

Deci s ion No.: 503830 DP Barcode: 0427039 Registrat i on No s. : 264

- 694, 264 -80 I

, 264 -8 02, 264-833, 264-

847

, 264-1099, 264- l I 0 3

Petiti o n No.: NA Regulator y Acti o n: R eg istrati on Revi ew Case No.: 7277 R i s k As s essment T y pe: Single Chemical / Agg r ega t e
TXR No.: NA CAS No.: 208465-21-8**~O** CFR: § 180.597 MRIO No.: NA



### FROM:

THROUGH:

TO: Kri s tin Rur y , Bi o logi s t

# '?-~ Na n cy D o dd

, Ch e mist

## ~ Whan g Ph ang, T ox icol og ist

Ri sk Assessment Branch 3

Health Effects Division (7509 P )

C hri s tin e Oli ng e r , C hi ef

## ~/"/~ Ri sk Assessme nt Branch 

### 3 

# l71-0

Health Effects Di v ision (7 509P)

Jolene Trujillo , C hemical Re v i ew M a nager Risk Mana ge ment and Im p l e m e ntation Br a nch 

### V

Pe st i cide R e -Re g i st rati o n Divi s ion (75 08P )

Mesosu l furon- meth y l is a syste mic herbicid e belonging t o the pyrimidinylsulfonylurea gro up of

herbicides. It inhibit s the ac tion of the plant e nzym e aceto l actatc sy nth ase (ALS)/aceto h y droxy

acid synt h ase (A H AS)

. Thi s d oc um en t evaluates th e existing uses of m es o s ulfuron-meth y l a s part of R eg i s tration Review and repre se nts th e draft ri sk assessme nt 

### (ORA). T he Age nc y i s reviewing a ll th e sulfonylurea h e rbi c id es jointl y under R egis trati o n R ev i ew.

Pa ge 1 of 25

### Mesos ul furo n- Me th y l Hu ma n Hea lt h Ri s k Asse ss m e nt 

### 0427039

Tab l e of Contents

1.0 Exec u t i ve S u mmary

............ . ...... . ............... . ... . ... . ....... . .............................. . .. .... . ... . .. .. ..... . ... 3

2

. 0 HED Recommendations

. . ............. . ....... .. ......... ... ...... .. .. . .......... . ...... . .. . ... . .. .. . .. .. ... .... . ......... . 3

2.1 To l erance Consi d eratio n s

.. . .. . .... . .. .. .. .. .. .. ... .. . .. ...... .. ............................... . ...... . .. . .. . .. . ....... 3

2.2 Data Deficie n c i es

.. . .. . .. . ... . ....... . .. .. .. .. ...... .. ..... ... ...................................... . ..... .. .. . .. . .. .. .. . .. . . 3

3.0 I ntrod u ct i on

............... ... ........................................................ . ...... . . .. ..... .. . .. .. . .. .. .. . .. . ........ 4

3 .1 Use Pro fil e & 

### Anticipated Exposu r e Pathways

. ... . . ... . .. . ... . .. . ... . .. .. ......... . ..... . ... . .. . ..... .. . 4

3

. 2 Considerat i on of Env i ronmenta l J u stice

. . .. . .... . .. .. .. .. ..... .. . .. . . . . . .. .............................. . . . .. 5

4.0 Hazard Characterization

. .. .. ...... .. ...... .. ...... . ....... .. .. .. .. . .. .. .. .. . .. .. .. . .. .. .. .. . .. . ...... . ............ . .. .. .. 6

5.0 Res i due Chemistry

. . ... . ....................... . ............ . . .. . . .. .. ...... .. .... ... .. . .. . ... . .. . ...... . .. . ...... . .. . .. . ... . .. 9

6

. 0 Dietary Risk Assessment

.. ..... .. .. .. . .. ... . . . ..... . . . ..... ... . .. .. ... . . ... .. . .. ..... . .................... . ............. . .. 9
6.1 Water Resid u e Profi l e

. . ........................... . .......................... . ............. . .. . .. .. .. . .. .. .. . .. . .. . ... . .. 9

6.2 Dietary (Food+ Water) Exposure Assessment

................... .. ...... . . . ...... . .. . .. . .............. . 10

7

. 0 Res i dentia l (Non-Occ u pat i ona l ) Exposure/R i sk C h aracterization

. ...... . .. . ... . .. . .. . .. .. . .. . 11

7.1 Spra) ' Drift

..... . ...... . ...... . ...... . ... . .............................................. . ..... . . .. . ..... .. .. . . ... . . .. .. ........ 11



### 7.2 Residentia l Bystander Post

- App l ication Inhalat i o n Expos ur e

................... . .. . .. . ... . . . 11

8.0 Aggregate Exposure/Risk C h aracterizat i on

....... .. ... . .. . .. .. .. .. .. . .. .. .. .. .... .... ....................... 12

9

. 0 C u mu l at i ve Expo s ure / Risk Characterizat i on

.... .. ....... . .. . ...... . ....... . . . .. .. .. . ..... . ............ . ... 12

10.0 Occu p ationa l Expos ur e/R i sk C h a r acterization

. . ... . . .. ....... . ......... . ................................. 12

11.0 Public Health and Pestic i de Epidemio l ogy Data

.... . .......... . ....................... . ..... .. . . ... . . . ... . 14

12.0 References

. .. .. .. . .. ......... . ................................. . ... . .... . ...... . .......... . .......... . ............... . .. . .. .. .. . .. . 

### 1 4 

### Appendix A: Toxicity Profile of Mesosu l furon-Methyl..

. .. ...... . .. .. .. .. ..... . ... . .. . ...... . . .. ..... .. .. . ..... . 15 Append i x B: D i etary Expos u re/Risk Mode l ing I n put and Output

..... .. ..... .. ... . ..... . .. ..... ..... . 19 Appendix C: Rev i e \ v of H u man Research

.. .. ... .. .. .. .. .. .. .. .. . ... .. .. . ...... . ...... . . ... .... .. ...... . ................ 20 Append i x D: Occupat i onal Non-cancer Ha n d l er Ex p osure Estimates a n d Algor i t h ms

... 21 Append i x E. Nome n clature and Phys i ca l / Chemica l Propert i es

........................... . ................. 22 Appe n dix F. I nternatio n a l Harmon i zation

.. ....... .. . .. .. . ... ...... . .. .. ...... . .. .. .. .. ........ . .. .. ........ .. .. .. ..... 23 Appendix G. DF

, R Data Wa i ver Rationa l e

.. . .... . ... . ... .. .. . ... . . ... .. .. . .. .. .. . .. .. .. .. . .. . ... . .. . .. .. ..... . .. . .. . .. . 25

Pag e 2 o f 25

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 3 of 25 1.0 Executive Summary

Mesosulfuron

- methyl, methyl 2

- [[[[(4,6

- dimethoxy

- 2

- p rimidinyl)amino]carbon yl]amino]sulfonyl]

- 4

- [[(methylsulfonyl)amino]methyl]benzoate

, is a systemic herbicide belonging to the pyrimidinylsulfonylurea class of chemicals. It is currently registered for use on wheat and triticale

. Bayer CropScience is the only registrant with
mesosulfuron

- methyl end

- use products

. Since the last risk assessme nt (K. O’Rourke, D298764,
3/04/2004 ) and scoping document ( N. Dodd, D406414, 04/15/2013)

, there have been no changes to the mesosulfuron use, hazard, or residue profile s

. However, dietary exposure to
mesosulfuron

- methyl has been reevaluated in order to in corporate updated consumption data and drinking water modeling estimates. Non

- dietary exposure has also been reevaluated to incorporate changes to occupational exposure assessment methodologies (unit exposures) and to incorporate a spray drift assessment. There are no risk estimate s of concern for the existing uses
of mesosulfuron

- methyl; however there are some data deficiencies that remain outstanding.

2 .0 HED Recommendations

2.1 Tolerance Considerations

Provided the residue chemistr y deficiency cited in Section 2.3 is resolved, the existing tolerances (40 CFR 180.597) are supported by the available residue chemistry data.

At this time, there are no Codex maximum residue limits ( MRLs )

, but there are Canadian MRLs.
On commodities fo r which both the US and Canada have tolerances/MRLs, the levels are the
same. Canada does not establish tolerances on livestock feed items

, whereas the US does. Canada has established tolerances on more livestock items at 0.01 ppm

, whereas the US set a

t olerance of 0.01 ppm only on meat byproducts of cattle, goat, horse, and sheep. Refer to Appendix F

.

HED notes that the tolerance expression for mesosulfuron

- methyl requires revision to state the following:
Tolerances are established for residues of me sosulfuron

- meth y l, 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

- dimethoxy

- 2

- pyrimid inyl)amino]carbonyl]amino]sulfonyl]

- 4

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

2. 2 Data Deficiencies

860.1340 Residue Analytical Method

T he independent laboratory validation of the livestock enforcement method, Method EM F07/00

- 0, is adequate provided that the method is revised to make it confirmatory

, preferably by using
three

- ion monitoring or total ion chromatogram full scan

. Provided that the method is revised to be confirmatory, EPA will not require that an interference study be conducte d to show whether

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 4 of 25 other pesticides registered on the same commodities interfere with determination of
mesosulfuron

- methyl (N. Dodd, D396429, D396433, D396434, 07/30/2013)

.

3.0 Introduction

3.1 Use Profile & Anticipated Exposure Pathways

Mesosulfuron

- m ethyl is only formulated as water

- dispersible granule (WG) formulations and only registered for use on wheat and triticale . Currently registered labels include one technical label, s ix agricultural labels, and three special local need (SLN) state labels. In general,
mesosulfuron

- methyl may be applied to wheat and triticale only once per year or once per growing season. Application timing varies depending on the target weed ( before or after emergence of the weeds or the crop itself ). The registered appli cation rates range from 0.0028 to
0.013 lb ai/A. Mesosulfuron

- methyl may be applied using groundboom and aerial application equipment; application via chemigation is not permitted

. The mesosulfuron

- methyl labels require occupational handlers to wear base line personal protective equipment (PPE): long sleeved shirts, long pants, shoes, and socks; chemical resistant gloves; and protective eyewear. The restricted entry intervals (REIs) listed on the mesosulfuron

- methyl labels are either 4 hours, 12 hours, or 24 hours.

Individuals may be exposed to mesosulfuron

- methyl via their diet (food and drinking water) and agricultural workers may be exposed (dermal ly and via inhalation) to mesosulfuron

- methyl during mixing, loading, and/or applying the herbicide as we ll as during post

- application
activities. There are no registered uses for mesosulfuron

- methyl that will result in direct non

dietary (i.e., residential) exposures. However, there is the potential for indirect exposure (incidental oral and dermal) to me sosulfuron

- methyl related to spray drift.

Table 3

. 1 . Summary of Directions for Use of Mesosulfuron

- Methyl.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) REI

(Hours) Use Directions and Limitations

Wheat and Triticale

Aerial and
Ground Equipment* Water

dispersible granule [264

- 801] 0.0028 1 0.0028 24 Apply as a foliar spray in wheat to
control wild oat and wild mustard. Apply to young and actively growing weeds. Do not apply within 30 days of harvest for forage, 50 days for hay, 55 days for grain and straw.

Water dispersible granule [264

- 802] 0.013 1 0.013 4 ** Apply when wheat from emergence up to jointing stage of growth. Do not apply within 30 days of harvesting wheat forage, and 60 days for hay, grain, or straw.

Water dispersible granule [264

- 833] 0.010 1 0.010 24 Apply to post

- emergent wheat up to jointing. PHI = 30 days for forage, 71 days for grain and straw.

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 5 of 25 Table 3

. 1 . Summary of Directions for Use of Mesosulfuron

- Methyl.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) REI

(Hours) Use Directions and Limitations

Water dispersible granule [264

- 847] 0.0029 1 0.0029 12 Apply from emergence. PHI for forage = 30 days, for grain and straw = 71

days.

Water dispersible granule [264

- 1099] 0.0036 1 0.0036 12 Apply from emergence. PHI for forage = 30 days, for grain and straw = 71

days.

Water dispersible granule [264

- 1103] 0.013 1 0.013 12 Apply up to the jointing stage of growth. PHI 30 days for forage, 60 days for hay, grain, straw.

*Chemigation is not permitted on the registered labels.
**See Section 10 .0 for a description of the requirements for reduced REI for EPA Reg. No. 264

- 802. At this time, the end

- use product meets the acute toxicity criteria for a reduced REI of 4 hours.



### 3

. 2 Consideration of Environmental Justice

Potential areas of environme ntal justice concerns, to the extent possible, were considered in the preliminary human health risk assessment for mesosulfuron

- methyl , in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to
well

- established procedures. In line wi th 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. Extens ive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Examination Surveys/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 and ethnic group. 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
post

- application are evaluated. Further considerations are cur rently 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.

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 6 of 25 4 .0 Hazard Characterization

The toxicology database for mesosulfuron

- methyl is complete. The data requirements for a dermal toxicity study, acute and subchronic neurotoxicity studies, a subchronic inhalation toxicity study, and an immunotoxicity study are waived (TXR: 0056562; 0 2/21/2013 & TXR: 0056723, 0 8/ 0 6/2013). The latest risk assessment was conducted in 2004 ( K. O’Rourke, D298764, 3/04/2004). No new toxicity and/or metabolism data have been received and the endpoints selecte d for the previous risk assessment remain the same. A summary of the acute,
subchronic

, and chronic toxicity profile is presented in Appendix A.

4 .1 Summary of Toxicological Effects

With oral administration in rats, absorption was quick (detected in the blood 15 minutes post

dose), but the quantity absorbed was low. Based on the radioactivity found in urine, feces, and the contents of the stomach and intestines; maximal absorption was approximately 30% of the administered dose. The primary route of elimination was via feces. Bioaccumulation was negligible as indicated by <0.1% of the administered dose in the tissues examined.

The existing data show that with repeated oral dosing mesosulfuron

- methyl produced very low toxicity in rats, mice, rabbits, and dogs. Low oral toxicity could be, in part, due to low oral absorption (30%). In the 90

- day oral toxicity studies in rats, mice, and dogs, no toxicity was seen at the highest dose levels tested, ranging from 648 to 1603 mg/kg/day. In developmental

to xicity studies in rats and rabbits, no maternal or developmental effects were found at the limit dose (1000 mg/kg/day). A two generation reproduction study in rats showed no parental, reproductive, or offspring effects at the highest dose tested (1387 mg/ kg/day), which exceeded the limit dose for a reproductive toxicity study. In the one year toxicity study in dogs, increased mucus secretion in the cardiac and fundic sections of stomach was seen in male dogs at 574 mg/kg/day.

No increase in tumor incid ence was seen in rats and mice, which received doses approaching or above the limit dose ( 952 mg/kg/day and 1356 mg/kg/day ) , respectively; in addition, no systemic toxicity was seen at highest tested dose levels for rats and mice in long

- term (chronic) stu dies.
Mesosulfuron

- methyl was not genotoxic. There was no evidence of neurotoxicity in the database.

The acute toxicity data indicate that mesosulfuron

- methyl had 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.

4 .2 Safe ty Factor for Infants and Children (FQPA Safety Factor)

The toxicity databas e of mesosulfuron

- methyl is complete and adequate to assess the qualitative or quantitative susceptibility in the young. There is no evidence of increased qualitative or quantitative susceptibility in the young ; there is no evidence of neurotoxicity with me so sulfuron

methyl

, and exposure estimates are unlikely to underestimate risk; therefore, the FQPA Safety

Factor (10x) is reduced to 1 x

.

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 7 of 25 4 .3 Toxicity Endpoint and Point of Departure Selections

There have been no changes to the prior dose

- response assess ment and cancer classification.
Some studies used for endpoint selection have conservative NOAEL/LOAEL values that have not been updated to reflect current standards for evaluating toxicity studies. U pdates would result in higher NOAEL/LOAEL values and, given the current risk picture, would not impact the overall findings of the risk assessment . An incidental oral POD was not selected because there were no effects seen in any applicable studies (90

- day oral toxicity studies, reproductive toxicity studies, or developmental toxicity studies) with which to derive an incidental oral POD.

Table 4

. 3. 1. Summary of T oxicity E ndpoints and P oints of D eparture for Mesosulfuron

- methyl for Use in
Human Risk Assessment

.

Exposure
Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, 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 A = 10

UF H = 10 FQPA SF = 1X Chronic RfD =

1.55 mg/kg/day

cPAD = 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) Quantification of incidental oral risk is not required because t here were no effects seen in any

applicable studies (90

- day oral toxicity studies, reproductive toxicity studies, or developmental toxicity studies) in order to derive an incidental oral POD.

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) UF A = 10

UF H = 10 FQPA SF = 1X 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, UF A = extrapolation from animal to human (interspecies)

, UF H = potential variation in sensitivity among members of the human population (intraspecies)

, 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 , FQPA = Food Quality
Protection Act.

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 8 of 25 4 .4 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemi cals. 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 suscepti ble 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 for metsulfuron

- methyl, 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 ),
metsulfuron

- methyl is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effec ts 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 es trogen, 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 whi ch, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and
establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 in ert ingredients. A second list of
che micals identified for EDSP screening was published on June 14, 2013 1 

### and includes some pesticides s che duled for Registration Review and che micals found in water

. Neither of these
lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the list s of
che micals, future lists, the test guidelines and the Tier 1 screening battery, please visit our
website. 2

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of
chemicals.

2 http://www.epa.gov/endo/

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 9 of 25 5 .0 Residue Chemistry

The nature of the residue in wheat , ruminants, and poultry is adequately understood based on
metabolism stud ies in wheat, dairy cows, and poultry

. Parent was the major residue in wheat forage and hay and in most livestock commodities. The resi due of concern for tolerance enforcement and dietary risk assessment in wheat and livestock commodities is the parent compound only.

An analytical reference standard for mesosulfuron

- methyl with an expiration date of 3/21/2016 is available at EPA’s National Pesticide Standards Repository (e

- mail dated 5/11/2015 from Gregory Verdin, Analytical Chemistry Branch/Biological and Economic Ana lysis Division).

The structure and the physical/chemical properties are summarized in Appendix E.

6. 0 Dietary Risk Assessment

An updated dietary exposure assessment has been completed for mesosulfuron

- methyl for the DRA to incorporate updated food co nsumption data and drinking water modeling estimates. The use pattern, PODs, and residue inputs to the dietary assessment have not changed since the previous assessment.

6 .1 Water Residue Profile

Screening ground water

- sourced drinking water exposur e estimates were generated with the
Pesticide Root Zone Model for Ground Water ( PRZM

- GW; v.1.07) for use in the SU dietary risk assessments. Rather than produce chemical

- specific estimated drinking water concentrations (EDWCs) following the usual assessme nt procedures, the Environmental Fate and Effects Division ( EFED ) provided coarse

- screen estimates that should exceed upper

- bound chemical

specific EDWCs for any SU. This was achieved by using model inputs that represent the use pattern of highest exposur e from any SU, the highest soil mobility of any SU residue of concern, and persistence to any route of degradation over time. The resulting highest coarse

- screen EDWCs from PRZM

- GW can be used as conservative estimates of exposure and are
summarized in Ta ble 6

. 1 ( G. Orrik, D427429, 08/12/2015)

.

The chronic dietary assessments for mesosulfuron

- methyl used the post

- breakthrough time it takes the compound to reach the ground water after application) mean value of 492 μg/L (0.492 ppm).

Table 6 .1

. PRZM

- GW Coarse

- Screen EDWCs for Sulfonylureas 1

.

Modeled Scenario K d or K OC Initial Application Dates (days post

emergence) Max. Daily Conc.

(μg/L) Mean

Breakthrough Time (yrs) Post

breakthrough Mean (μg/L)

WI corn K d 7 449 11.5 415

K OC 7 504 6.9 425

DMV corn K d 7 489 5.3 369

K OC 7 560 3.3 378

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 10 of 25 Table 6 .1

. PRZM

- GW Coarse

- Screen EDWCs for Sulfonylureas 1

.

Modeled Scenario K d or K OC Initial Application Dates (days post

emergence) Max. Daily Conc.

(μg/L) Mean

Breakthrough Time (yrs) Post

breakthrough Mean (μg/L)

FL citrus K d 7 429 3.2 351

K OC 7 467 2.3 349

FL potato K d 7 375 2.6 272

K OC 7 407 2.2 275

GA peanut K d 7 197 5.2 156

K OC 7 206 3.9 158

NC cotton K d 7 640 8.7 492

K d 37 641 8.7 491

K d 67 637 8.7 490

K OC 7 742 5.7 484

K OC 37 751 5.7 483

K OC 67 744 5.7 482

1 Maximum values are bold ed and were used in the chronic dietary assessment

.



### 6

. 2 Dietary (Food + Water) Exposure Assessment

HED has conducted a screening

- level chronic dietary risk assessment for mesosulfuron

- methyl using tolerance

- level residues in foods and a sulfonylurea

- class

- wide screening

- level estimate of residues in drinking water (G. Orrik, D427429, 08/12/2015). Expos ure and risk estimates were obtained from the Dietary Exposure Evaluation Model using the Food Commodity Intake Database (DEEM

- FCID; version 3.16 ). The model uses food consumption data from the 200 3

- 2008 NHANES /WWEIA (National Health and Nutrition Examina tion Survey , What We Eat in
America ) database, coupled with recipe files and residues in foods, to derive estimates of dietary exposure and risk. Generally, HED is concerned when dietary exposure estimates exceed 100% of the population adjusted dose (PAD) . In the case of mesosulfuron

- methyl , the dietary risk estimates (Table 6

. 2 ) range from < 1 .0 to 1.7 % of the cPAD and are below HED’s level of concern. Because of the very conservative assumptions used in the analysis (tolerance level residues, 100 % crop treated, upper

- bound modeled drinking water estimates), actual exposure and risk are expected to be muc h lower than those shown in Table 6 .2 . The listings of inputs and outputs to the assessment are included in Appendix B . HED did not conduct an acute dietary exposure/risk assessment because an acute dietary POD was not selected for mesosulfuron

methyl. Mesosulfuron

- methyl is considered “not likely to be carcinogenic to humans”; therefore a cancer dietary risk assessment was also not conducted

.

Table 6

. 2. Summary of dietary exposure and risk estimates for Mesosulfuron

- methyl.

Population Group Chronic Estimates

Exposure, mg/kg bw/day Risk, % cPAD

Total US Population 0.010351 <1 .0 All Infants (< 1 year old) 0.026592 1.7

Children 1

- 2 years old 0.014983 1 .0

Children 3

- 5 years old 0.012643 <1 .0

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 11 of 25 Table 6

. 2. Summary of dietary exposure and risk estimates for Mesosulfuron

- methyl.

Population Group Chronic Estimates

Exposure, mg/kg bw/day Risk, % cPAD

Children 6

- 12 years old 0.009120 <1 .0

Youth 13

- 19 years old 0.007565 <1 .0

Adults 20

- 49 years old 0.010317 <1 .0

Adults 50

- 99 years old 0.010193 <1 .0

Female 13

- 49 years old 0.010279 <1 .0



### 7.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no registered residential uses or occupational uses resulting in residential exposure to
mesosulfuron

- methyl. Therefore, a quantitative residential exposure assessment was not performed.

7

. 1 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g. groundboom ) employed
for meso sulfuron

- methyl

.

An i ncidental oral POD w as not established for mesosulfuron

- methyl because t here were no effects seen in any applicable studies of an appropriate duration to evaluate short

- term incidental oral exposure resulting from spray drift of mes osulfuron

- methyl (90

- day oral toxicity studies, reproductive toxicity studies, or developmental toxicity studies). A dermal POD was not
established because t here were no dermal or systemic effects seen in the subchronic dermal toxicity study; and there wa s no developmental or reproductive toxicity seen throughout the database. Therefore a quantitative spray drift assessment was not conducted for mesosulfuron

methyl.

7

. 2 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The

A gency has evaluated the SAP report and has develope d a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis. 3 

### During Registration Review, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for mesosulfuron

- methyl

.

3 Available at: http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 201 4

- 0219

.

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 12 of 25 8.0 Aggregate Exposure/Risk Characterization

The Food Quality Protection Act of 1996 directs EPA to assess aggregate exposure to pesticide
chemical residues . Exposures to be aggregated includ e anticipated dietary , residential handler, and residential post

- application exposures. Since there are no residential uses for mesosulfuron

methyl that would result in contributions to the aggregate assessment , short

- and intermediate

term aggregate risk assessments are not required

. A ggregate exposure and risk estimates are equivalent to the dietary exposure and risk estimates discussed in Section 6 of this document, and
are not of concern.

9.0 Cumulative Exposure/Risk Characterization

In 2015, EPA’s Off

ice of Pesticide Programs released a guidance document entitled, Pesticide Cumulative Risk Assessment: Framework for Screening Analysis [ http://www.epa.gov/oppfead1/cb/csb_page/updates/2015/frame work

- for

- screening

analysis.html ]. This document provides gu idance on how to screen groups of pesticides for cumulative evaluation using a two

- step approach beginning with the evaluation of available toxicological information and if necessary, followed by a risk

- based screening approach. This framework supplements the existing guidance documents for establishing common mechanism groups (CMGs) [1] 

### and conducting cumulative risk assessments (CRA) [2]



### . The Agency has
utilized this framework to evaluate the SUs of which mesosulfuron

- me thyl is a member (J. D’Agostino, D4 28798

, 0 9/ 0 9/15). Although the SUs share some chemical and toxicological characteristics, the toxicological database does not support a testable hypothesis for a common
mechanism of action. No further mechanistic data are required and no further cumulati ve evaluation is necessary.

10.0 Occupational Exposure/Risk Characterization

Dermal exposure during handling activities was not considered because systemic toxicity was not observed at the limit dose in the dermal study. An occupational handler exposure and risk assessment was conducted using a n inhalation POD derived from the chronic oral toxicity study in dogs. This is considered a conservative assessment because of the exposure duration of the selected study for the POD. On ly short

- and intermediate

- term exposures are expected for
mesosulfuron

- methyl; however the POD conservatively represents effects likely only seen after
intermediate

- term or chronic exposure durations.

The occupational handler inhalation risk estimate s indicate that short

- and intermediate

- term

non

- cancer inhalation MOEs are not of concern to HED (i.e. MOEs > 100 ) with baseline attire (no respirator). The lowest MOE of 89,000 represents the most protective worst

- case occupational scenario: mixing/load ing dry flowables (water

- dispersible granules) to support aerial applications to high acreage crops (i.e. wheat ).

[1] Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999)

[2] Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity (USEPA, 2002)

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 13 of 25 Dermal exposure during post

- application activities was not considered because no systemic toxicity was observed at the limit dose in the de rmal study. Based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessmen t was not performed for mesosulfuron

- methyl at this time. If new policies or procedures are put into place, the Agency may revi sit the need for a quantitative occupational post

- application inhalation exposure assessment for mesosulfuron

- methyl

.

The requirement for a dislodgeable foliar residue (DFR) study has been waived at this time for
mesosulfuron

- methyl. For additional det ails, see Appendix G.

Restricted Entry Interval (REI)

Based on the acute toxicity categories and post

- application assessment for mesosulfuron

- methyl, the Worker Protection Standard (WPS) Interim Restricted Entry Interval (REI) for mesosulfuron

methyl is 12

- hours. REIs may be further reduced if certain criteria are met in accordance with the Pesticide Registration (PR) Notice 95

- 3 [Reduction of WPS Interim REIs for Certain Low Risk Pesticides] 4 

### . In PR Notice 95

- 3, there are a set of criteria listed fo r the active ingredient that must be met for chemicals to be eligible for a reduced REI. These criteria include:

1. The active ingredient is in Toxicity category III or IV based upon data for acute dermal toxicity, acute inhalation toxicity, primary skin ir ritation, and primary eye irritation. Acute oral toxicity data were used if no acute dermal data were available. If EPA lacked data on primary skin irritation, acute inhalation, or primary eye irritation of the active ingredient, the Agency reviewed data o n that end

- point for similar active ingredients (analogs), and excluded such active ingredients from consideration for the reduced REI, if the analog is in Toxicity Category I or II for that endpoint.

2. The active ingredient is not a dermal sensitizer (or in the case of biochemical and microbial active ingredients, no known reports of hypersensitivity exist).
3. The active ingredient is not a cholinesterase inhibitor (NMethyl carbamate and Organophosphate) as these chemicals are known to cause large numbers of p esticide poisonings and have the potential for serious neurological effects.

4. No known reproductive, developmental, carcinogenic, or neurotoxic effects have been associated with the active ingredient. If active ingredients did not have data available for
th ese chronic health effects, EPA considered data on appropriate chemical and biological analogs. Active ingredients that have been classified as carcinogenic in Category B (probable human carcinogen) or Category C with a potency factor, Q* (possible human

c arcinogen, for which quantification of potential risk is considered appropriate), or are scheduled for the Health Effects Division's Cancer Peer Review process, were omitted
from consideration.
5. EPA does not possess incident information (illness or injury r eports) that are ``definitely'' or ``probably'' related to post

- application exposures to the active ingredient.

Upon review of the criteria for the active ingredient only , it appears that mesosulfuron

- methyl is
consistent with the criteria in PRN 95

- 3 tha t allow for a 4

- hour REI. Note : The PR Notice also includes similar criteria for the end

- use product. These criteria have not been evaluated by

4 Available: http://www.epa.gov/PR_Notices/pr95

- 3.html

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 14 of 25 HED. Based solely on the active ingredient criteria, HED would recommend for reduction of the
REI for mesosulfuron

- methyl.

11.0 Public Health and Pesticide Epidemiology Data

T he OPP Incident Data System (IDS)

, the Centers for Disease Control and Prevention/Natio nal 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 2013 and no incid ents of concern were identified (S. Recore, D409035, 02/07/2013); therefore additional analysis is not required

. Mesosulfuron

- methyl is also not included in the Agricultural Health Study (A HS ) , and therefore this study does not provide any additional info rmation on mesosulfuron

- methyl . The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

1 2 .0 References

Author Barcode Date Title

C. Stafford D298702 3/25/04 PP# 1F06298. Review of Residue Analytical Methods Submitted to Support Food Tolerances for Mesosulfuron

- methyl. Chemical # 122009.

N. Dodd D396429 7/30/13 Mesosulfuron

- methyl. Independent Laboratory Validation and Storage Stability Data on Whea t.
N. Dodd D406414 4/16/13 Mesosulfuron

- methyl. Human Health Assessment Scoping Document in Support of Registration Review.

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.
K. O’Rourke D298764 4/4/04 Human Health Risk Assessment for Mesosulfuron

- methyl to Support Request for New Active Ingredient Uses on Wheat.

S. Mathur D297240 1/15/04 Product Chemistry Review of Mesosulfuron

- methyl Technical/MUP

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. K. Rury TXR #

0056723 8/6/13 Sulfonylureas: Summary of Hazard and Science Policy Council (HASPOC) Meeting on July 18, 2013: Recommendations on Data Requirement for Immunotoxicity Studies for Sulfonylurea Pesticides.

S. Winfield D298763 3/3/04 Occupational and Residential Risk Assessment to Support Request for a Section 3 Registration of Mesosulfuron

- methyl on Wheat

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 15 of 25 Appendix A : Toxicity Profile of Mesosulfuron

- Methyl

Table A.1. Mesosulfuron

- methyl Toxicity Data Requirements

.

Test Technical Required Satisfied

870.1100 Acute Oral Toxicity

................................ ...................... 870.1200 Acute Dermal Toxicity

................................ ................. 870.1300 Acute Inhalation Toxicity

................................ ............. 870.2400 Primary Eye Irritation

................................ ................... 870.2500 Primary Dermal Irritation

................................ ............. 870.2600 Dermal Sensitization

................................ ..................... yes

yes

yes

yes

yes

yes 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 yes

yes waived 1

--- waived 1

870.3700 Developmental Toxicity (rodent)

................................ .. 870.3700 Developmental Toxicity (nonrodent)

............................ 870.3800 Reproduction

................................ ................................ yes

yes

yes yes

yes

yes 870.4100 a Chronic Toxicity (rodent)

................................ ............. 870.4100 b Chronic Toxicity (nonrodent)

................................ ....... 870.4200 a Carcino genicity (rat)

................................ ..................... 870.4200 b Carcino genicity (mouse)

................................ ............... 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 Effects

...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes 870.6100 Acute Delayed Neurotox. (hen)

................................ .... 870.6100 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200 a Acute Neurotox. Screening Battery (rat)

...................... 870.6200 b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Developmental Neuro toxicity

................................ ....... no

no

yes

yes

no ---

--- waived 1

waived 1

--- 870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ....................... 870.7800 Immunotoxicity

................................ ............................ yes

no

yes y es

--- waived 2
Data requirement waived by HASPOC for the subchronic dermal, 90

- day inhalation, acute/subchronic neurotoxicity, and immunotoxicity studies : 1: TXR# 005 6 562 and 2: T XR# 0056723

.

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 16 of 25 Table A.2. Acute Toxicity of Mesosulfuron

- methyl

– Technical

. Guideline

No. Study Type MRID No. Results Toxicity Category

870.1100 Acute oral toxicity

- rats 45386321 LD 50 > 5000 mg/kg [M/F] IV

870.1200 Acute dermal toxicity

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

870.1300 Acute inhalation

toxicity

- rats 45386323 LC 50 > 1.33 mg/kg [M/F] III

870.2400 Acute eye irritation

-

rabbits 45386324 Conjunctival irritation at 24 hrs in 1/3 of
test animal s

. C leared by 48 hrs. III

870.2500 Acute dermal irritation

rabbits 45386325 Non Irritant IV

870.2600 Skin sensitization

guinea pigs 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).

Table. A.3. Subchronic, Chronic and Other Toxicity of Mesosulfuron

- methyl Technical

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, 908 mg/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.

70.3200
21/28

- Day dermal toxicity Waived (TXR: 0056562; 2/21/2013)

.

870.3465
90

- Day inhalation toxicity Waived (TXR: 0056562; 2/21/2013)

.

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 45430405 (2000)

Acceptable/guideline Parental/Systemic NOAEL = 1175.2/ 1387.6 [M/F] mg/kg/day

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 17 of 25 Table. A.3. Subchronic, Chronic and Other Toxicity of Mesosulfuron

- methyl Technical

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

Reproduction and fertility effects in

rats 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 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.

N o 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 Negative ± S9 up to cytotoxic 5000 μg/ml plate

Gene Mutation

870.5300
Mammalian cell
culture 45386404 (1998)

Acceptable/ guideline Negative ± S9 up to cytotoxic 2500 μg/ml and precipitation 250 μg/ml

Cytogenetics

870.5375
Chromosomal
aberrations 45386403 (1998)

Acceptable/ guideline Negative ± S9 precipitation  100 μg/ml

Cytogenetics
870.5395
Micronucleus test

on mouse 45386406 (1998)

Acceptable/ guideline Negative at the highest dose tested (limit dose) 2000 mg/kg ( 0, 200, 1000, or 2000 mg/kg )

870.5550
Unscheduled DNA Synthesis 45386405 (1998)

Acceptable/ guideline (a.i.) Negative ± S9 precipitation  100 μg/mL

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 18 of 25 Table. A.3. Subchronic, Chronic and Other Toxicity of Mesosulfuron

- methyl Technical

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

870.6200a Acute neurotoxicity screening battery Waived (TXR: 0056562; 2/21/2013)

.

870.6200b
Subchronic neurotoxicity screening battery Waived (TXR: 0056562; 2/21/2013)

.

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. Based on
the radio activity found in urine, feces, and the contents of the stomach and intestines; maximal absorption was approximately 30% of the
administered dose. At 72 hours post

- dose (or 168 hours following the final dose of the repeated study), urinary excretion accoun ted 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 fece s 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/cm 2 or 0.3 mg
ai/cm 2 For both dose groups at each sampling interval, the majority of the applied dose was not absorbed (73.75

- 88.10% dose) following a 6

- hour exposure period. A significant fraction of this material was found on the dressings at six hours and was not available for absorption.

870.7800 Immunotoxicity Waived (TXR: 0056723, 8/6/2013)

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 19 of 25 Appendix B : Dietary Exposure/Risk Modeling Input and Output

Filename: C: \ Users \ ndodd \ Documents \ DEEM Version 3.16 \ Mesosulfuron

- methyl 041315.r08

Chemical: Mesosulfuron

- methyl RfD(Chronic): 1.55 mg/kg bw/day NOEL(Chronic): 0 mg/kg bw/day RfD(Acute): 0 mg/kg bw/day NOEL(Acute): 0 mg/kg bw/day Date created/last modified: 04

- 13

- 2015/16:14:08 Program ver. 3.16, 03

- 08

- d

------------------------- ---------------------------------------------------------- EPA Crop Def Res Adj.Factors Comment Code Grp Commodity Name (ppm) #1 #2

---------- ---- ---------------------- --------- ---------- ------ ------ ------- 1500401000 15 Wheat, grain 0.030000 1.000 1.000 1500401001 15 Wheat, grain

- babyfood 0.030000 1.000 1.000 1500402000 15 Wheat, flour 0.030 000 1.000 1.000 1500402001 15 Wheat, flour

- babyfood 0.030000 1.000 1.000 1500403000 15 Wheat, germ 0.100000 1.000 1.000 1500404000 15 Wheat, bran 0.030000 1.000 1.000

3100 046000 31 Beef, meat byproducts 0.010000 1.000 1.000 3100046001 31 Beef, meat byproducts

- babyfood 0.010000 1.000 1.000 3100048000 31 Beef, kidney 0.010000 1.000 1.000 3100049000 31 Beef, liver 0.010000 1.000 1.000 3100049001 31 Beef, liver

- babyfood 0.010000 1.000 1.000 3200170000 32 Goat, meat byproducts 0.010000 1.000 1.000 3200172000 32 Goat, kidney 0.0 10000 1.000 1.000 3200173000 32 Goat, liver 0.010000 1.000 1.000 3500340000 35 Sheep, meat byproducts 0.010000 1.000 1.000 3500342000 35 Sheep, kidney 0.010000 1.000 1.000

35 00343000 35 Sheep, liver 0.010000 1.000 1.000 8601000000 86A Water, direct, all sources 0.492000 1.000 1.000 8602000000 86B Water, indirect, all sources 0.492000 1.000 1.000

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 20 of 25 Appendix C : Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data are subject to ethics review pursuant to 40 CFR 26, have received th at review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/pos t

- app

- exposure

- data.html

.

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 21 of 25 Appendix D : Occupational Non

- cancer Handler Exposure Estimates and Algorithms

.

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2014 ); Level of mitigation: Baseline, except for aerial application which is baseline with Eng.
Controls.

2 Based on registered labels (Reg. No. 264

- 802 (WDG) and 264

- 1103 (WDG). Th e s e are the label s with the highest application rates for each formulation.
3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate ( lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (80 kg).
5 Inhalation MOE = Inhalation NOAEL ( 155 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Table D. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Mesosulfuron

- Methyl

.

Exposure Scenario Crop or Target Level of Concern Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum

Application Rate 2 Area Treated or

Amount Handled Daily 3 Inhalation

Baseline (no respirator) Dose (mg/kg/day) 4 MOE 5

Mixer/Loader

Mixing/Loading WDG for Aerial

Application Wheat 100 8.96 0.013 lb ai/A 1200 acres 0.00175 89,000

Mixing/Loading WDG for Groundboom Application 200 acres 0.000291 530,000

Applicator

Aerial Application Wheat 100 0.0049 0.013 lb ai/A 1200 acres 0.000000955 160,000,000

Groundboom Application 0.043 200 acres 0.0000111 14,000,000

Flagger

Flagging for Aerial Application Wheat 100 0.35 0.013 lb ai/A 350 acres 0.0000199 7,800,000

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 22 of 25 A ppendix E. Nomenclature and Physical/Chemical Properties

Chemical Identity Table

Table E.1. Nomenclature

Chemical Structure

Empirical Formula C 16 H 19 N 5 O 9 S 2 Common Name mesosulfuron

- methyl

IUPAC Name 2

- [(4,6

- dimethoxypyrimidin

- 2

- ylcarbamoyl)sulfamoyl]

- α

- methanesulfonamido

- p

toluic acid , methyl ester

CAS Name 2

- [[[[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]amino]sulfonyl]

- 4

- [[(methylsulfonyl)amino]methyl]benzoic acid , methyl ester CAS Registry Number 208465

- 21

- 8

Chemical Class pyrimidinylsulfonylurea herbicide

Table E.2. Physical/Chemical Properties. 1

Parameter Value Reference (MRID)

Color cream 45386210 Physical State solid powder 45386211

Odor weakly pungent 45386212
pH 5.1 @ 25  C 45386220
Density 1.53 gm/cc at 23  C 45386214 Water solubility at 20°C water (pH =5.66) buffer pH 4 buffer pH 5 buffer pH 7 buffer pH 9 buffer pH 10 2.14 x 10

- 2 + 0.17 x 10

- 2

2.15 x 10

- 3 + 0.14 x 10

- 3

7.24 x 10

- 3 + 0.36 x 10

- 3

0.483 + 0.008
15.39 + 0.32
13.80

Solvent solubility , g/L, at 20  C isopropanol 9.6 x 10

- 2

aceto ne 13.66

aceto nitrile 8.37

n

- hexane <2.29 x 10

- 4 methylene chloride 3.79 ethy l acetate 2.03
toluene 1.26 x 10

- 2 45386215

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 23 of 25 Vapor pressure at 20  C 3.5 x 10

- 12 Pascal 45386217
Dissociation constant, pK
a , at
20  C 4.35 ± 0.04

45386218
Octanol/water partition
coefficient log P o/w = 1.90 (pH 4); 1.39 (pH 5);

- 0.48 (pH 7);

- 2.06 (pH 9);

- 2.10 (pH 10) 45386219

UV/visible absorption spectrum Not available

1 D297240, Shyam Mathur, PhD, 1/15/04



### A ppendix F

. International Harmonization

Mesosulfuron

- methyl (12 2009 ; 4/06/15 )

Table 3. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 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 ]carbon yl]amino]sulfonyl]

- 4

- [[(methylsulfonyl)amino]m ethyl]benzoate None

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

US Canada Mexico 1 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

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 24 of 25 Table 3. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 Codex Completed by: M. Negussie; 4/10 /201 5

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

### Mesosulfuron

- Methyl Human Health Risk Assessment D427039

Page 25 of 25 Appendix G . DFR Data Waiver Rationale

Dislodgeable Foliar Residue (DFR): In accordance with 40CFR158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farm s) uses that could result in post

application exposure to foliage. In the absence of chemical

- specific DFR data, EPA uses default
values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure

Assessment includes an analysis of a numbe r of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studies. Since that time, the Agricultural Re

- entry Task Force has submitted information (MRID 49299201) that corrects an application rate error made in the original submission of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result, the range of F AR 

### values was revised from 2%

- 89% to 2%

- 47%. In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical. At this time, the ARTF submission did not alter the selection of 25% as the reasonable, high

- end default value.

Since there was no dermal POD selected for mesosulfuron

- methyl, an occupational post

application assessment is not required at this time. Therefore, no additional DFR data are required and the 40CFR DFR data requirement is waived.