
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION


MEMORANDUM


Date: March 25, 2013

SUBJECT:	Halosulfuron-Methyl:  Human Health Risk Assessment for Proposed New Uses on Artichoke and Caneberry ( Crop subgroup 13-07A)

 
PC Code:  128721
DP Barcode:  D404095 
Decision No.:  465913
Registration No.:  81880-15, 81880-18, 81880-2
Petition No.:  2E8050
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  NA
TXR No.:  NA
CAS No.:  100784-20-1
MRID No.:  NA
40 CFR:  180.479


FROM:	Sheila Healy, Risk Assessor 
      Meheret Negussie, Chemist
		Nancy Tsaur, Chemist, ORE Assessor
		Risk Assessment Branch 3
		Health Effects Division (7509P)

THROUGH:	Christine Olinger, Branch Chief
		Risk Assessment Branch 3
		Health Effects Division (7509P)

TO:		Barbara Madden/Sidney Jackson (RM 05)
		Risk Integration, Minor Use & Emergency Response Branch
		Registration Division (7505P)



1.0	Executive Summary	4
2.0	HED Recommendations	7
2.1	Data Deficiencies	7
2.2	Tolerance Considerations	7
2.2.1	Enforcement Analytical Method	7
2.2.2	International Harmonization	8
2.2.3	Recommended Tolerances	8
2.2.4	Revisions to Petitioned-For Tolerances	8
2.3	Label Recommendations	8
3.0	Introduction	8
3.1	Chemical Identity	9
3.2	Physical/Chemical Characteristics	9
3.3	Pesticide Use Pattern	10
3.4	Anticipated Exposure Pathways	11
3.5	Consideration of Environmental Justice	11
4.0	Hazard Characterization and Dose-Response Assessment	11
4.1	Summary of Toxicological Effects	12
4.2	Safety factor for Infants and Children (FQPA Safety Factor)	12
4.2.1	Completeness of the Toxicology Database	13
4.2.2	Evidence of Neurotoxicity	13
4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	13
4.2.4	Residual Uncertainty in the Exposure Database	14
4.3	Toxicity Endpoint and Point of Departure Selections	14
5.0	Dietary Exposure and Risk Assessment	16
5.1	Residues of Concern Summary and Rationale	16
5.2	Food Residue Profile	16
5.3	Water Residue Profile	17
5.4	Dietary Risk Assessment	17
5.4.1	Description of Residue Data Used in Dietary Assessment	17
5.4.2	Percent Crop Treated Used in Dietary Assessment	17
5.4.3	Acute Dietary Risk Assessment	18
5.4.4	Chronic Dietary Risk Assessment	18
5.4.5	Cancer Dietary Risk Assessment	18
5.4.6	Summary Table	18
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	20
6.1	Residential Handler Exposure	20
6.2.1	Post-Application Exposure	21
6.3	Combined Exposure	21
6.4	Residential Bystander Postapplication Inhalation Exposure	22
6.5	Spray Drift	22
7.0	Aggregate Exposure/Risk Characterization	23
7.1	Acute Aggregate Risk	23
7.2	Short-Term Aggregate Risk	23
7.3	Intermediate-Term Aggregate Risk	24
7.4	Chronic Aggregate Risk	24
7.5	Cancer Aggregate Risk	24
8.0	Cumulative Exposure/Risk Characterization	24
9.0	Occupational Exposure/Risk Characterization	24
9.1	Short- and Intermediate-Term Handler Risk	25
9.2	Short- and Intermediate-Term Post-Application Risk	28
9.2.1	Dermal Postapplication Risk	28
9.2.2	Inhalation Postapplication Risk	28
10.0	References	28
Appendix A.  Toxicology Profile and Executive Summaries	30
A.1	Toxicology Data Requirements	30
A.2	Toxicity Profiles	31
Appendix B.  Physical/Chemical Properties	35
Appendix C.  Review of Human Research	36
Appendix D.  International Residue Limits	37

1.0	Executive Summary

On behalf of Canyon Group L.L.C., c/o Gowan Company, the Interregional Research Project No. 4 (IR-4) of Rutgers University is proposing to add new uses of the active ingredient (ai), halosulfuron-methyl on caneberry (subgroup 13-07A) and artichoke.  Halosulfuron-methyl is a sulfonylurea herbicide which inhibits the plant enzyme acetolacetate synthase and is used for pre- and post-emergent control of annual broadleaf weeds and nutsedges in several agricultural crops as well as residential turf grass and ornamentals.  

The most recent risk assessment for halosulfuron-methyl was conducted in 2012 for uses on Proso Millet and Crop Group 17, Grass, Forage, Fodder, and Hay (D396458, C. Walls, 07/19/12).  In accordance with the 2007 revised 40 CFR Part 158 Toxicology data requirements, an immunotoxicity study and a subchronic inhalation toxicity study are required for halosulfuron methyl.  However, HED has waived the inhalation toxicity study data requirement at this time (TXR0054045).  

Pending submission of an analytical standard for the rearrangement ester (RRE) of halosulfuron-methyl, there are no additional toxicology or residue chemistry issues that would preclude granting unconditional registration for the requested uses of halosulfuron-methyl on caneberry subgroup 13-07A and artichoke.

Proposed Use Profile
Halosulfuron-methyl is formulated as a water dispersible granule (WG) and applied as postemergence broadcast foliar sprays using ground equipment only for caneberries and artichokes.  Application through any type of irrigation system is prohibited.  Halosulfuron-methyl may be applied to artichoke at a maximum seasonal application rate of 2 oz/A (0.094 lb ai/A); the label does not specify maximum applications per season.  For caneberry, halosulfuron-methyl may be applied twice per season at a maximum annual application rate of 2 oz/A (0.094 lb ai/A).  The restricted entry interval (REI) is 12 hours.  

These new uses are proposed to be added to two end-use product (EP) labels: Sandea(R) Herbicide (EPA Reg. No. 81880-18) with 75% ai by weight and GWN-3061 Herbicide (EPA Reg. No. 81880-2) with 75% ai by weight.

Exposure Profile
Based on application rate and label information, exposure to halosulfuron methyl is expected to occur for acute-, short- , intermediate-term exposures.  Chronic exposure (other than dietary) is not expected for the proposed use patterns.  The proposed agricultural uses on caneberry and artichoke would result in new dietary exposures in both food and drinking water.  There are also existing residential uses that would result in non-occupational exposure from handler and post-application activities.  In occupational settings, exposure is also expected during handler activities for proposed uses.  

Toxicity/Hazard
Halosulfuron-methyl has low acute toxicity via the oral (Toxicity Category IV), dermal (Toxicity Category III), and inhalation (Toxicity Category IV) routes.  Halosulfuron-methyl is a non-irritant for skin and eyes (Toxicity Category IV) and is not a dermal sensitizer.  With repeated dosing, halosulfuron-methyl produces non-specific effects, which are frequently characterized by reduced body weight/body weight gain in the test animals.  In the prenatal developmental toxicity study in rats, increases in resorptions, soft tissue (dilation of the lateral ventricles) and skeletal variations, and decreases in body weights were seen in the fetuses compared to clinical signs and decreases in body weights and food consumption in the maternal animals at a similar dose level.  In the rabbit developmental toxicity study, increases in resorptions and post-implantation losses and decrease in mean litter size were seen in the presence of decreases in body weight and food consumption in maternal animals were observed.  However, a clear No Observable Adverse Effect Level (NOAEL) for these effects was established in both rat and rabbit developmental toxicity studies.  Halosulfuron-methyl did not produce reproductive effects.  No neurotoxic effects were observed in the acute or subchronic neurotoxicity studies. Halosulfuron-methyl is classified as "not likely to be carcinogenic to humans."  It is negative for mutagenicity in a battery of genotoxicity studies.  

The toxicology database is adequate, with the exception of the requirement for an immunotoxicity study.  The requirement for a subchronic inhalation toxicity study has been waived. 

The toxicity endpoints and points of departure (POD) for risk assessment were selected for the following exposure scenarios: acute and chronic dietary, short- and intermediate-term incidental oral, dermal and inhalation.  A summary of toxicity endpoints and points of departure is presented in Table 4.3.1.  Because of a common effect (i.e., body weight gain changes) seen in the studies selected for the endpoints for all three routes of exposure, Margins of Exposure (MOEs) and exposures can be combined where appropriate. The level of concern (LOC) for residential and occupational exposures via dermal and inhalation routes is a MOE less than 100. The Food Quality Protection Act (FQPA) safety factor is 1X.  

Dietary Exposure (Food and Water) and Risk Estimates
The residue chemistry data and environmental fate data are adequate to assess human exposure.  There was no indication of an adverse effect attributable to a single dose for the general U.S. population.  However, an acute reference dose (aRfD) was established for females 13-49 years old.  Conservative acute and chronic dietary exposure assessments were performed for halosulfuron-methyl using tolerance-level residues and 100% crop treated.  The estimated drinking water concentration (EDWC) for rice was 59.2 ug/L and used directly in both the acute and chronic assessments.  For all processed commodities, the Dietary Exposure Evaluation Model (DEEM) version 7.81 default processing factors were assumed.  The results of the acute and chronic dietary (food and drinking water) analyses are below the Agency's level of concern (LOC) for the general U.S. population and all population subgroups.  The acute dietary (food and drinking water) exposure is estimated at <1% of the acute Population Adjusted Dose (aPAD) for the females 13-49 years old.  The dietary (food and drinking water) exposure is estimated at 2% of the chronic Population Adjusted Dose (cPAD) for the general U.S. population and 5.5 % of the cPAD for children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure to halosulfuron-methyl.  Halosulfuron-methyl is classified as "not likely to be carcinogenic to humans;" therefore, cancer risk was not quantitatively assessed. 

Residential Exposure and Risk Estimates
There are no proposed residential uses at this time; however, there are existing residential turf uses that have been reassessed to reflect updates to HED's 2012 Residential SOPs along with policy changes for body weight assumptions.  Short-term combined (dermal + inhalation) residential handler MOEs range from 7,200 to 190,000 and, therefore, are not of concern.  Short-term post-application MOEs for all residential scenarios range from 1,000 to 11,000,000 and, likewise, are not of concern.
       
Residential Aggregate Exposure Risk Estimates
There is potential for short-term aggregate exposure to halosulfuron methyl via the dietary (which is considered background exposure) and residential (which is considered primary) pathways.  All aggregate MOEs are greater than 100, which indicates that exposure and risk do not exceed HED's LOC.  The adult and children short-term aggregate (dietary + residential) MOEs are 1,800 and 840, respectively.  Intermediate-term and chronic aggregate risk are expected to be equivalent to chronic exposure via the dietary pathway.

Occupational Exposure and Risk Estimates
Agricultural Handlers:  There is potential for short- and intermediate-term occupational exposure to halosulfuron-methyl during handling activities (e.g. mixing, loading, application).  All handler scenarios result in MOEs greater than the LOC (MOEs >= 100) at baseline or with recommended PPE.  For artichoke, the baseline short-term combined (dermal + inhalation) MOEs range from 650 to 14,000; for caneberry, MOEs range from 650 to 48,000.  For artichoke, the baseline intermediate-term combined (dermal + inhalation) MOEs range from 88 to 1,800; for caneberry, MOEs range from 88 to 6,400.  At baseline, the handheld equipment (mechanically-pressurized handgun) results in an MOE of 88 for both caneberry and artichoke.  However, with recommended PPE of gloves, the MOE increases to 290.

Agricultural Post-application:  There is no potential for dermal or inhalation short- and intermediate-term occupational exposure during post-application activities based on the proposed use pattern for artichokes and caneberries.  Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for halosulfuron-methyl at this time.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for halosulfuron-methyl.

Environmental Justice Considerations
Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment.  Dietary and non-dietary exposures were considered.

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 studies (listed in Appendix C) have been determined to require a review of their ethical conduct, and one of these studies is also subject to review by the Human Studies Review Board.  All of the listed studies have received the appropriate review.


2.0	HED Recommendations

Provided an analytical reference standard for the RRE of halosulfuron-methyl is submitted, HED recommends granting an unconditional registration for the requested use of halosulfuron-methyl on artichoke and caneberry.  Additional data are needed prior to the registration as outlined in Section 2.1 below.  Tolerance recommendations are discussed in Section 2.2.  There are no label modifications recommended for the proposed new uses.  

2.1	Data Deficiencies

860.1650 Submittal of Analytical Reference Standards

   * An analytical reference standard for the rearrangement ester (RRE) of halosulfuron-methyl must be submitted to the EPA National Pesticide Standards Repository.  

875.2100 Submittal of Turf Transferable Residue (TTR)

   * A TTR study is required for halosulfuron-methyl at this time since the dermal MOE for children 1 to <2 years old is less than 10 times the LOC of 100 (MOE = 960), based on default values for the fraction of application rate available for transfer after a turf application (DP404839, N. Tsaur, 02/21/2013).

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An adequate analytical method is available for enforcement of tolerances for halosulfuron-methyl residues in plants.  The gas chromatography (GC) method quantifies halosulfuron-methyl as its rearrangement ester (RRE; 1-H-pyrazole-4-carboxylic acid, 3-chloro-5-[(4,6-dimethoxy-2-pyrimidinyl)amino]-1-methyl, methyl ester) using thermionic-specific detection (TSD, nitrogen specific).  Monsanto Analytical Method RES-109-97-4 (MRID 44495801) has been validated as an enforcement method by the Analytical Chemistry Branch (ACB)/Biological and Economic Analysis Division (BEAD).  The limit of quantitation on rice straw, sugarcane, milo grain, field corn grain, cotton gin byproducts, and almond nutmeats was estimated to be 0.05 ppm (DP#250584, G. Jeffrey Herndon, 10/28/98). For confirmation, the RRE can be determined by GC/MS with monitoring at m/z 327.

Residues of halosulfuron-methyl and 3-CSA are not recoverable by the FDA Multiresidue Protocols.
2.2.2	International Harmonization

There are currently no Codex or Canadian maximum residue limits (MRLs) established for residues of halosulfuron-methyl in/on any commodity.

2.2.3	Recommended Tolerances

HED has examined the residue chemistry database for halosulfuron-methyl.  Pending submission of a reference standard for the RRE of halosulfuron-methyl (see requirements under Submittal of Analytical Reference Standards), there are no residue chemistry issues that would preclude granting a Section 3 registration for the requested uses on artichoke and caneberry, or the establishment of a tolerance for residues of the halosulfuron-methyl, methyl 3-chloro-5-[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-amino]sulfonyl]-1-methyl-1H-pyrazole-4-carboxylate, including its metabolites and degradates, in/on the commodities below. Compliance with the tolerance levels specified is to be determined by measuring only halosulfuron-methyl.

Table 2.2.3.   Tolerance Summary for Halosulfuron-Methyl
                                   Commodity
                     Established/Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                                   Comments
                         Correct Commodity Definition
Artichoke
                                     0.05
                                     0.05
                                       
Caneberry  subgroup 13-07A
                                     0.05
                                     0.05
                                       

2.2.4	Revisions to Petitioned-For Tolerances

There are no revisions to the tolerance petition (Table 2.2.3).

2.3	Label Recommendations

The labeled use pattern for caneberries must be clarified (for both products EPA Reg. No. 81880-2 and EPA Reg. No. 81880-16).  The proposed labels indicate that aerial application is just for corn, sorghum, and rice, but the specific use directions/limitations of caneberries do not explicitly state: "Do not apply by air."  This statement must be added on both labels in the caneberry section.

3.0	Introduction

Halosulfuron-methyl is a selective herbicide belonging to the sulfonylurea group of herbicides.  It inhibits the action of the plant enzyme acetolactate synthase.  The enzyme is not found in mammals (including humans).  Halosulfuron-methyl is used for the pre- and postemergence control of annual broadleaf weeds and nutsedges in selected crops, residential turfgrass, and ornamentals.  Permanent tolerances are established for a variety of field, fruit, vegetable crop, and livestock commodities under 40 CFR §180.479 at levels ranging from 0.01 to 20 ppm.   Halosulfuron-methyl is sold in the US as dry flowable/water-dispersible granule formulations or as emulsifiable concentrates.

The petitioner, IR-4 on behalf of Canyon Group LLC (agent Gowan Company) has submitted a request for amended registration of two 75% WG formulations (Sandea Herbicide, EPA Reg. No. 81880-18, and GWN-3061, EPA Reg. No. 81880-2) for use on artichoke and caneberry.  The proposed uses reflect ground application to caneberry at 0.024 - 0.094 lb ai/A or to artichoke at 0.047 - 0.094 lb ai/A.  The proposed postharvest intervals (PHIs) are 15 days for caneberry and 5 days for artichoke. 


3.1	Chemical Identity

Table 3.1.  Test Compound Nomenclature.
Chemical structure
                                       
Common name
Halosulfuron-methyl
Company experimental name
MON 12000, NC-319
IUPAC name
Methyl 3-chloro-5-(4,6-dimethoxypyrimidin-2-ylcarbamoylsulfamoyl)-1-methylpyrazole-4-carboxylate
CAS name
Methyl 3-chloro-5-[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-1-methyl-1H-pyrazole-4-carboxylate
CAS registry number
100784-20-1
End-use product (EP)
75% dry flowable SANDEA Herbicide; EPA Reg. No. 81880-18) and 75% WG (GWN-3061 Herbicide; EPA Reg. No. 81880-2)
Chemical structure of
3-chlorosulfonamide moiety (3-CSA)
                                       
          3-Chloro-1-methyl-5-sulfamoyl-1H-pyrazole-4-carboxylic acid

3.2	Physical/Chemical Characteristics

An octanol/water partition coefficient of 1.67 at pH 5 and 23ºC suggests that halosulfuron-methyl is not fat soluble.  In fact, halosulfuron-methyl has significant water solubility especially at elevated pH.  The low vapor pressure indicates little vaporization. Halosulfuron-methyl, like most other sulfonylurea herbicides, is extremely mobile with a median Koc of 104 g/mL and Kf (Freundlich partition) values ranging from 0.32 to 3.6 in four test soils.  Its persistence in soil and water appears to be highly variable.  Halosulfuron-methyl has the potential to leach to groundwater, and also presents concerns for transport to surface water by runoff. 

3.3	Pesticide Use Pattern

Halosulfuron-methyl is a sulfonylurea herbicide proposed for pre- and post-emergence control of broadleaf weeds and nutsedge.  The petitioner is proposing to add artichoke and caneberry (subgroup 13-07A) to these two labels.  The proposed use patterns are presented in Table 3.3.
TABLE 3.3.  Summary of Directions for Use of Halosulfuron-Methyl.
                               Applic. Timing, 
                               Type, and Equip.
                                 Applic. Rate 
                                   (lb ai/A)
                                   Max. No.
                                  Applic. per
                                    Season
                                  Max. Annual
                                 Applic. Rate
                                   (lb ai/A)
                                   PHI (day)
                        Use Directions and Limitations
Caneberry subgroup 13-07A including: blackberry, loganberry, raspberry, black and red, wild raspberry, cultivars, varieties, and/or hybrids of these
Application to either side of crop row, Ground
                        0.5-1 oz (East of the Rockies)
              0.75-2 oz (West of the Rockies) SANDEA or GWN-3061
                                 (0.024-0.094)
                                       2
                                     2 oz
                                    (0.094)
                                      15
Apply a single or sequential application with an interval of 45 days (0.024-0.094 lb ai/A) uniformly with ground equipment in a minimum of 15 gals of water per acre to the ground on either side of the row. Do not apply less than 15 days before harvest. Do not apply if excessive weed growth prevents herbicide contact with ground. Use a non-ionic surfactant with post-emergence applications.[a]
                                   Artichoke
Application to either side of crop row, Ground only
                           1-2 oz SANDEA or GWN-3061
                                 (0.047-0.094)
                                 Not specified
                                     2 oz
                                    (0.094)
                                       5
Apply at 0.047-0.094 lb ai/A uniformly with ground equipment in a minimum of 15 gals of water per acre to the ground on either side of the row and avoiding crop foliage. Do not apply less than 5 days before harvest. Do not apply by air. Use a non-ionic surfactant with post-emergence applications.
a	Note to RD: The labeled use pattern for caneberries must be clarified (for both products EPA Reg. No. 81880-2 and EPA Reg. No. 81880-16).  The proposed labels indicate that aerial application is just for corn, sorghum, and rice, but the specific use directions/limitations of caneberries do not explicitly state: "Do not apply by air."  This statement should be added on both labels in the caneberry section.

3.4	Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new uses of halosulfuron-methyl on artichoke and caneberry (subgroup 13-07A).  Humans may be exposed to halosulfuron-methyl in food and drinking water, since halosulfuron-methyl may be applied directly to growing crops and application may result in halosulfuron-methyl reaching surface and ground water sources of drinking water.  Currently, there are residential uses of halosulfuron-methyl on turf, so there is likely to be exposure in residential settings.  In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  There is a potential for post-application exposure for workers re-entering treated fields.  There is also potential for residential post-application exposure from turf use.

Risk assessments have been previously conducted for halosulfuron-methyl, dated 07/19/12 (D396458, C. Walls).  This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of halosulfuron-methyl, but also considers the existing uses as well, particularly for the dietary and residential exposure assessments.  

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.epa.gov/environmentaljustice/resources/policy/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 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 by the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age 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 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.

4.0	Hazard Characterization and Dose-Response Assessment

The most recent human health risk assessment was conducted for uses on proso millet and Crop Group 17 (C. Walls, 07/19/12, D396458).  Since then, the requirement for a subchronic inhalation study has been waived (TXR 0054045).  Additionally, an immunotoxicity waiver has been submitted and is under review.  The hazard characterization and toxicity endpoints for risk assessment remain unchanged since the 2006 risk assessment for uses on alfalfa (M. Rust, 9/21/2006, D331643).  

4.1	Summary of Toxicological Effects

Halosulfuron-methyl is a member of the sulfonylurea class of herbicides, and it inhibits acetolactate synthase, a specific plant enzyme not found in mammals.  The mode of action in mammals for halosulfuron-methyl is undetermined.  

The metabolism data indicated that with oral administration, halosulfuron-methyl was absorbed rapidly with incomplete absorption from the gastrointestinal tract.  Within 72 hours, the absorbed halosulfuron-methyl was eliminated in the urine and feces.  Desmethyl NC-319 and the 5-hydroxy derivative were the major urinary and fecal metabolites.  No tissue retention was demonstrated.  The absorption, elimination, and metabolism showed no sex dependence.  

Halosulfuron-methyl has low acute toxicity (Toxicity Category III-IV) by oral, dermal, and inhalation routes of exposure.  It is not a dermal sensitizer.  With repeated dosing, the available data show that the dog is the most sensitive mammalian species.  In the dog, decreased body weight was seen in the chronic oral toxicity study and decreased body weight gain was observed in females in the subchronic oral toxicity study.  In the rat and mouse, there was a decrease in body weight gains at high dose levels in short- and long-term oral and dermal studies.  
 
In the prenatal developmental toxicity study in rats, increases in resorptions, soft tissue (dilation of the lateral ventricles) and skeletal variations, and decreases in body weights were seen in the fetuses compared to clinical signs and decreases in body weights and food consumption in the maternal animals at similar dose level.  In the rabbit developmental toxicity study, increases in resorptions and post-implantation losses and decrease in mean litter size was observed in the presence of decreases in body weight and food consumption in maternal animals.  However, a clear NOAEL for these effects was established in both rat and rabbit developmental toxicity studies.  Halosulfuron-methyl did not produce reproductive effects.  No neurotoxic effects were observed in the acute or subchronic neurotoxicity studies.

An estimated dermal absorption rate of 75% is based on results of an oral developmental toxicity study and a 21-day dermal toxicity study in the same species (rat).

Halosulfuron-methyl is negative for mutagenicity in a battery of genotoxicity studies.  It is classified as "not likely to be carcinogenic to humans" based on lack of evidence for carcinogenicity in mice and rats following long-term dietary administration.  

4.2	Safety factor for Infants and Children (FQPA Safety Factor)

The FQPA safety factor has been reduced to 1X for the reasons detailed below (4.2.1 - 4.2.4).  

4.2.1	Completeness of the Toxicology Database

The toxicology database for halosulfuron-methyl is complete with the exception of an immunotoxicity study .  Current data requirements in 40 CFR §158 include an immunotoxicity study (OPPTS Guideline 870.7800) for pesticide registration.  A waiver request for this data requirement has been submitted and is under review.  In the absence of specific immunotoxicity studies, HED has evaluated the available toxicity database to determine whether an additional database uncertainty factor is needed to account for potential immunotoxicity.  The toxicology database of this chemical does not show any evidence of biologically relevant effects on the immune system.  The overall weight of the evidence suggests that this chemical does not directly target the immune system.  HED does not believe that immunotoxicity testing will result in a NOAEL less than that (10 mg/kg/day) used to derive the current cRfD of 0.1 mg/kg/day.  Consequently, HED believes the existing data are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under the FQPA, and an additional database uncertainty factor (UFDB) does not need to be applied at this time.

The requirement for a subchronic inhalation study has been waived (TXR 0054045).

4.2.2	Evidence of Neurotoxicity

Halosulfuron methyl is not an apparently neurotoxic chemical based on clinical observations of neurotoxicity during the conduct of developmental or chronic studies.  No untoward neurobehavioral signs were observed at doses approaching the limit dose in any of the short- term studies in rats or mice (subchronic oral, 21-day dermal) or chronic studies.  No neurotoxic effects were observed during acute or subchronic neurotoxicity studies in which animals were dosed at systemically toxic dose levels.  A developmental neurotoxicity study is not required at this time.

4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no quantitative evidence for increased susceptibility following pre- and/or post-natal exposure.  However, there was qualitative evidence for increased susceptibility.  In the rat study, increases in resorptions, soft tissue (dilation of the lateral ventricles) and skeletal variations, and decreases in body weights were seen in the fetuses compared to clinical signs and decreases in body weights and food consumption in the maternal animals.  In the rabbit study, increases in resorptions and post-implantation losses and decrease in mean litter size were seen in the presence of decreases in body weight and food consumption in maternal animals.  Thus, in both species, the developmental effect was considered to be qualitatively more severe than maternal effects (i.e., qualitative evidence for susceptibility).  In both studies, there are clear NOAELs/LOAELs for developmental and maternal toxicities, developmental effects were seen in the presence of maternal toxicity, and the effects were only seen at the high dose.  Additionally, in rats developmental effects were seen at a dose which is approaching the limit-dose. The degree of concern is low and there are no residual uncertainties for prenatal toxicity in both rats and rabbits.

4.2.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.  Since the dietary and non-dietary exposure estimates were based on several conservative assumptions, HED does not believe that the exposure estimates are underestimated.  The dietary assessments conducted with DEEM-FCID were conservative and utilized tolerance level residues for all crops, default processing factors for all commodities, and 100% crop treated was assumed for all commodities.  The DEEM analysis also assumed that all drinking water will contain halosulfuron methyl at the highest EDWC levels modeled by the Environmental Fate and Effects Division (EFED) for ground water or surface water.  For these reasons it can be concluded that the dietary analysis does not underestimate risk from exposure to halosulfuron methyl. Similarly, HED does not believe that the non-dietary occupational and residential exposures are underestimated because they are also based on conservative assumptions, including maximum application rates, labeled personal protective equipment (PPE), and standard values for unit exposures and acreage treated/amount handled.

4.3	Toxicity Endpoint and Point of Departure Selections

There have been no changes to the prior dose-response assessment for halosulfuron methyl.  The PODs and toxicity endpoints selected for various exposure scenarios applicable to this risk assessment are summarized in Tables 4.3.1 (Non-Occupational and Occupational).  For the short- and intermediate-term inhalation exposure, the toxicity endpoints and points of departure were derived from the oral toxicity studies as indicated in the Table 4.3.1. 

Table 4.3.1  Summary of Toxicological Doses and Endpoints for Halosulfuron-methyl for Use in Dietary, Occupational and Non-Occupational Human Health Risk Assessments
Exposure/
Scenario
Point of Departure
Uncertainty/FQPA Safety Factors
RfD, PAD, Level of Concern for Risk Assessment
Study and Toxicological Effects
Acute Dietary
(Females 13-49 years of age)
NOAEL= 50 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x
Acute RfD = 0.5 mg/kg/day

aPAD =0.5 mg/kg/day
Developmental Toxicity - Rabbit
LOAEL = 150 mg/kg/day based on decreased mean litter size, increased number of resorptions (total and per dam) and increased postimplantation loss (developmental toxicity).
Acute Dietary (General Population including Infants and Children)
No adverse effect attributable to a single dose was identified; therefore, no dose/endpoint was selected for this exposure scenario.

Chronic Dietary (All Populations)
NOAEL= 10 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x 
Chronic RfD = 0.1
mg/kg/day

cPAD = 0.1 mg/kg/day
Chronic Toxicity - Dog
LOAEL = 40 mg/kg/day based on decreased body weight gains in females.
Incidental Oral Short-Term (1-30 days)
NOAEL= 50 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x 
Residential LOC for MOE = 100
Developmental Toxicity - Rabbit
LOAEL = 150 mg/kg/day based on decreased body weight gain, food consumption, and food efficiency (maternal toxicity). 
Incidental Oral Intermediate-Term (1-6 months)
NOAEL= 10 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x 
Residential LOC for MOE = 100
13 Week Subchronic Toxicity - Dog
LOAEL = 40 mg/kg/day based on decreased body weight gains and food efficiency along with hematological and clinical chemistry changes.
Dermal Short-Term (1-30 days)
NOAEL= 100 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x 
Residential and Occupational LOC for MOE = 100
                                       
21-Day Dermal Toxicity Study - Rat
LOAEL = 1000 mg/kg/day based on decreased body weight gain in males.
Dermal Intermediate-Term (1-6 months)[+]
NOAEL=10 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x 
Residential and Occupational 
LOC for MOE = 100

13 Week Subchronic Toxicity - Dog
LOAEL = 40 mg/kg/day based on decreased body weight gains and food efficiency along with hematological and clinical chemistry changes.
Inhalation Short- Term (1-30 days)
NOAEL = 50 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x 
Residential and Occupational  LOC for MOE = 100
Developmental Toxicity - Rabbit
LOAEL = 150 mg/kg/day based on decreased body weight gain, food consumption, and food efficiency (maternal toxicity).
Inhalation Intermediate-Term (1-6 months)
NOAEL= 10 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x 
Residential and Occupational LOC for MOE = 100

13 Week Subchronic Toxicity - Dog
LOAEL = 40 mg/kg/day based on decreased body weight gains and food efficiency along with hematological and clinical chemistry changes.
Cancer (oral, dermal, inhalation)
Classification: "not likely to be carcinogenic to humans" by the oral route, based on no evidence of carcinogenicity from studies in rats and mice.
[+]: A 75% dermal absorption factor should be used in route-to-route extrapolation for the intermediate term dermal exposure risk.  Toxicity via the inhalation route is presumed to be equivalent to oral toxicity.
NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (inter-species).  UFH = potential variation in sensitivity among members of the human population (intra-species).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable



5.0	Dietary Exposure and Risk Assessment 

5.1	Residues of Concern Summary and Rationale

The nature of the residue in plants is adequately understood based on acceptable metabolism studies with corn, sugarcane, and soybean; all studies investigated pre- and postemergence uses.  The metabolism of halosulfuron-methyl was similar in the three tested crops but dependent on the mode of application (pre- or postemergence).  When halosulfuron-methyl was applied preemergence, initial breakdown of the herbicide in the soil and preferential uptake of the pyrazole moieties resulted in the primary residue being 3-CSA, which has been determined to be less toxic than the parent.  With a postemergence application, the major residue was the parent compound with minimal translocation of the herbicide in the plant, except in grain where the major residue was 3-CSA. 

Based on the very low toxicity of the metabolite 3-CSA, relatively low toxicity of the parent compound, and low residue levels of both parent compound and the 3-CSA metabolite, HED previously concluded that the residue of concern in plants is the parent compound, halosulfuron-methyl.

HED has previously concluded that the residue of concern in ruminants is halosulfuron-methyl. However, because the approved enforcement method for livestock commodities quantifies the parent compound and metabolites containing the 3-CSA moiety by converting residues to 3-CSA, tolerances for residues of parent and its metabolites in livestock commodities are determined as 3-CSA, expressed in halosulfuron-methyl equivalents.  

Halosulfuron methyl is the only residue included in the drinking water assessment.

Table 5.1.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants
Primary Crop
Halosulfuron-methyl
Halosulfuron-methyl

Rotational Crop
Halosulfuron-methyl
Halosulfuron-methyl
Livestock
Ruminant
Halosulfuron-methyl*
Halosulfuron-methyl, 3-CSA

Poultry
Halosulfuron-methyl*
Halosulfuron-methyl, 3-CSA
Drinking Water
Halosulfuron-methyl
Not Applicable
*Residues are determined as 3-CSA and expressed in halosulfuron-methyl equivalents.

5.2	Food Residue Profile

The submitted magnitude of the residue data, summarized in Table 2.2.3, are in accordance with OCSPP guidelines and adequate for risk assessment and tolerance assessment.  For both crops, the number and locations of field trials are adequate.  Both artichoke and caneberry trials reflect a single banded postemergence application (backpack) of a 75% ai formulation at a target application rate of ~0.093 lb ai/A.  A non-ionic surfactant was used in both trials.  The available data will support tolerances at the LOQ of 0.05 ppm for both artichoke and caneberry at respective preharvest intervals of 5 and 13-15 days.   

The  field trial studies are supported by adequate storage stability data.

Adequate confined and limited field rotational crop data are available.  HED previously concluded that the residue of concern in rotational crops is halosulfuron-methyl.  Based on the absence of the parent compound in the confined studies and in the limited field rotational crop studies, with the exception of one forage sample, HED previously concluded that rotational crop tolerances and restrictions are not required for halosulfuron-methyl.

5.3	Water Residue Profile

Estimated surface water and groundwater concentrations are shown in Table 5.3.1. 
The dietary exposure assessment used the value of 59.2 ppb for acute and chronic assessments.  The drinking water assessment is based on Tier I surface water model simulation for the halosulfuron-methyl use on rice since the resulting EWDCs are greater than those estimated for the proposed uses (D394244, J. Meléndez, 05/15/12; D404096, M. Barrett, 03/26/13).   

Table 5.3.1.  Tier I Estimated Drinking Water Concentrations (EDWCs) for Human Health Drinking Water Risk Assessment
DRINKING WATER SOURCE
(MODEL USED) 
USE
(rate modeled)
MAXIMUM ESTIMATED DRINKING WATER CONCENTRATION  (EDWC)[c]  ( ppb) 
Groundwater
(SCI-GROW)
Fallow ground
(0.125 lb a.i./A/season) [a]
Acute
                                     0.065


Chronic
                                   <0.065
Surface Water
(Tier 1 Rice Model v.1.0)
Paddy Water/Tail Water; Rice
(0.0625 lb a.i./A/season) [b]
Acute
                                     59.2

                                       
Chronic
                                   <59.2
a Covers all uses other than rice; for the corn, fallow ground, and sugarcane use patterns of halosulfuron-methyl, based on a seasonal application 0.125 lb a.i./A.
b Seasonal rate is 0.0625 lb a.i./A, which is half of the rate of fallow ground.
c Surface water concentrations calculated by the Tier I Rice Model v1.0 and ground water concentrations calculated by SCI-GROW do not distinguish between peak and chronic concentration.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

Conservative acute and chronic dietary exposure assessments were conducted.  Tolerance level residues were used for the existing and proposed uses in both the acute and chronic assessments.  The EWDC value of 59.2 was used as the drinking water residue in both the acute and chronic assessments.  Additionally, DEEM version 7.81 default processing factors were assumed in both assessments, as well.

5.4.2	Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary analyses assumed that 100% of the crop was treated (100% CT)

5.4.3	Acute Dietary Risk Assessment

An acute dietary (food and drinking water) exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID) Version 3.16.  This software uses 2003-2008 food consumption data from the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).  A conservative dietary exposure assessment was performed for halosulfuron methyl for the current uses and the  proposed new uses on artichoke and caneberry (Subgroup 13-07A).  The result of the acute dietary (food and drinking water) analysis is below the Agency's LOC for females 13 -49 years old.  For the general U.S. population, an appropriate dose/endpoint attributable to a single dose was not observed in the reviewed oral toxicity studies therefore, an acute dietary assessment was not conducted.  The acute dietary exposure estimate at the 95[th] percentile is <1% of the acute population adjusted dose (aPAD) for females 13-49 years old, the only population subgroup of concern.  The result of the acute dietary exposure analysis is reported in Table 5.4.6.

5.4.4	Chronic Dietary Risk Assessment

A chronic dietary (food and drinking water) exposure and risk assessment was conducted using DEEM-FCID(TM), Version 3.16.  A conservative dietary exposure assessment was performed for halosulfuron methyl for the current uses, and proposed new uses on artichoke and caneberry (Subgroup 13-07A).  The results of the chronic dietary (food and drinking water) analysis are below the Agency's level of concern for the general U.S. population and all population subgroups.  The dietary (food and drinking water) exposure is estimated at 2% of the chronic Population Adjusted Dose (cPAD) for the general U.S. population and 5.5% of the cPAD for all children 1-2 years old, the most highly exposed population subgroup.  The results of the chronic dietary exposure analyses are reported in Table 5.4.6.

5.4.5	Cancer Dietary Risk Assessment

Halosulfuron methyl is classified as "not likely to be carcinogenic to humans;" therefore, cancer risk was not assessed. 

5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Halosulfuron-Methyl
                              Population Subgroup
                                 Acute Dietary
                               (95th Percentile)
                                Chronic Dietary
                                     Cancer
                                        
                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                      N/A
                                      N/A
                                    0.002050
                                      2.0
                                      N/A
                                      N/A
 All Infants (< 1 year old)
 
 
                                    0.004871
                                      4.9
                                        
                                        
 Children 1-2 years old
 
 
                                    0.005508
                                      5.5
 
 
 Children 3-5 years old
 
 
                                    0.003884
                                      3.9
 
 
 Children 6-12 years old
 
 
                                    0.002433
                                      2.4
 
 
 Youth 13-19 years old
 
 
                                    0.001579
                                      1.6
 
 
 Adults 20-49 years old
 
 
                                    0.001791
                                      1.8
 
 
 Adults 50+ years old
 
 
                                    0.001737
                                      1.7
 
 
 Females 13-49 years old
                                    0.003733
                                     <1
                                    0.001785
                                      1.8
 
 
 Values for the highest exposed population for each type of risk assessment are bolded

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses with this petition; however, there are existing residential turf uses that have been reassessed in the most recent risk assessment (C. Walls, D396458, 07/19/12) to reflect updates to HED's 2012 Residential SOPs along with policy changes for body weight assumptions.  The revision of residential exposures impacts the human health aggregate risk assessment for halosulfuron methyl.

6.1	Residential Handler Exposure

There are no proposed residential uses at this time.  All of the existing residential uses have been previously reassessed to reflect updates to the HED 2012 Residential SOPs along with policy changes for body weight assumptions (N. Tsaur, DP394460, 06/12/12).  There are no registered products that would lead to any residential handler or post-application risk estimates of concern.  Summaries of the short-term combined (dermal + inhalation) risk estimates for residential handlers are included in Table 6.1.  The maximum application rate for each exposure scenario is presented as the worst case scenario.  All risk estimates are greater than the LOC of 100 and therefore not of concern (MOEs range from 7,200 to 190,000).

Table 6.1.	Short-Term Residential Handler Exposure and Risk Estimates for Water Dispersible Granule Application of Halosulfuron-Methyl on Residential Turf.
                               Exposure Scenario
                             Application Rate [a]
                            Area Treated Daily [b]
                           Baseline Unit Exposure b
                               Baseline Dose [d]
                                Baseline MOE e
                                  Total MOE f
                                       
                                       
                                       
                                    Dermal
                                  Inhalation
                                    Dermal
                                  Inhalation
                                       
                                       
                                       
                                    lb ai/A
                                     Acres
                                   mg/lb ai
                                   mg/kg/day
                                    Dermal
                                  Inhalation

                         Manually-Pressurized Handwand
                                     0.14
                                     0.115
                                      69
                                      1.1
                                    0.0135
                                   0.000215
                                     7,400
                                    230,000
                                     7,200
                               Hose-End Sprayer
                                     0.14
                                     0.50
                                     13.4
                                     0.022
                                    0.0114
                                   0.0000187
                                     8,800
                                   2,700,000
                                     8,800
                                   Backpack
                                    Sprayer
                                     0.14
                                     0.115
                                      69
                                      1.1
                                    0.0135
                                   0.000215
                                     7,400
                                    230,000
                                     7,200
                                 Sprinkler Can
                                     0.14
                                     0.023
                                     13.4
                                     0.022
                                   0.000523
                                  0.000000859
                                    190,000
                                  58,000,000
                                    190,000
a	Application Rates based on maximum application rates of registered residential turf uses for halosulfuron-methyl.
b	Based on HED's SOPs: Lawns/Turf  (January 2012). 0.115A = 5 gallons x (label rate: 1000 ft[2]/1 gallon).  0.023 A = 1000 ft[2].
c	Baseline Dermal: no gloves, short pants. Inhalation: no respirator.  
d	Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) x application rate (lb ai/A) x area treated (Acres/day) x absorption factor (%) / body weight (80 kg). Dermal absorption factor = 100%. No inhalation absorption factor.
e	MOE = NOAEL / daily dose (mg/ - kg/ - day).  ST Dermal NOAEL = 100 mg/kg/day. ST Inhalation NOAEL = 50 mg/kg/day. 
f	Total MOE = 1/ [(1/Dermal MOE) + (1/Inhalation MOE)]. Level of concern = 100.	





1.78.1 Post-Application Exposure

Adults and children performing physical post-application activities on turf (e.g. golfing, mowing) may receive dermal exposure to halosulfuron-methyl residues.  Young children 1 to <2 years old may also receive incidental oral post-application exposure to halosulfuron-methyl from treated turf.  The scenarios, routes of exposure, and lifestages previously assessed include: Physical activities on turf, adults (dermal) and children 1 to < 2 years old (dermal and incidental oral); Mowing, adults (dermal) and children 11 to < 16 years old (dermal); and Golfing, adults (dermal), children 11 to < 16 years old (dermal), and children 6 to < 11 years old (dermal).  Post-application risk estimates for all residential scenarios are greater than the LOC of 100 and therefore not of concern (MOEs range from 960 to 11,000,000). 

6.3	Combined Exposure

HED combines risk estimates resulting from separate post-application exposure scenarios when it is likely they can occur on the same day based on the use pattern and the behavior associated with the exposed population and when the toxicological effects are similar.  For halosulfuron-methyl, the toxicological effects are similar for the dermal, inhalation, and incidental oral routes; therefore, the exposures via these routes were combined where appropriate.  For residential handlers, dermal and inhalation exposures were combined.  For post-application scenarios, dermal and incidental oral exposures were combined for children 1 to < 2 years old. 

The incidental oral scenarios (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) should be considered inter-related and it is likely that they occur interspersed amongst each other across time.  Combining all three of these scenarios with the dermal exposure scenario would be overly-conservative because of the conservative nature of each individual assessment.  Therefore, the post-application exposure scenarios that were combined for children 1 to < 2 years old are the dermal and hand-to-mouth scenarios.  This combination should be considered a protective estimate of children's exposure to pesticides used on turf.

All combined (dermal + inhalation) post-application scenarios resulted in MOEs greater than 100 and were not of concern.  Handler dermal exposure is not combined with post-application dermal exposure because a homeowner is unlikely to be conducting post-application activities on the same day in which they apply the chemical.  Table 6.3 shows the combined residential risk estimates for adults and children.

Table 6.3.  Short-Term Residential Exposures for the Halosulfuron-Methyl Combined Risk Estimates
                                  Population
                               Handler MOEs [1]
                       Residential Handler Total MOE [3]
                           Post-Application MOEs [2]
                  Residential Post-Application Total MOE [4]
                                       
                                    Dermal
 Inhalation
                                       
                                    Dermal
                                  Inhalation
                                     Oral
                                       
                                     Adult
                                     7,400
                                    230,000
                                     7,200
                                     1,900
                                      N/A
                                      N/A
                                     1,900
                         Child 11 to < 16 years old
                                      N/A
                                    21,000
                                       
                                       
                                    21,000
                         Child 6 to < 11  years old
                                       
                                    18,000
                                       
                                       
                                    18,000
                          Child 1 to < 2 years old
                                       
                                      960
                                       
                                    23,000
                                      920
1	Handler MOE represents high-end handler exposure, where the exposure duration is appropriate to assess.
2 	Post-application MOE represents high-end incidental oral exposure for the relevant exposure duration.
3	Total MOE = 1 / [(1/Dermal MOE) + (1/Inhalation MOE)].  Dermal NOAEL = 100 mg/kg/day. Inhalation NOAEL = 50 mg/kg/day.
4	Total MOE = 1/ [(1/Dermal MOE) + (1/Incidental Oral MOE)]. Dermal NOAEL = 100 mg/kg/day. Incidental Oral NOAEL = 50 mg/kg/day.

6.4	Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for halosulfuron-methyl at this time primarily because the chemical is only formulated as a WG, has low acute inhalation toxicity (Toxicity Category IV), has low vapor pressure (<1 x 10[-7] mm Hg at 25 ºC), and has a low proposed use rate (0.094 lb ai/A).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for halosulfuron-methyl.

6.5	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for halosulfuron-methyl.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risk estimates associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers.  This exposure scenario is representative of a worst case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios.   

It is noted that the 0.14 lb ai/acre application rate for turf was modeled to estimate post-application residential exposure of children.  As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of farm children via spray drift from agricultural halosulfuron-methyl applications.

6.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  For halosulfuron-methyl, potential exposures from food, drinking water, and residential scenarios were aggregated.

7.1	Acute Aggregate Risk

Refer to Section 5.4.3 which discusses acute dietary (food and drinking water) exposure in detail.  The dietary route alone is relevant for acute exposure and risk assessment; the acute dietary exposure and risk assessment conducted for halosulfuron-methyl is screening-level, wherein the assessment assigns tolerance level residue values to all food commodities proposed to be treated with halosulfuron-methyl and modeled residue values to all drinking water.  No aggregate risk concerns were identified.

6.2 Short-Term Aggregate Risk

There is potential short-term exposure to halosulfuron-methyl via the dietary (which is considered background exposure) and residential (which is considered primary) pathways.  For adults, these pathways lead to exposure via the oral (background) and dermal (post-application primary) routes.  For children, these pathways lead to exposure via the oral (background), and incidental oral and dermal (primary) routes.  MOEs are greater than 100, which indicates that exposure and risk do not exceed HED's level of concern.  

The recommended residential exposure for use in the aggregate assessment of adults and children 1 to <2 years old reflects the combined post-application dermal plus hand-to-mouth exposures from turf treated with liquid applications.  The adult and children short-term aggregate dietary and residential MOEs are 1,800 and 840, respectively.

Table 7.2.  Short-Term Aggregate Risk Calculations
                                  Population
                              Short-Term Scenario
                                       
                           LOC for Aggregate Risk[1]
                                Dietary MOE[2]
                       MOE Oral Residential Exposure[3]
                      MOE Dermal Residential Exposure[4]
                Aggregate MOE (food, water, and residential)[5]
                                    Adult 
                                       
                                      100
                                    28,000
                                      NA
                                     1,900
                                     1,800
                          Child 1 to < 2 years old
                                      100
                                     9,100
                                    23,000
                                      960
                                      840
[1] LOC = 100 (based on inter- and intra- species uncertainty factors totaling 100X).
[2] MOE dietary = [(short-term oral NOAEL 50 mg/kg/day)/(chronic dietary exposure)].   See Tables 4.3.1 and 5.4.6
[3] MOE oral = [(short-term oral NOAEL)/(hand-to-mouth residential exposure)].  See Table 6.3
4 MOE dermal = [(short-term dermal NOAEL)/(high end dermal residential exposure)].    See Table 6.3
[5] MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE dermal)] 

7.3	Intermediate-Term Aggregate Risk

Intermediate-term exposure is not expected for the adult or child residential exposure pathway.  Therefore, the intermediate-term aggregate risk would be equivalent to the chronic dietary exposure estimate.  Refer to Section 5.4.4.

7.4	Chronic Aggregate Risk

Chronic exposure is not expected for the adult residential (dermal and inhalation) exposure pathway.  Therefore, the chronic aggregate risk would be equivalent to the chronic dietary exposure estimate.  Refer to Section 5.4.4.

7.5	Cancer Aggregate Risk

Halosulfuron methyl is classified as "not likely to be carcinogenic to humans;" therefore, an aggregate cancer assessment was not conducted.

7.0 Cumulative Exposure/Risk Characterization

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 halosulfuron methyl and any other substances and halosulfuron methyl does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that halosulfuron methyl has a common mechanism of toxicity with 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/.

8.0 Occupational Exposure/Risk Characterization

9.1	Short- and Intermediate-Term Handler Risk

For caneberries and artichokes, halosulfuron-methyl is proposed to be applied up to two times per season, pre- and post-emergent to weed growth at a maximum application rate of 2 oz/A (0.094 lb ai/A).  The maximum handheld rate is proposed at 0.0094 lb ai/gal (based on a minimum of 10 gallons of water per acre).  Handlers may apply either of the EPs as a foliar spray using only ground equipment for caneberries and artichokes.  Since chemigation was both permitted and prohibited on the labels, it was assessed to be protective.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses.  The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: mixing/loading dry flowables to support groundboom and chemigation applications; applying sprays with groundboom equipment; and mixing/loading/applying sprays for ground-directed application via mechanically-pressurized handguns. 

All handler scenarios result in MOEs greater than the LOC (MOEs >= 100) at baseline or with recommended PPE, and are not of concern to HED.  At baseline, short-term combined (dermal + inhalation) MOEs range from 650 to 48,000.  With the exception of handheld equipment, baseline intermediate-term combined (dermal + inhalation) MOEs range from 120 to 6,400.  At baseline, the handheld equipment (mechanically-pressurized handgun) results in an MOE of 88.  However, with required PPE of gloves, the MOE is 290.  Tables 9.1.1 and 9.1.2 summarize the risk estimates for the proposed uses.







Table 9.1.1.  Short-Term Occupational Handler Non-Cancer Exposure and Risk Estimates for Halosulfuron-Methyl at Baseline
                               Exposure Scenario
                                Crop or Target
                            Dermal Unit Exposure[a]
                          Inhalation Unit Exposure[a]
                          Maximum Application Rate[b]
                    Area Treated or Amount Handled Daily[c]
                                    Dermal
                                  Inhalation
                                     Total
                                       
                                       
                                       
                                       
                                       
                                       
                                    Dose[d]
                                    MOE[e]
                                    Dose[f]
                                    MOE[g]
                                    MOE[h]
                                       
                                       
                                   μg/lb ai
                                       
                                       
                                   mg/kg/day
                                       
                                   mg/kg/day
                                       
                                       
                           Mixer/Loader at Baseline
            Mixing/Loading Dry Flowables for Groundboom Application
                                 Caneberries,
                                  Artichokes
                                      227
                                     8.96
                                     0.094
                                    lb ai/A
                                      80
                                     acres
                                    0.0213
                                     4,700
                                   0.000840
                                    60,000
                                     4,400
                                       
           Mixing/Loading Dry Flowables for Chemigation Application
                                       
                                 Caneberries,
                                  Artichokes
                                       
                                       
                                       
                                      350
                                     acres
                                    0.0931
                                     1,100
                                    0.00368
                                    14,000
                                     1,000
                            Applicator at Baseline
                        Applying Sprays via Groundboom
                                       
                                 Caneberries,
                                  Artichokes
                                       
                                     78.6
                                       
                                     0.34
                                       
                                     0.094
                                    lb ai/A
                                      80
                                     acres
                                       
                                    0.00738
                                       
                                    14,000
                                       
                                   0.0000319
                                       
                                   1,600,000
                                       
                                    14,000
                                       
                      Mixer/Loader/Applicator at Baseline
  M/L/A for Ground-Directed Application via Mechanically-Pressurized Handgun
                                 Caneberries,
                                  Artichokes
                                     1300
                                      3.9
                                    0.0094
                                   lb ai/gal
                                     1000
                                    gallons
                                     0.153
                                      650
                                   0.000458
                                    110,000
                                      650
a	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2012). Level of mitigation: baseline.
b	Based on registered or proposed label (Reg. No. 81880-2).
c	Exposure Science Advisory Council Policy #9.1.
d	Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
e	Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day). ST Dermal NOAEL = 100 mg/kg/day. LOC = 100.
f	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
g	Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day). ST Inhalation NOAEL = 50 mg/kg/day. LOC = 100.
h	Total MOE = 1 / (1/Dermal MOE  +  1/Inhalation MOE).




Table 9.1.2.  Intermediate-Term Occupational Handler Non-Cancer Exposure and Risk Estimates for Halosulfuron-Methyl
                               Exposure Scenario
                                Crop or Target
                            Dermal Unit Exposure[a]
                          Inhalation Unit Exposure[a]
                          Maximum Application Rate[b]
                    Area Treated or Amount Handled Daily[c]
                                    Dermal
                                  Inhalation
                                     Total
                                       
                                       
                                       
                                       
                                       
                                       
                                    Dose[d]
                                    MOE[e]
                                    Dose[f]
                                    MOE[g]
                                    MOE[h]
                                       
                                       
                                   μg/lb ai
                                       
                                       
                                   mg/kg/day
                                       
                                   mg/kg/day
                                       
                                       
                           Mixer/Loader at Baseline
            Mixing/Loading Dry Flowables for Groundboom Application
                                 Caneberries,
                                  Artichokes
                                      227
                                     8.96
                                     0.094
                                    lb ai/A
                                      80
                                     acres
                                    0.0159
                                      630
                                   0.000840
                                    12,000
                                      600
                                       
           Mixing/Loading Dry Flowables for Chemigation Application
                                       
                                 Caneberries,
                                  Artichokes
                                       
                                       
                                       
                                      350
                                     acres
                                    0.0698
                                      140
                                    0.00368
                                     2,700
                                      130
                            Applicator at Baseline
                        Applying Sprays via Groundboom
                                       
                                 Caneberries,
                                  Artichokes
                                       
                                     78.6
                                       
                                     0.34
                                       
                                     0.094
                                    lb ai/A
                                      80
                                     acres
                                       
                                    0.00553
                                       
                                     1,800
                                       
                                   0.0000319
                                       
                                    310,000
                                       
                                     1,800
                                       
                      Mixer/Loader/Applicator at Baseline
  M/L/A for Ground-Directed Application via Mechanically-Pressurized Handgun
                                 Caneberries,
                                  Artichokes
                                     1300
                                      3.9
                                    0.0094
                                   lb ai/gal
                                     1000
                                    gallons
                                     0.114
                                      88
                                   0.000458
                                    22,000
                                      88
     Mixer/Loader/Applicator with Recommended PPE (Single Layer + Gloves)
  M/L/A for Ground-Directed Application via Mechanically-Pressurized Handgun
                                 Caneberries,
                                  Artichokes
                                      390
                                      3.9
                                    0.0094
                                   lb ai/gal
                                     1000
                                    gallons
                                    0.0343
                                      290
                                   0.000458
                                    22,000
                                      290
a	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2012). Level of mitigation: baseline.
b	Based on registered or proposed label (Reg. No. 81880-2).
c	Exposure Science Advisory Council Policy #9.1.
d	Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) x DAF (75%) / BW (80 kg).
e	Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day). IT Dermal NOAEL = 10 mg/kg/day. LOC = 100.
f	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day) / BW (80 kg).
g	Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day). IT Inhalation NOAEL = 10 mg/kg/day. LOC = 100.
h	Total MOE = NOAEL (mg/kg/day) / Dermal Dose + Inhalation Dose.

9.2	Short- and Intermediate-Term Post-Application Risk

9.2.1	Dermal Postapplication Risk

Dermal post-application exposure is not expected from caneberries or artichokes treated with halosulfuron-methyl because the label indicates that contact with the planted crop should be avoided.

The REI specified on the proposed label is based on the acute toxicity of halosulfuron-methyl.  Halosulfuron-methyl is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential.  It is not a skin sensitizer.  Short- and intermediate-term post-application risk estimates were not of concern on day 0 (12 hours following application) for all post-application activities.  Under 40 CFR 156.208 (c) (2) (iii), ai's classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to halosulfuron-methyl.      

9.2.2	Inhalation Postapplication Risk

Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for halosulfuron-methyl at this time because the chemical has low vapor pressure (<1 x 10[-7] mmHg at 25ºC) and is applied at a low rate (0.0625 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) and is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force.  The Agency may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for halosulfuron-methyl.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from mixing/loading pesticides is likely to result in higher exposure than post-application exposure.  Thus, handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

10.0	References

Barrett, M., 03/26/2013, DP404096, Halosulfuron methyl Drinking Water Assessment for Additional Food/Feed Uses on Artichokes and Caneberry Subgroup 13-07A.

Cheng, L., 11/26/2012, DP405659,  Halosulfuron-methyl.  Section 3 Registration on Artichoke and Caneberry Subgroup 13-07A.  Summary of Analytical Chemistry and Residue Data.

Meléndez, J., 05/15/2012, DP394244, Halosulfuron methyl Drinking Water Assessment for Additional Food/Feed Uses on Proso Millet, Pasture and Rangeland Grass Forage, Fodder and Hay (Crop Group 17).

Negussie, M., 03/11/2013, DP405660,  Halosulfuron-methyl. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Artichoke and Caneberry Subgroup 13-07A.

Smegal, D., 02/22/2012, TXR 0054045,  Halosulfuron-methyl:  Su mmary of hazard and Science Policy Council (HASPOC) Meeting of February 9, 2012:  Recommendations on waiver requests for 28-day inhlataion study..

Tsaur, N., 02/21/2013, DP404839,  Halosulfuron-Methyl.  Occupational and Residential Exposure Assessment for Proposed IR-4 Uses on Caneberry (subgroup 13-07A)and Artichokes.  

Tsaur, N., 06/12/2012, DP396460,  Halosulfuron-Methyl.  Occupational Exposure Assessment for Proposed New Uses on Proso Millet and Crop Group 17 (Grass, Forage, Fodder, and Hay) with An Updated Residential Exposure Assessment of All Existing Residential Uses.

Walls, C., 07/19/2012, DP396458,  Halosulfuron-Methyl:  Human Health Risk Assessment for Proposed New Uses on Proso Millet and Crop Group 17 (Grass, Forage, Fodder, and Hay).
.


Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.500) for  Food Use for Halosulfuron-methyl are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Acute Eye Irritation	
870.2500    Acute Dermal Irritation	
870.2600    Skin Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      Yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    90-Day Oral Toxicity in Rodents	
870.3150    90-Day Oral Toxicity in Nonrodents	
870.3200    21/28-Day Dermal Toxicity	
870.3250    90-Day Dermal Toxicity	
870.3465    90-Day Inhalation Toxicity	
                                      yes
                                      yes
                                      yes
                                      no
                                      CR
                                      Yes
                                      yes
                                      yes
                                       -
                                     -[a]
870.3700a  Prenatal Developmental Toxicity (rodent)	
870.3700b  Prenatal Developmental Toxicity (nonrodent)	
870.3800    Reproduction and Fertility Effects	
                                     yes 
                                     yes 
                                      yes
                                      Yes
                                      yes
                                      yes
870.4100b  Chronic Toxicity (nonrodent)	
870.4200b  Carcinogenicity (mouse)	
870.4300    Combined Chronic Toxicity/Carcinogenicity	
                                      no
                                      yes
                                      yes
                                      Yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Bacterial Reverse Mutation Test	
870.5300    Mutagenicity -- Mammalian Cell Gene Mutation Test	
870.5375    Mutagenicity -- Structural Chromosomal Aberrations	
870.5395    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      Yes
                                      yes
                                      yes
                                      yes
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Developmental Neurotoxicity	
                                      yes
                                      yes
                                      no
                                      Yes
                                      yes
                                       -
870.7485    Metabolism and Pharmacokinetics	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      no
                                      no
                                      Yes
                                       -
                                      no
a Inhalation requirement is waived for the current and proposed uses (D. Smegal, TXR 0054045, 02/22/12)
A.2	Toxicity Profiles

Table A.2.1.  Acute Toxicity of Halosulfuron-Methyl Technical.

                                   OPPTS No.

                                  Study Type

                                     MRID

                                    Results

                               Toxicity Category
                                   870.1100
Acute Oral- Rats
                                   42139413
LD50:  Males = 10,435  mg/kg
           Females = 7758 mg/kg
           Combined = 8866 mg/kg
                                      IV
                                   870.1200
Acute Dermal- Rats
                                   42139415
LD50 >2000  mg/kg (limit test)
                                      III
                                   870.1300
Acute Inhalation- Rats
                                   42139417
LC50 >6 mg/L
                                      IV
                                   870.2400
Primary Eye Irritation- Rabbits
                                   42139419
Mild transient (<24 hr) irritation involving the conjunctiva and iris.
                                      IV
                                   870.2500
Primary Skin Irritation- Rabbits
                                   42139421
Non-irritant
                                      IV
                                   870.2600
Dermal Sensitization- Guinea pigs
                                   42139423
Not a skin sensitizer (maximization test)
                                      N/A


Table A.2.2. Toxicity Profile of Halosulfuron-Methyl Technical.


                                 Guideline  No.

                                  Study Type 

                     MRID No. (Date)/Classification/ Doses

                                    Results

870.3100 (82-1)

Subchronic oral toxicity study in rats 

43616301 (1995)/ Acceptable/Guideline 
Doses: 0, 100, 1000, 10000, or 20000 ppm (diet) (M/F: 6.7/7.6, 66.5/75.8, 682.8/772.8, 1400/1578 mg/kg/day)

NOAEL = M > 1400, F = 75.8 mg/kg/day
LOAEL = M not determined, F = 772.8 mg/kg/day based on decreased body weight gains.

870.3100 (82-1)
 

Subchronic oral toxicity study in rats (28 day range-finder)



42171501 (1988)/ Acceptable/Nonguideline  
Doses: 0, 100, 400, 1600, or 6400 ppm (diet)
(M/F: 7.4/8.9, 28.8/37.3, 116/147, 497/640 mg/kg/day)

NOAEL = M = 116, F =147 mg/kg/day
LOAEL = M = 497, F = 640 mg/kg/day based on decreased body weight gains, decreased organ weights and changes in clinical chemistry parameters.


870.3150 (82-1)

Subchronic oral toxicity study in nonrodents - dogs 

42171502 (1991)/ Acceptable/Nonguideline
 Doses: 0, 2.5, 10, 40, and 160 mg/kg/day (capsule) 

NOAEL = 10 mg/kg/day
LOAEL = 40 mg/kg/day based on decreased body weight gains and food efficiency along with hematology and clinical chemistry changes.


870.3200 (82-2)

21-day dermal toxicity  in rats



42661417 (1990)/ Acceptable/Guideline
Doses: 0, 10, 100, or 1000 mg/kg/day

NOAEL = 100 mg/kg/day
LOAEL = 1000 mg/kg/day based on a dose-related decrease in total body weight gain in males.  Total body weight gain was also decreased in the 100 mg/kg/day group females, but the 1000 mg/kg/day group females were comparable to the control group.
870.3465 (82-4)
90-day inhalation study in rats
This data requirement has been waived (TXR D. Smegal, TXR 0054045, 02/22/12)

870.4100 (83-1b) 

Chronic oral toxicity study in dogs


42396211 (1991)/ Acceptable/Guideline
Doses: 0, 0.25, 1.0, 10.0, or 40 mg/kg/day (capsule).

NOAEL = 10 mg/kg/day
LOAEL = 40 mg/kg/day based on decreased body weight gains in males and females, decreased relative food efficiency in females along with hematological and clinical chemistry changes. 	

870.4300 (83-5)

Combined Chronic/ Carcinogenicity in rats



42661418 (1992)/ 
Acceptable/Guideline
Doses: 0, 10, 100, 1000, or 2500, 5000 (males only) ppm (diet)
(M/F: 0.44/0.56, 4.4/5.6, 43.8/56.3, 108.3/138.6, 225.6 (M) mg/kg/day)

NOAEL = M=108.3, F=56.3 mg/kg/day
LOAEL = M=225.6, F=138.6 mg/kg/day based on marginal decrease in body weight gain in both males and females.

No evidence of carcinogenicity.

870.4200 (83-2) 

Carcinogenicity study in mice  



42661419 (1992)/ Acceptable/Guideline
Doses: 0, 30, 300, 3000, or 7000 ppm (diet)
(M/F: 4.0/5.2, 41.1/51.0, 410.0/509.1, or 971.9/1214.6 mg/kg/day)

NOAEL = M=410.0, F > 1214.6 mg/kg/day
LOAEL = M=971.9, F>1214.6 mg/kg/day based on decreased body weight gains and necropsy findings (increase incidence of microconcretion/mineralization in the testis and epididymis). 

No evidence of carcinogenicity.

870.3700 (83-3) 



Developmental toxicity in rats



42139425 (1990)/ Acceptable/Guideline
Doses: 0, 75, 250, or 750 mg/kg/day (gavage)

Maternal NOAEL = 250 mg/kg/day.
Maternal LOAEL = 750 mg/kg/day, based on increased incidence of clinical observations, reduced body weight gains, reduced food consumption and food efficiency.
Developmental NOAEL = 250 mg/kg/day.  
Developmental LOAEL = 750 mg/kg/day, based on decreased mean fetal body weight and mean litter size, increased fetal and litter incidences of soft tissue and skeletal variations.

870.3700 (83-3b)

Developmental toxicity study in rabbits


42139426 (1990)/ Acceptable/Guideline
Doses: 0, 15, 50, or 150 mg/kg/day (gavage)

Maternal NOAEL = 50 mg/kg/day
Maternal LOAEL = 150 mg/kg/day based on reduced body weight gain, food consumption and food efficiency.
Developmental NOAEL = 50 mg/kg/day
Developmental LOAEL = 150 mg/kg/day based on group decreased mean litter size, increased number of resorptions and resorptions per dam, and increased postimplantation loss.

870.3700 (83-3b)

Developmental toxicity study in rabbits



43621901 (1995) 3-chlorosulfonamide acid
Metabolite/
Acceptable/Guideline
Doses: 0, 30, 300, or 1000 mg/kg/day  

Maternal Toxicity NOAEL => 1000 mg/kg/day
Maternal Toxicity LOAEL > 1000 mg/kg/day
Developmental Toxicity NOAEL => 1000 mg/kg/day
Developmental Toxicity LOAEL > 1000 mg/kg/day

870.3800 (83-4)

Two-Generation reproduction study in rats



42139427 (1991)/ Acceptable/Guideline
Doses: 0, 100, 800, or 3600 ppm (diet)
( F0 Males: 6.3, 50.4, and 223.2 mg/kg/day; F0 Females: 7.4, 58.7, and 261.4 mg/kg/day)

Parental/Systemic NOAEL = M=50.5, F=58.7 mg/kg/day 
Parental/Systemic LOAEL = M=223.2, F=261.4 mg/kg/day based on decreased body weights, body weight gains, and reduced food consumption during the premating period in both sexes.
Offspring NOAEL = 51/59 mg/kg/day
Offspring LOAEL = 223.2/261.4 mg/kg/day based on decreased body weight in the F1 pups and marginal decreased body weight in F2 pups.
Reproductive NOAEL > = 223.2/261.4 mg/kg/day.


870.6200a (82-7)

Acute neurotoxicity in rats.

45754701 (1994) and 46199501 (1989)[positive control study]/  Acceptable/Guideline
Doses: 0, 200, 600, or 2000 mg/kg (limit dose)
NOAEL = 600 mg/kg.  
LOAEL = 2000 mg/kg (limit dose) based on mortality in males. 

870.6200b (82-7)

Subchronic neurotoxicity study in rats.

45754702 (1992)/ Acceptable/Guideline
Doses: M: 0, 100, 1000, or 10,000 ppm; F:  0, 100, 1000, or 4000  ppm (diet) (M/F: 0/0, 6.3/8.1, 62.8/82.6, or 706.0/315.9 mg/kg/day)

NOAEL = M = F = 1000 ppm (M/F: 62.8/82.6 mg/kg/day). 
LOAEL = M = 10,000 ppm; F =4000 ppm (M: 706.0 mg/kg/day) in males based on decreased body weight and body weight gain and (F: 315.9 mg/kg/day) in females based on decreased body weight gain. 

870.7485 (83-6)

Metabolism

42139433 (1990)/ Acceptable/Guideline
5 or 250 mg/kg single dose or 5 mg/kg/day repeated doses

Absorption was rapid, incomplete and similar in both sexes.  Elimination was mostly by urine and feces within 72 hours, appearing to be independent of dose and sex.  Desmethyl NC-319 and the 5-hydroxy derivative were the major urinary and fecal metabolites.

870.7800(83-6)
Immunotoxicity
A waiver request for this data requirement has been submitted and is under review.

870.5100  
(84-2 a) 

Mutagenic - Ames
Salmonella typhimurium and E. Coli.

42139428 (1991)/ Acceptable 
(+/-S9) 5 strains S. typh. Conc.: 1 - 10000 microgm/plate; E. Coli WpuvrA Conc.: 333 - 10000 microgram/plate

Negative. Concentrations => 5000 microgm/plate found to be insoluble and/or cytotoxic.

870.5100  
(84-2 a) 

Mutagenic - Gene Mutation

43616302 (1995)/ Acceptable 
(+/-S9) 5 strains S. typh. Conc.: 50 - 5000 microgm/plate

Negative. Conducted with 3-chlorosulfonamide acid-the principal soil metabolite of halosulfuron-methyl.

870.5300  (84-2)

Mutagenic - Gene Mutation - Hamster (Chinese)

43616303 (1995) - Metabolite/ Acceptable 
(+/-S9) Conc.: 350-3100 microgm/mL 

Negative. Conducted with 3-chlorosulfonamide acid-the principal soil metabolite of halosulfuron-methyl.

870.5300  (84-2)

Mutagenic - (HGPRT) - Hamster (Chinese).

42139431 (1991) - Metabolite/ Unacceptable 
Conc.: 100-1000 microgm/mL 

Conclusions indefinite due to partly to relatively high negative and low positive control values, solubility problems with test article.

870.5300  (84-2)

Mutagenic - (HGPRT) - Hamster (Chinese).

42661420 (1993)/ Acceptable 
(+/-S9) Conc.: 50-900 microgm/mL

Negative.  Did not induce forward mutations at the HGPRT locus in Chinese Hamster ovary cells. Concentrations above 700 ug/mL were insoluble.

870.5375 (84-2)

Mutagenic - In vitro Clastogenic - Hamster (Chinese) 

42139429 (1989)/ Acceptable 
(+/-S9) Conc.: 449-1810 microgm/mL

Negative.  No chromosomal aberrations.

870.5395  (84-2)

Mutagenic - Micronucleus Assay - Mouse (CD-1)

43616304 (1995) - Metabolite/Acceptable
 Doses: 1250, 2500 or 5000 mg/kg

Negative.  Conducted with 3-chlorosulfonamide acid-the principal soil metabolite of halosulfuron-methyl.  No overt toxicity for the treated animals or cytotoxicity for the target organ (bone marrow cells) was observed.

870.5395  (84-2)

Mutagenic - Micronucleus Assay - Mouse

42139430 (1989)/ Acceptable 
Doses: 500, 1667 0r 5000 mg/kg.

Negative. Did not induce significant elevations in the frequencies of micronucleated polychromatic erythrocytes.

870.5500 
(84-2)

Mutagenic - Unscheduled DNA synthesis - Rat

42139432 (1990)/ Acceptable
(+/-S9) Conc.: 25-1000 microgm/mL

Negative. Fail to induce unscheduled DNA synthesis in primary rat hepatocytes.  



Appendix B.  Physical/Chemical Properties

Table C1.  Physicochemical Properties of Halosulfuron-methyl.
Parameter
Value
Reference
Melting point/range
175.5-177.2 ºC
MRID 42139403; DP#s 173627 & 180565, 7/30/92, G.J. Herndon
pH
4.11 at 25 ºC (1% w/v slurry)

Density
1.618 g/mL at 25 ºC

Water solubility at 20 ºC
pH 5	0.0015 g/100 mL
pH 7	0.165 g/100 mL
pH 9	0.747 g/100 mL

Solvent solubility at 20 ºC
methanol	0.1616 g/100 mL
n-hexane	0.001278 g/100 mL

Vapor pressure
<1 x 10[-7] mm Hg at 25 ºC

Dissociation constant, Ka
3.61 x 10[-4] at 22.4 ºC

Octanol/water partition coefficient, Log(KOW) at 23 ºC
1.67 at pH 5
-0.0186 at pH 7
-0.542 at pH 9

UV/visible absorption spectrum
Not available

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 to determine their dermal and inhalation exposure.  Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF).  EPA has reviewed all the studies supporting these multi-pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted.  All applicable requirements of EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

Appendix D.  International Residue Limits

               Halosulfuron-methyl (PC Code 128721); 10/31/2012
Table A.1 Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada
Mexico[2]
Codex
40 CFR 180.479 (a) (2):
Tolerances are established for residues of the herbicide halosulfuron-methyl, methyl 3-chloro-5-[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-1-methyl-1H-pyrazole-4-carboxylate, including its metabolites and degradates, in the table below. Compliance with the tolerance levels specified in the following table is to be determined by measuring only halosulfuron-methyl.
None

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

                                      US
Canada
Mexico[2]
Codex
Artichoke 
                                     0.05
                                       
                                       
                                       
Caneberry subgroup 13-07A
                                     0.05
                                       
                                       
                                       

                                       
                                       
                                       
                                       

                                       
                                       
                                       
                                       

                                       
                                       
                                       
                                       

                                       
                                       
                                       
                                       

                                       
                                       
                                       
                                       

                                       
                                       
                                       
                                       
Completed:  M. Negussie; 11/21/2012
[1] Includes only commodities of interest for this action.  Tolerance values should be the HED 
recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

