Glyphosate Human-Health Risk Assessment D372052

Page 1 of 27 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: 31-August-2010

Subject: Glyphosate. Section 3 Registration for Application of the Potassium Salt of Glyphosate to Glyphosate-Tolerant Sweet Corn. Human-Health Risk

Assessment.

P C Codes: 103613 (glyphosate potassium salt) and 417300 DP Barcode: D372052

Decision No.: 423791 Registration Nos.: 524-537; 524-549

Petition No.: 9F7644 Regulatory Action: Section 3 Risk Assessment Type: aggregate Case No.: 178

TXR No.: not applicable CAS No.: 70901-20-1

MRID No.: none 40 CFR: 180.364

From: Tom Bloem, Chemist Anwar Y. Dunbar, Ph.D., Pharmacologist Risk Assessment Branch I/Health Effects Division (RABI/HED; 7509P)

Through: Dana M. Vogel, Branch Chief George F. Kramer, Ph.D., Senior Chemist RABI/HED (7509P)

To: James Tompkins/Eric Kraft RM 25 Registration Division (RD; 7505P)

The Office of Pesticide Programs (OPP) HED assesses the risks posed to humans from exposure to pesticide chemicals. The RD of OPP asked HED to evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from all registered/proposed uses for glyphosate ( N -(phosphonomethyl) glycine). A summary of the findings and an assessment of human risk are provided in this document. The hazard assessment was provided by Anwar Dunbar (RABI); the residue chemistry review, dietary exposure analysis, and risk assessment were provided by Tom Bloem (RABI); and the drinking water assessment was provided by James Hetrick of the Environmental Fate and Effects Division (EFED).Glyphosate Human-Health Risk Assessment D372052

Page 2 of 27 Table of Contents

1.0 EXECUTIVE SUMMARY 3

2.0 INGREDIENT PROFILE 9

2.1 S UMMARY OF R EGISTERED /P ROPOSED U SES 9

2.2 S TRUCTURE AND N OMENCLATURE 10

3.0 HAZARD CHARACTERIZATION 11

3.1 H AZARD P ROFILE 11

3.2 FQPA C ONSIDERATIONS 13

3.3 E NDOCRINE D ISRUPTION 13

3.4 D OSE -R ESPONSE A SSESSMENT 14

3.5 R ECOMMENDATION FOR A GGREGATE E XPOSURE R ISK A SSESSMENTS 15

4.0. DIETARY EXPOSURE/RISK CHARACTERIZATION 16

4.1 M ETABOLISM IN P RIMARY C ROPS

, L IVESTOCK

, AND R OTATIONAL C ROPS 16

4.2 A NALYTICAL M ETHODOLOGY 17

4.3 D RINKING W ATER R ESIDUE P ROFILE 18

4.4 F OOD R ESIDUE P ROFILE 18

4.5 I NTERNATIONAL R ESIDUE L IMITS AND HED-R ECOMMENDED T OLERANCES 19

4.6 D IETARY E XPOSURE AND R ISK 20

5.0 RESIDENTIAL (NON-OCCUPATIONAL) RISK 21

6.0 AGGREGATE RISK ASSESSMENT 23

7.0 CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT 24

8.0 OCCUPATIONAL EXPOSURE/RISK PATHWAY 24

9.0 DATA NEEDS AND LABEL REQUIREMENTS 24

9.1 T OXICOLOGY 24

9.2 R ESIDUE C HEMISTRY 24

9.3 O CCUPATIONAL AND R ESIDENTIAL E XPOSURE 24

ATTACHMENT 1: CHEMICAL NAMES AND STRUCTURES. 25

ATTACHMENT 2: TOXICITY PROFILE. 26Glyphosate Human-Health Risk Assessment D372052

Page 3 of 27 1.0 Executive Summary

Background: Glyphosate ( N -(phosphonomethyl) glycine) is a nonselective Group 9 herbicide that is currently registered for pre- and post-emergence application to a variety of fruit, vegetable, and field crops. Tolerances are currently established for residues of glyphosate in/on various plant commodities (including field corn) at 0.2-400 ppm (40 CFR §180.364(a)) and for the combined residues of glyphosate and N -acetyl-glyphosate (expressed as glyphosate) in/on field corn, soybean, aspirated grain fractions (AGF), and livestock commodities at 0.1-310 ppm. The Glyphosate Reregistration Eligibility Decision (RED) document was issued September 1993.

Monsanto proposed application of Roundup WeatherMAX® (EPA Reg. No. 524-537) or Roundup Power MAX® (Reg. No. 524-549) to Roundup Ready ® sweet corn. Monsanto also proposed the following tolerances for residues of glyphosate: corn, sweet, kernel plus cob with husk removed - 3.0 ppm and corn, sweet, forage - 9.0 ppm. HED notes that the following sweet corn tolerances for residues of glyphosate are currently established: corn, sweet, grain - 0.1 ppm and grain, cereal, forage, fodder, and straw, gr oup 16, except field corn, forage and field corn, stover - 100 ppm.

The petitioner indicated that the Roundup Ready ® sweet corn was developed through conventional breeding techniques with Monsanto's Roundup Ready ® field corn (Roundup Ready 2 Technology). The petitioner indicated that the following two Roundup Ready ® sweet corn seeds will be developed: (1) MON 89034 × MON 88017 - sweet corn genetically modified to

express c ry3Bb1 gene from Bacillus thuringiensis (controls corn root worm and other Coleopteran species), 5-enolpyruvylshikim ate-3-phosphate synthase (EPSPS) from Agrobacterium sp. strain CP4 (CP4 EPSPS; provides tolerance to glyphosate), and transgenes cry1A.105 and cry2Ab2 derived from Bacillus thuringiensis (controls European corn borer and other Lepidopteran species) and (2) MON 89034 × NK603 - sweet corn genetically modified to express EPSPS from Agrobacterium sp. strain CP4 (CP4 EPSPS; provides tolerance to glyphosate) and transgenes cry1A.105 and cry2Ab2 derived from Bacillus thuringiensis (controls European corn borer and other Lepidopteran species).

Hazard Characterization: Glyphosate is of low acute toxicity following oral, dermal, and inhalation exposure, since all studies are in Toxicity Category III or IV. It is a mild eye irritant (Toxicity Category III), slight skin irritant (Toxicity Category IV), and is not a dermal sensitizer in guinea pigs. Inhalation risk assessments (any time period) are not required based on the low toxicity of the formulation products (Toxicity Category III or IV) and the physical characteristics of the technical product (wet cake). An acute dose and endpoint have not been selected for any population subgroups because no effects that could be attributed to a single exposure (dose) were observed in oral toxicity studies including the deve lopmental toxicity studies in rats and rabbits. Therefore, a dose and endpoint were not identified for acute dietary risk assessment.

A chronic feeding/carcinogenicity study in rats found no systemic effects in any of the parameters examined (body weight, food consumption, clinical signs, mortality, clinical pathology, organ weights, and histopathology). In a second chronic feeding/carcinogenicity study in rats tested at higher dietary levels, a lowest-observed-adverse-effect level (LOAEL) was identified at 20,000 parts per million (ppm; approximately 940 mg/kg/day) based on decreased body-weight gains in females and increased incidence of cataracts and lens abnormalities,Glyphosate Human-Health Risk Assessment D372052

Page 4 of 27 decreased urinary pH, increased absolute liver weight, and increased relative liver weight/brain weight in males. No evidence of carcinogenicity was found in rats. There was also no evidence of carcinogenicity in mice. In a chronic toxicity study in dogs, no systemic effects were found in all examined parameters.

On 26-Jun-1991, the HED Carcinogenicity Peer Review Committee (CPRC) evaluated the weight of the evidence on glyphosate with particular emphasis on its carcinogenic potential. The Committee concluded that glyphosate should be classi fied as a “Group E” chemical (evidence of non-carcinogenicity for humans), based upon lack of convincing carcinogenicity evidence in adequate studies in two animal species (mice and rats).

Acceptable developmental toxicity studies in the rat and rabbit are available, as is an acceptable 2-generation reproduction study in the rat. No significant reproductive and developmental toxic effects were found. On the basis of developmental studies in rats and rabbits and reproductive findings in rats, glyphosate exhibited no evidence of increased susceptibility of offspring. Neurotoxicity has not been observed in any of th e acute, subchronic, chronic, developmental, or reproductive studies performed with glyphosate.

In the rat metabolism study, absorption was estimated to be 30-36% in males and females following a single 10 mg/kg oral dose. Glyphosate was excreted unchanged in the feces and urine (97.5% minimum). The only metabolite present in the excreta was small amounts of aminomethyl phosphonic acid (AMPA). Less than 1% of the absorbed dose remained in the carcass, primarily the bone. Repeated dosing did not significantly alter metabolism, distribution,

and excretion.

Food Quality Protection Act (FQPA) Safety Factor (SF): The RABI risk assessment team recommends that the FQPA SF be reduced to 1X, which is consistent with the previous FQPA Safety Factor Committee decision (6-Apr-1998). This recommendation is based on the following considerations (see Table 3.4.1 for a summary of the toxicological doses and endpoints for glyphosate for use in human-health risk assessment):

● There are no residual uncertainties for pre- or postnatal toxicity.

● There is no evidence of neurotoxicity in any of the toxicology studies conducted. Although an acute and subchronic neurotoxicity studies are now required as a part of new data requirements in the 40CFR §158 for conventional pesticide registration, the Agency does not believe that conducting these studies will result in a lower point of departure (POD) than that currently used for overall risk assessment, and therefore, a database uncertainty factor (UF DB ) is not needed to

account for lack of these studies.

● There is no quantitative or qualitative evidence of increased susceptibility of rats or rabbit

fetuses to in utero exposure in developmental studies. A focal tubular dilation of the kidneys was observed in a three-generation reproductive st udy on rats at the 30-mg/kg/day level [highest dose tested (HDT)], however a two-generational reproductive study on rats did not observe the same effect at the 1500-mg/kg/day level (HDT ), nor were any adverse reproductive effects observed at any dose level. A clear no-observed adverse-effect level (NOAEL) was established and the chronic reference dose (cRfD) was set at a level well below this effect.

● The toxicology database for glyphosate does not show any evidence of treatment-related effects on the immune system. The overall weight of evidence suggests that this chemical does not directly target the immune system. An immunotoxicity study is required as a part of the new dataGlyphosate Human-Health Risk Assessment D372052

Page 5 of 27 requirements in the 40 CFR Part 158 for conventional pesticide registration; however, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower POD than that currently use for overall risk assessment, and therefore, a UF DB is not needed to account for lack of this study.

● The dietary exposure analysis is conservative as it assumed tolerance level residues and 100% crop treated.

Residential and Non-Occupational Exposure and Risk Assessment: The proposed use to sweet corn is not anticipated to result in residential exposure. However, residential exposure are anticipated from the registered broadcast and spot treatment to home lawns, gardens and recreational areas including parks and golf courses (homeowner application is permitted). Additional registered uses include lawn renovation and applications to lakes and ponds, including reservoirs.

Handlers/Applicators: Based on the registered residential use patterns, there is a potential for shortterm dermal and inhalation exposures to homeowners who mix and apply products containing glyphosate. However, since short- and intermedia te-term dermal or inhalation endpoints were not selected, no residential handler/applicator assessment is needed.

Post-Application: Post-application dermal and inhalation assessments are not needed since shortand intermediate-term dermal or inhalation endpoi nts were not selected. However, based on the registered use patterns, toddlers may have short- term post-application incidental oral exposures from hand-to-mouth, object to mouth, and soil ingestion behavior on treated lawns and swimmers may have short-term post-application incidental oral exposures from treated surface water.

The incidental oral ingestion exposure for toddler s resulting from turf treatment was previously assessed using the Standard Operating Procedures (SOPs) for Residential Exposure Assessments, Draft, 17-Dec-1997 and Exposure Science Advisory Committee (ExpoSAC) Policy No. 11, 22-Feb-2001: Recommended Revisions to the SOPs for Residential Exposure (1.62 lb ae/acre). Also assessed were short-term post-application incidental oral exposures for adult, children, and toddler swimmers (assumed 3.75 lb ae/acre and a depth of 1 foot). The exposure assumptions used in the swimmer assessment are based on HED’s SOPs for Residential Exposure Assessments, Draft, 17-Dec-1997 and subsequent updates for swimming pools adapted

for this assessment.

HED combines risk values resulting from separate residential exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. Since the residential uses of glyphosate on turf and in ponds and lake are not likely to co-occur, these uses were not combined. For glyphosate, all non-dietary sources of post-application exposure to turf were combined to obtain a screening level estimate of potential exposure which could be used for the aggregate assessment.

All of the margins of exposure (MOEs) are greater than 100 ( ≥ 5,800) and, therefore, do not exceed HED's level of concern (LOC). It should be noted that there is a lawn renovation use of glyphosate that may be applied at a much higher application rate than the assessed turf rate (1.62 lb ae/acre). However, since non-dietary exposure is not expected to result from the lawn renovation use, an assessment is not needed. Dietary (food and water) Risk Assessment: A chronic dietary risk assessment was conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-Glyphosate Human-Health Risk Assessment D372052

Page 6 of 27 FCID TM , ver. 2.03) which incorporates consumption data from United States Department of Agriculture (USDA) Continuing Survey of Food Intake by Individuals (CSFII; 1994-1996 and 1998). The chronic analysis assumed tolerance-level residues, 100% crop treated, and DEEM (ver 7.81) default processing factors for all commod ities and incorporated glyphosate drinking water monitoring data. The resulting chronic risk estimates (food and water) were ≤ 12% chronic population adjusted dose (cPAD) and, therefore, do not exceed HED's LOC (children (1-2 years old) were the most highly exposed population).

Aggregate Risk Assessment: In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Based on the registered/proposed agricultural and residential uses, HED conducted short-term (food, water, residential incidental oral) and chronic (food and water) aggregate risk

assessments.

Short-Term Aggregate Risk Assessment: Based on the proposed/registered uses, HED anticipates short-term incidental oral exposure to young child ren (swimmer and turf nondietary ingestion) and adults (swimmer). The short-term aggregate assessment combines dietary exposure with the single highest potential residential exposure.

For young children, short-term aggregate exposure includes chronic dietary (food and water) and incidental oral ingestion exposure resulting from the turf use (highest exposure of all possible scenarios). For adults, short-term aggregate exposure includes chronic dietary exposure (food and water) and incidental oral ingestion exposure resulting from the aquatic use (highest exposure of all possible scenarios). Since the aggregate MOEs are ≥ 720, short-term aggregate exposure to glyphosate does not exceed HED's LOC. HED notes that since the short- /intermediate-term incidental oral endpoints are identical, the short-term risk assessments are protective of intermediate-term exposure.

Chronic Aggregate Risk Assessment: Because HED does not anticipate significant chronic residential exposure as a result of the proposed/registered glyphosate uses, aggregate chronic risk assessment takes into consideration dietary (food and water) exposure only. The chronic aggregate exposure and risk estimates do not exceed HED's LOC ( ≤ 12% cPAD).

Occupational Risk Assessment: Based on the glyphosate toxicological database, HED concluded that short-/intermediate/long-term dermal and inhalation risk assessments are unnecessary. Therefore, occupational handler/applicator and post-application assessments are not required.Glyphosate Human-Health Risk Assessment D372052

Page 7 of 27 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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess di etary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant (see below). Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for t oddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Human Studies: The occupational exposure/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 the Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF) Database and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies in these multi-pesticide generic exposure databases, and on the basis of available evidence has found them to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been

satisfied.Glyphosate Human-Health Risk Assessment D372052

Page 8 of 27 HED Recommendation: Provided the petitioner submits a revised Section F (see below), HED concludes that the toxicological, residue chemistry, and occupational/residential exposure databases support a conditional registration for application of glyphosate to Roundup Ready ®
sweet corn. An unconditional registration may be established upon submission of data which adequately addresses the toxicological deficiencies specified below.

Summary of Deficiencies:

• Acute and subchronic neurotoxicity studies.

• Immunotoxicity study.

• Based on an acute toxicity review for the formulated products (D295196, B. Backus, 2-Feb2004), there is some question as to whether the proposed 4-hour REI is appropriate. RD should ensure that 4-hour REI is acceptable.

● Section F: HED request a revised Section F dele ting the proposed sweet corn forage tolerance, specifying a tolerance of 3.5 ppm for residues of glyphosate in/on corn, sweet, kernel plus cob with the husk removed, and specifying a tolerance of 0.10 ppm for residues of glyphosate and N

acetyl-glyphosate in/on poultry, meat. HED notes that the currently established sweet corn grain

tolerance should be deleted.

In accordance with the most recent guidance concerning tolerance expressions, HED also recommends that the tolerance expression for 180.364(a)(1) and 180.364(a)(2) be changed as

indicated below.

180.364(a)(1): Tolerances are established for residues of glyphosate, including its metabolites and degradates, in or on the commodities listed below resulting from the application of glyphosate, the isopropylamine salt of glyphosate, the ethanolamine salt of glyphosate, the dimethylamine salt of glyphosate, the ammonium salt of glyphosate, and the potassium salt of glyphosate. Compliance with the following tolerance levels is to be determined by measuring only glyphosate ( N

-(phosphonomethyl) glycine)

180.364(a)(2): Tolerances are established for residues of glyphosate, including its metabolites and degradates, in or on the commodities listed below resulting from the application of glyphosate, the isopropylamine salt of glyphosate, the ethanolamine salt of glyphosate, the dimethylamine salt of glyphosate, the ammonium salt of glyphosate, and the potassium salt of glyphosate. Compliance with the following tolerance levels is to be determined by measuring only glyphosate ( N

-(phosphonomethyl) glycine) and its metabolite N -acetyl-glyphosate ( N -acetyl- N -(phosphonomethyl)glycine; expressed as glyphosate)Glyphosate Human-Health Risk Assessment D372052

Page 9 of 27 2.0 Ingredient Profile

Glyphosate is a non-selective herbicide which acts via blocking the activity of the EPSPS enzyme. EPSPS is produced only by green plants and is involved in the synthesis of the amino

acids tyrosine

, tryptophan , and phenylalanine

.

2.1 Summary of Registered/Proposed Uses

Registered: Glyphosate is registered for use on a variet y of fruit, vegetable, and field crops as well as for aquatic and terrestrial (including home lawns/gardens and recreational areas) uses. Glyphosate is also registered for use on transgenic crop varieties such as canola, field corn, cotton, soybeans, sugar beets, and wheat.

Proposed: Table 2.1.1 is a summary of the petitioner proposed Roundup Ready® sweet corn application scenarios for Roundup WeatherMAX® (EPA Reg. No. 524-537) and Roundup Power MAX® (Reg. No. 524-549); both of these products are soluble-concentrate (SC) formulations consisting of glyphosate as the pota ssium salt at 4.51 lb ae/gallon with restrictedentry intervals (REI) of 4 hours. The proposed labels are adequate.

Table 2.1.1: Summary of Proposed Roundup Ready® Sweet Corn Application Scenario.

Formulation (EPA Reg. No.) App. Timing App. Rate (lb ae/acre) Max. App. Rate (lb ae/acre) Use Directions and Limitations

preplant, at

planting,

preemergence not specified 3.72

post emergence

through 48

inches tall 1.55 4.62 Roundup WeatherMAX® (EPA Reg. No. 524-537; SC; 4.51 lb ae/gal)

Roundup Power MAX® (Reg. No. 524-549; SC; 4.51 lb ae/gal)

maximum

seasonal application rate -- 5.98 -Allow a minimum of 10 days between in-crop applications. -Ground (3-40 gallons per acre (GPA)) and (3-15 GPA) aerial application is permitted provided the plants are <30 inches tall; application to plan ts 30-48 inches tall should be made with only drop-nozzle ground equipment (3-40 GPA; drop-nozzle application is desirable for plants 24-30 inches tall). -Application is to be avoided if the plants reach the reproductive stage. -Application through irrigation systems is prohibited. -Allow a minimum of 30 days between application and harvest of forage or grain; interval from application to harvest of stover is not specified. -Application must be at least 30 days prior to planting any crop not listed on the labels.Glyphosate Human-Health Risk Assessment D372052

Page 10 of 27 2.2 Structure and Nomenclature

Tables 2.2.1 and 2.2.2 are summaries of glyphosate nomenclature and physical chemical properties, respectively.

Table 2.2.1: Glyphosate Nomenclature.

Compound P O

OH OH N H

OH O

Common name Gl yp hosate ( PC code 471300 )

Com p an y ex p erimental name DPX-B2856

IUPAC/CAS name N

- (p hos p honometh y l )g l y cine

CAS re g istr y numbe r 1071-83-6

Table 2.2.2: Physicochemical Prop erties of Technical Grade Glyphosate.

Melting point 189.5 ± 0.5 °C

pH 1.9 at 20 °C

Density 1.705 g/cm 3 at 20 °C

Water solubility 10.5 g/L at 20 °C The Pesticide Manual, 13 th Edition

Solvent solubility acetone 0.078 g/L methanol 0.231 g/L hexane 0.026 g/L ethyl acetate 0.012 g/L dichloromethane 0.233 g/L n-octanol 0.020 g/L propan-2-ol 0.020 g/L toluene 0.036 g/L European Commission: Glyphosate 6511/VI/99-final, 1/21/02

Vapor pressure 9.8 x 10 -8 mm Hg at 25 °C The Pesticide Manual, 13 th Edition

Dissociation constant, pK

a 0.8 (1 st phosphoric), 2.3 (carboxylate), 6.0 (2 nd phosphoric), and 11.0 (amine) Knuuttila. 1979 Acta Chem. Scand. B

33:623-626

Octanol/water partition coefficient, Log(K OW ) -3.2 (pH 2-5, 25 °C)

UV/visible absorption spectrum ε = 0.086 (295nm) European Commission: Glyphosate 6511/VI/99-final, 1/21/02Glyphosate Human-Health Risk Assessment D372052

Page 11 of 27 3.0 Hazard Characterization

The toxicity profile for glyphosate is provided in Attachment 2.

3.1 Hazard Profile

Glyphosate is of low acute toxicity following or al, dermal, and inhalation exposure, since all studies are in Toxicity Category III or IV. It is a mild eye irritant (Toxicity Category III), slight skin irritant (Toxicity Category IV), and is not a dermal sensitizer in guinea pigs. Inhalation risk assessments (any time period) are not required based on the low toxicity of the formulation products (Toxicity Category III or IV) and the physical characteristics of the technical product (wet cake). An acute dose and endpoint have not been selected for any population subgroups

because no effects that could be attributed to a single exposure (dose) were observed in oral toxicity studies including the developmental toxicity studies in rats and rabbits. Therefore, a dose and endpoint were not identified for acute dietary risk assessment.

A chronic feeding/carcinogenicity study in rats found no systemic effects in any of the parameters examined (body weight, food consumption, clinical signs, mortality, clinical pathology, organ weights, and histopathology). In a second chronic feeding/carcinogenicity study in rats tested at higher dietary levels, a LOAEL was identified at 20,000 parts per million (ppm; approximately 940 mg/kg/day) based on decreased body-weight gain in females and increased incidence of cataracts and lens abnormalities, decreased urinary pH, increased absolute liver weight, and increased relative liver weight/brain weight in males. No evidence of carcinogenicity was found in rats. There was also no evidence of carcinogenicity in mice. In a chronic toxicity study in dogs, no systemic effects were found in all examined parameters.

On 26-Jun-1991, the HED CPRC evaluated the weight of the evidence on glyphosate with particular emphasis on its carcinogenic potential. The Committee concluded that glyphosate should be classified as a “Group E” chemical (evidence of non-carcinogenicity for humans), based upon lack of convincing carcinogenicity evidence in adequate studies in two animal species (mice and rats).

Acceptable developmental toxicity studies in the rat and rabbit are available, as is an acceptable 2-generation reproduction study in the rat. No significant reproductive and developmental toxic

effects were found. A focal tubular dilation of the kidneys was observed in a three-generation reproductive study on rats at the 30-mg/kg/day level (HDT), however a two-generational reproductive study on rats did not observe the same effect at the 1500-mg/kg/day level (HDT), nor were any adverse reproductive effects observed at any dose level. In 1991, the HED RfD

Committee concluded that the focal tubular dilati on of the kidneys at the 30-mg/kg/day level was a spurious rather than a glyphosate-related effect.

In a prenatal developmental toxicity study in rats, maternal (systemic) effects observed included mortality, increased clinical signs, and reduced body-weight gain at the HDT (3500 mg/kg/day). Developmental (fetal) effects were observed only in the high-dose group and included decreases in total implantations/dam and nonviable fetuses/dam, increased number of litters and fetuses with unossified sternebrae, and decreased mean fe tal body weights. In a prenatal developmental toxicity study in rabbits, maternal (systemic) effects observed included mortality and clinical signs of toxicity at the HDT (350 mg/kg/day). In the rabbits, developmental toxicity was notGlyphosate Human-Health Risk Assessment D372052

Page 12 of 27 observed at any dose. On the basis of developmental studies in rats and rabbits and reproductive findings in rats, glyphosate exhibited no evidence of increased susceptibility of offspring.

Neurotoxicity has not been observed in any of th e acute, subchronic, chronic, developmental, or reproductive studies performed with glyphosate.

In the rat metabolism study, absorption was estimated to be 30-36% in males and females following a single 10 mg/kg oral dose. Glyphosate was excreted unchanged in the feces and urine (97.5% minimum). The only metabolite present in the excreta was small amounts of AMPA. Less than 1% of the absorbed dose remained in the carcass, primarily the bone. Repeated dosing did not significantly alte r metabolism, distribution, and excretion.

AMPA: AMPA is a metabolite of glyphosate. In a 90-day oral toxicity study in rats, a LOAEL was identified for AMPA at 1200 mg/kg/day ba sed on body-weight loss and histopathological lesions of the urinary bladder. Previously the HED Metabolism Committee determined that, based on toxicological considerations, AMPA need not be regulated and should be dropped from the tolerance expression (Memo, R.B. Perfetti, 19-Aug-92). Furthermore, in a 17-Mar-94 meeting, the HED Metabolism Committee discussed whether uses that result in significantly higher residues of AMPA in plants and livestock commodities in the future would require that AMPA be reintroduced into the tolerance expression of glyphosate. The Committee determined that, based on toxicological considerations, AMPA need not be regulated regardless of levels observed in foods or feeds (Memo, R.B. Perfetti, 17-Mar-94).

N-Acetyl-Glyphosate: N- acetyl-glyphosate is a metabolite of glyphosate which is formed in certain transgenic crops. The acute oral LD 50 was greater than 5000 mg/kg in rats. Based on structural similarity with glyphosate, structure-ac tivity relationships [(SAR); lack of structural alerts for carcinogenicity, mutagenicity, and endocrine effects], low acute toxicity, low subchronic toxicity, and lack of mutagenicity, N- acetyl-glyphosate is considered to be equally toxic as glyphosate.

N-Acetyl-AMPA: N- acetyl-AMPA is a minor metabolite of glyphosate which is formed in certain transgenic crops. N- acetyl-AMPA is expected to be of low acute toxicity and was negative for mutagenicity. It is not expected to be absorbed quickly from the gastrointestinal (GI) tract since it is a charged molecule at the physiological pH. Therefore, it is expected to be

less toxic than N -acetyl-glyphosate. The metabolism study in rats with N -acetyl-glyphosate indicated that about 99% of the parent compound was isolated in the excreta. Based on this and the minimal plant residue concentrations, N -acetyl-AMPA was excluded as a residue of concern.Glyphosate Human-Health Risk Assessment D372052

Page 13 of 27 3.2 FQPA Considerations

The RABI risk assessment team recommends that the FQPA SF be reduced to 1X, which is consistent with the previous FQPA Safety Factor Committee decision (6-Apr-1998). This recommendation is based on the following considerations:

● There are no residual uncertainties for pre- or postnatal toxicity.

● There is no evidence of neurotoxicity in any of the toxicology studies conducted. Although an acute and subchronic neurotoxicity studies are now required as a part of new data requirements in the 40CFR §158 for conventional pesticide registration, the Agency does not believe that conducting these studies will result in a lower POD than that currently used for overall risk assessment, and therefore, a UF DB is not needed to account for lack of these studies.

● There is no quantitative or qualitative evidence of increased susceptibility of rats or rabbit

fetuses to in utero exposure in developmental studies. A focal tubular dilation of the kidneys was observed in a three-generation reproductive study on rats at the 30-mg/kg/day level (HDT), however a two-generational reproductive study on rats did not observe the same effect at the 1500-mg/kg/day level (HDT), nor were any adve rse reproductive effects observed at any dose

level. A clear NOAEL was established and the chronic reference dose was set at a level well

below this effect.

● The toxicology database for glyphosate does not show any evidence of treatment-related effects on the immune system. The overall weight of evidence suggests that this chemical does not directly target the immune system. An immunotoxicity study is required as a part of the new data requirements in the 40 CFR Part 158 for conventional pesticide registration; however, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower POD than that currently use for overall risk assessment, and therefore, a UF DB is not needed to account for lack of this study.

● The dietary exposure analysis is conservative as it assumed tolerance level residues and 100% crop treated.

3.3 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will pr oceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios.Glyphosate Human-Health Risk Assessment D372052

Page 14 of 27 This list should not be construed as a list of known or likely endocrine disruptors.

Glyphosate was among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

3.4 Dose-Response Assessment

Acute Dietary Endpoint (Females age 13-49): An acute reference dose (aRfD) was not established for females age 13-49, based on the absence of an appropriate toxicological endpoint attributable to a single exposure (dose), including fe tal toxicity in developmental toxicity studies.

Acute Dietary Endpoint (General Population): An acute reference dose (aRfD) was not established for any population subgroup or the general population, including infants and children, based on the absence of an appropriate toxicological endpoint attributable to a single exposure (dose), including maternal toxicity in developmental toxicity studies.

Chronic Dietary Endpoint: The developmental toxicity study in rabbits was used to select the endpoint for establishing the chronic RfD (cRf D) of 1.75 mg/kg bw/day. The maternal NOAEL was 175 mg/kg/day based on mortality, diarrhea, soft stools, and nasal discharge seen at the LOAEL of 350 mg/kg/day. The NOAEL selected was the lowest observed in all of the major toxicity studies, and is the most protective for pregnant females as well as the general population.

Incidental Oral Short- and Intermediate-Term: The developmental toxicity study in rabbits

was chosen for the short- and intermediate-ter m incidental oral endpoint. The maternal NOAEL was175 mg/kg/day based upon mortality, diarrhea, so ft stools, and nasal discharge seen at the LOAEL of 350 mg/kg/day. The NOAEL selected was the lowest observed in all of the major toxicity studies, and is protective against the offspring effects observed in the 2-generation reproduction study seen at higher doses (decreased body-weight gain during lactation for both sexes).

Dermal Absorption: Dermal endpoints for glyphosate were not selected, due to lack of toxicity in the 21-day dermal toxicity up to the highest dose tested. There is also low concern for developmental toxicity. Consequently, dermal absorption does not need to be addressed in the

risk assessment.

Short-, Intermediate- and Long-Term Dermal: Short-, intermediate- and long-term dermal endpoints were not selected based on the absence of hazard in the 21-day dermal toxicity study in rabbits. Additionally, there were no developmental or reproductive toxicity concerns relevant to dermal endpoint selection.

Short-, Intermediate- and Long- Term Inhalation: Short-, intermediate- and long-termGlyphosate Human-Health Risk Assessment D372052

Page 15 of 27 inhalation endpoints were not selected based on the absence of hazard in the 28-day inhalation toxicity study in rats. Additionally, there were no developmental or reproductive toxicity concerns relevant to inhalation endpoint selection.

Table 3.4.1. Summary of Toxicological Doses and E ndpoints for Glyphosate for Use in Human-Health Risk

Assessments 1

. Exposure/

Scenario POD Uncertainty/ FQPA SF RfD, PAD, LOC Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) An endpoint of concern (effect) attributable to a single dose was not identified in the database. Quantification of acute risk to general populati on including infants and children is not required.

Chronic Dietary (All Populations) NOAEL= 175 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x cPAD = cRfD = 1.75 mg/kg/day Developmental Toxicity Study - Rabbit: Maternal LOAEL = 350 mg/kg/day based on diarrhea, nasal discharge and death in maternal animals Short- (1-30 days) and Intermediate-(1-6 months)

Term Incidental Oral NOAEL= 175 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x LOC (residential)

= MOE < 100 Developmental Toxicity Study - Rabbit: Maternal LOAEL = 350 mg/kg/day based on diarrhea, nasal discharge and death in maternal animals

Short- (1-30 days), Intermediate (1-6 months) and Long- (6 < months)

Term Dermal None None None Based on the lack of toxicity up to the HDT (1,000 mg/kg/day) in the 21 day dermal toxicity study in rabbits and the lack of concern for developmental and reproductive effects, the quantification of dermal risks is not required.

Short- (1-30 days), Intermediate (1-6 months) and Long- (6 < months)

Term Inhalation None None None Based on the lack of toxicity up to the highest concentration tested ( 0.36 mg/L) in the 28-day inhalation toxicity study in rats, and the physical characteristics of the technical (wetcake), the quantification of inhalati on risks is not required. Cancer (oral, dermal, inhalation) Classification: Group E; no evidence of carcinogenicity; risk assessment not required.

1 UF = uncertainty factor, FQPA SF = Special FQPA sa fety factor, NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, PAD = population-adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, HDT = highest dose tested.

3.5 Recommendation for Aggregate Exposure Risk Assessments

For oral exposure, the dietary, incidental oral, and drinking water exposures can be combined.Glyphosate Human-Health Risk Assessment D372052

Page 16 of 27 4.0. Dietary Exposure/Risk Characterization

4.1 Metabolism in Primary Crops, Livestock, and Rotational Crops

Table 4.1.1 is a summary of the conclusion made by HED concerning the residues of concern in primary crops, livestock, rotational crops, and drinking water.

Table 4.1.1: Residues of Concern for To lerance Expression and Risk Assessment.

Matrix Residues Included in Risk Assessmen t Residues Included in Tolerance Expression

p rimar y cro p s ( excludin g so y bean an d field corn ) g l yp hosate g l yp hosate soybean and field corn glyphosate and N -acetyl-glyphosate glyphosate and N -acetyl-glyphosate

livestock glyphosate and N -acetyl-glyphosate glyphosate and N -acetyl-glyphosate rotational crops glyphosate glyphosate drinking water glyphosate glyphosate

Primary Crops: Metabolism studies conducted with nontransgenic corn, cotton, soybeans, and wheat were previously submitted and reviewed. Based on these data, HED concluded that the residue of concern in nontransgenic plants is glyphosate (Memo, R. Perfetti, 19-Oct-1992; RED, R. Perfetti, 27-Oct-1992; Memo, R. Perfetti, 17- Mar-1994). Metabolism studies have also been submitted on glyphosate-tolerant canola (D 242628, T. Bloem, 30-Nov-1998) and glyphosatetolerant field corn (Roundup Ready ® field corn; D217539, G. Kramer, 14-Mar-1996). The glyphosate-tolerant canola and field corn were ge netically modified to express the EPSPS gene

derived from Agrobacterium sp. (strain CP4) which codes for an EPSPS protein that has reduced affinity for glyphosate as compared to the endogenous EPSPS protein. The glyphosate-tolerant canola and corn were also genetically engineered to express the oxireductase gene which converts glyphosate to the nonherbicidal AMPA. Metabolism in these varieties of transgenic canola and corn was essentially the same as the nontransgenic plants. Therefore, it was concluded that the terminal residue to be regulated, in nontransgenic plants and transgenic field corn and canola modified to express the Agrobacterium sp. EPSPS and oxireductase genes, is glyphosate.

Subsequent to this decision, HED approved DuP ont requests permitting the commercialization of Optimum TM GAT TM soybean and Optimum TM GAT TM field corn (D346713, T. Bloem, 12-Mar2008; D357880, T. Bloem, 29-Oct-2008; D361315, T. Bloem, 14-Jan-2010). Optimum TM

GAT TM soybean was engineered to express the gat 4601 gene (derived from Bacillus licheniformis ; soil bacterium) and Optimum TM GAT TM field corn was engineered to express the

gat4621 gene (derived from Bacillus licheniformis ; soil bacterium) and the zm-hra gene (modified version of maize acetolactate synthase (ALS) gene). The gat 4601 and the gat 4621 genes confer tolerance to glyphosate via acetylation of the secondary amine group of glyphosate (results in formation of the nonherbicidal N -acetyl-glyphosate); the zm-hra gene in Optimum TM

GAT TM field corn, encodes for an ALS protein which is not sensitive to the ALS-inhibiting herbicides. As a result of the introduction of these seed lines, HED concluded that the residues of concern in plants for tolerance expression and risk assessment should change from glyphosate to the combined residues of glyphosate and N-acetyl-glyphosate (D346713, T. Bloem, 12-Mar2008). Subsequent to this decision, it was determined that only the tolerance expression for field corn and soybean would change from glyphosate to the combined residues of glyphosate and N

acetyl-glyphosate; the tolerance expression for all other crops would remain as glyphosate.Glyphosate Human-Health Risk Assessment D372052

Page 17 of 27 The current action is requesting over-the-top application of glyphosate to Roundup Ready® Sweet Corn. The petitioner indicated that the Roundup Ready® Sweet Corn was developed through conventional breeding techniques with Monsanto's Roundup Ready® field corn. As indicated above, Roundup Ready ® field corn was genetically modified to express an EPSPS gene

isolated from Agrobacterium sp. (CP4 EPSPS) which produces an EPSPS protein which is not inhibited by glyphosate; as indicated above, a metabolism study has been conducted with this variety of field corn with HED concluding that the residue of concern was glyphosate. HED concludes that these data and decisions are translatable to Roundup Ready® Sweet Corn.

Livestock: The qualitative nature of the residue in livestock following dosing with glyphosate and AMPA is adequately understood. Studies with lactating goats and laying hens fed a mixture of glyphosate and AMPA indicate that the primary route of elimination was by excretion (urine and feces). The MARC determined that the terminal residue to be regulated in livestock is glyphosate (Memo, R. Perfetti, 19-Oct-1992; RED, R. Perfetti, 27-Oct-1992; Memo, R. Perfetti, 17-Mar-1994).

Since the Optimum TM GAT TM soybean and field corn metabolism studies resulted in significant

residues of N -acetyl-glyphosate, DuPont submitted summaries of in vitro (rumen fluid, fertile hen egg, and rat liver S9 supernatant) and in vivo (rat metabolism study) studies conducted with

the N -acetyl-glyphosate metabolite and submitted goat and hen metabolism studies conducted

with the N -acetyl-glyphosate metabolite. Based on these data and the glyphosate metabolism studies, HED concluded that the residues of concern in livestock following consumption of glyphosate and N -acetyl-glyphosate, for tolerance expression and risk assessment purposes, are glyphosate and N -acetyl-glyphosate (D346713, T. Bloem, 12-Mar-2008; D361315, T. Bloem, 14-Jan-2010). Based on these data and since the relevant variety of sweet corn does not result in any addition metabolites, HED concludes that the previous decisions concerning the residues of concern in livestock remain appropriate.

Rotational Crops: Based on a previously-reviewed confined rotational crop studies (3.71 lb ae/acre; MRIDs 41543201 and 41543202, A. Abramovitch, 14-Oct-1992) which resulted inglyphosate residues of glyphosate >0.01 ppm in barley grain only (0.018 ppm; 125-day plantback interval (PBI)) and the limit of quantitation (LOQ) for the tolerance enforcement method of 0.05 ppm, HED concluded that a 30-day PBI was appropriate for all nonlabeled crops (D200041, G. Kramer, 12-May-1994; field rotational crop st udy has not been submitted). HED notes that the rate employed in the confined rotational crop study was 0.6x the proposed Roundup Ready ®
sweet corn rate; however, based on the proposed post-emergent single application rate of 1.55 lb ae/acre, 30-day preharvest interval (PHI), and the LOQ for the tolerance enforcement method, HED concludes that the proposed 30-day PBI for all crops is acceptable.

4.2 Analytical Methodology

The field corn forage, stover, and kernel plus cob with husk removed (K+CWHR) samples collected from the crop field trials submitted in support of the current petition were analyzed for residues of glyphosate and AMPA using an ad equately validated high-performance liquid chromatograph (HPLC) equipped with a fluorescence detector method. Based on the lower limit of method validation (LLMV), the LOQ is 0.05 ppm for each analyte/matrix.

The data collection method is similar to the current enforcement method (Memo, R. Perfetti,Glyphosate Human-Health Risk Assessment D372052

Page 18 of 27 10/27/92). Based on this similarity and since acceptable recoveries were attained in the field trials, HED concludes that the current enforcement method is adequate to enforce the tolerances associated with the current petition.

4.3 Drinking Water Residue Profile
D376484, J. Hetrick, 2-Jul-2010

The available field and laboratory data indicate that glyphosate adsorbs strongly to soil and would not be expected to move vertically below the 6 inch soil layer. Based on unaged batch equilibrium studies glyphosate and glyphosate residues are expected to be immobile with Kd(ads) values ranging from 62 to 175. The mechanism of adsorption is unclear; however, it is speculated that it may be associated with vacant phosphate sorption sites or high levels of metallic soil cations. The data indicate that chemical and photochemical decomposition is not a significant pathway of degradation of glyphosate in soil and water. However, glyphosate is readily degraded by soil microbes to AMPA, which is degraded to CO 2 , although at a slower rate than parent glyphosate. Based on the low vapor pressure of glyphosate, vol atilization from soils will not be an important dissipation mechanism. The low octanol/water partition coefficient suggests that glyphosate will have a low tendency to accumulate in fish. Based on these data, HED concluded that glyphosate is the only residue of concern in drinking water.

Estimated Drinking Water Concentrations: EFED previously provided a 230-ppb estimated drinking water concentration (EDWC) for glyphos ate resulting from direct application to a standard farm pond (3.75 lb ae/acre; D264647 and D264649, P. Jennings, 12-Aug-2000). EFED has subsequently revised this estimate using the index reservoir and concludes that the EDWC for direct aquatic application is not expected to exceed 153.67 ppb for a daily peak and 8.11 ppb for the annual average (D376484, J. Hetrick, 2-Jul-2010). In this same memorandum, EFED provided the following EDWCs resulting from the proposed sweet corn applications scenario: surface water - 38.488 ppb peak and 2.6 ppb annual average (Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS)); groundwater - peak and annual average of 0.0273 ppb (Screening Concentration in Ground water (SCI GROW)). EFED also provided the following summary of the United States Geological Survey (USGS) National Water-Quality Assessment Program (NAWQA) glyphosate surface and ground water monitoring data: surface water - 35 ppb peak and 1.81 ppb annual average; groundwater - 273 ppb peak and 13.5 ppb annual average. Based on this information, EFED recommended using the NAWQA annual average groundwater monitoring number of 13.35 ppb in chronic assessments.

4.4 Food Residue Profile
D380164, T. Bloem, 31-Aug-2010

Magnitude of the Residue - Roundup Ready ® Sweet Corn: The petitioner is proposing preplant, at planting, and/or preemergent application (maximum of 3.72 lb ae/acre) and postemergent application (through 48 inches tall; maximum of 4.62 lb ae/acre) of glyphosate to Roundup Ready ® sweet corn (maximum seasonal application rate of 5.98 lb ae/acre (see Table 3)). In support of this request, two scientifically acceptable field trial studies were submitted with each conducted with glyphosate-tolerant field corn (MRID 47589202 and 47589201); HED notes that although field corn was used, the commodities were harvested at the appropriate crop stage for sweet corn. The studies employed several differe nt application scenarios with highest maximum and mean residues attained under the application scenario performed in MRID 47589202;Glyphosate Human-Health Risk Assessment D372052

Page 19 of 27 however, the geographical representation of these data do not fulfill the requirements suggested in OPPTS 860.1500. The application scenario employed in one of the treated plots from the MRID 47589201 field trial study was similar to that employed in MRID 47589202 and these data were combined for purposes of setting a tolerance. The combination of these trials yields acceptable geographical representation and adequately represent the proposed application scenario. Based on these data, the tolerance calculator recommended for the following tolerances for residues of glyphosate: corn, sweet, kernel plus cob with husk removed - 2.5 ppm; corn, sweet, forage - 8.0 ppm; corn, sweet, stover - 11 ppm. Since the recommended forage and stover tolerances are less than the currently established tolerances for these commodities, HED concludes the revision of the currently established is unnecessary. Based on the currently available data, HED concludes that a tolerance for residues of glyphosate in/on corn, sweet, kernel plus cob with husk removed tolerance of 3.5 ppm is appropriate (a revised Section F is requested). HED is recommending for a 3.5 ppm tolerance rather than the 2.5 ppm tolerance recommended by the calculator as the highest residue from the fiel d trials was 3.1 ppm. A processing study was not submitted and is not required as Table of OPPTS 860.1000 indicates that there are no processed

commodities for sweet corn.

Magnitude of the Residue - Livestock: The revised OPPTS 860.1000 Table 1 (J. Stokes; Jun2008) indicates that sweet corn forage (roughage), stover (roughage), and cannery waste (carbohydrate concentrate; forage residue data used as a surrogate) are the only feed commodities associated with the current petition and these may only be fed to dairy cattle (no beef cattle, hog, or poultry feed commodities associated with the current petition). Since the current petition does not require a revision to the currently established sweet corn forage or stover tolerances, HED concludes that the currently-established livestock tolerances remain appropriate.

Monsanto also requested a reduction in the poultry meat tolerance from 4.0 ppm to 0.1 ppm as they believe the tolerance level was inadvertently increased when the poultry tolerances were moved from Section 180.364 (a)(1) (glyphosate) to 180.364 (a)(2) (glyphosate and N -acetyl glyphosate). Based on a review of historical 180.364 information the tolerance value and expression were changed at the same time (see 40 CFR 180.364 for years 2008 and 2009). The change in the poultry tolerance expression was due to the introduction of a new line of genetically modified soybean and field corn with the HED reviews indicating that the tolerance expressionshould be changed with the tolerance value remaining the same (D346713, T. Bloem 12-Mar2008; D357880, T. Bloem, 29-Oct-2008). Therefor e, HED concludes that the poultry meat tolerance should be reduced to 0.10 ppm. A revised Section F is requested.

Magnitude of the Residue - Rotational Crops: Based on a previously-reviewed confinedrotational crop studies (3.71 lb ae/acre; MRIDs 41543201 and 41543202, A. Abramovitch, 14-Oct1992) which resulted in glyphosate residues of glyphosate >0.01 ppm in barley grain only (0.018 ppm; 125-day PBI and the LOQ for the tolerance enforcement method of 0.05 ppm, HED concluded that a 30-day PBI was appropriate for all nonlabeled crops (D200041, G. Kramer, 12- May-1994; field rotational crop study has not been submitted). HED notes that the rate employed in the confined rotational crop study was 0.6x the proposed Roundup Ready ® sweet corn rate; however, based on the proposed post-emergent single application rate of 1.55 lb ae/acre, 30-day PHI, and the LOQ for the tolerance enforcement method, HED concludes that the proposed 30-day PBI for all crops is acceptable.

4.5 International Residue Limits and HED-Recommended TolerancesGlyphosate Human-Health Risk Assessment D372052

Page 20 of 27 Table 4.5.1 is a summary the proposed and HED recommended tolerances for residues of glyphosate (180.364(a)(1)) or glyphosate and N -acetyl glyphosate (180.364(a)(2)). A revised Section F is requested specifying the correct tolerance levels. HED notes that there is a Canadian tolerance for residues of glyphosate and AMPA on corn of 3.0 ppm and a codex tolerance for residues of glyphosate in/on poultry meat at 0.05 ppm. Since the residues of concern differ, harmonization is not possible.

Table 4.5.1. Tolerance Summary.

Commodity Proposed Tolerance (ppm) HED-Recommended Tolerance (ppm) Comments

180.364 (a)(1)

corn, sweet, kernel plus cob with husks removed 3.0 3.5

corn, sweet, forage 9.0 not required revised Section F is requested

180.364 (a)(2)

poultry, meat 0.1 0.10 revised Section F is requested

4.6 Dietary Exposure and Risk
D380165, T. Bloem, 31-Aug-2010

A chronic dietary risk assessment was conducted using DEEM-FCID TM (ver. 2.03) which incorporates consumption data from US DA CSFII (1994-1996 and 1998). Acute and cancer dietary risk assessments were not conducted since an appropriate endpoint attributable to a single dose was not identified for the general U.S. population or any population subgroup and glyphosate is classified as not likely to be a human carcinogen, respectively. The chronic analysis assumed tolerance-level residues, 100% crop treated, and DEEM TM (ver 7.81) default processing factors for all commodities and incorporated glyphosate drinking water monitoring data. The resulting chronic risk estimates (food and water) were ≤ 12% cPAD and, therefore, do not exceed HED's LOC (children (1-2 years old) were the most highly exposed population). Table 4.6.1 is a summary of the chronic dietary exposure estimates.

Table 4.6.1: Summary of Chronic Dietary Exposure and Risk.

Population Subgroup cPAD (mg/kg/day) Exposure (mg/kg/day) %cPAD

General U.S. P opulation 0.089832 5.1
All Infants (< 1 year old) 0.147643 8.4

Children 1-2 years old 0.212275 12
Children 3-5 years old 0.208971 12
Children 6-12 years old 0.144940 8.3
Youth 13-19 years old 0.089079 5.1
Adults 20-49 years old 0.072633 4.2
Adults 50+ years old 0.057683 3.3
Females 13-49 years old 1.75

0.067442 3.9Glyphosate Human-Health Risk Assessment D372052

Page 21 of 27 5.0 Residential (Non-Occupational) Risk

The proposed use to sweet corn is not anticipated to result in residential exposure. However, residential exposure are anticipated from the registered broadcast and spot treatment to home lawns, gardens and recreational areas including parks and golf courses (homeowner application is permitted). Additional registered uses include lawn renovation and applications to lakes and ponds, including reservoirs.

Handlers/Applicators: Based on the registered residential use patterns, there is a potential for short-term dermal and inhalation exposures to homeowners who mix and apply products containing glyphosate. However, since short- and intermedia te-term dermal or inhalation endpoints were not selected, no residential handler/applicator assessment is needed.

Post-Application: Post-application dermal and inhalation assessments are not needed since shortand intermediate-term dermal or inhalation endpoi nts were not selected. However, based on the registered use patterns, toddlers may have short- term post-application incidental oral exposures from hand-to-mouth, object to mouth, and soil ingestion behavior on treated lawns and swimmers may have short-term post-application incidental oral exposures from treated surface water.

The Agency previously assessed post-application incidental oral ingestion exposure for toddlers resulting from turf treatment were previously assessed (1.62 lb ae/acre; D321992, J. Tomerlin, 29- Sep-2006) using the SOPs for Residential Exposure Assessments, Draft, 17-Dec-1997 and ExpoSAC Policy No. 11, 22-Feb-2001: Recommended Revisions to the SOPs for Residential Exposure. Also assessed were short-term post-a pplication incidental oral exposures for adult, children, and toddler swimmers (assumed 3.75 lb ae/acre and a depth of 1 foot). The exposure assumptions used in the swimmer assessment are based on HED’s SOPs for Residential Exposure Assessments, Draft, 17-Dec-1997 and subsequent updates for swimming pools adapted for this assessment; the Residential SOP assumptions are considered conservative for use in assessing this

scenario.

HED combines risk values resulting from separate residential exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. Since the residential uses of glyphosate on turf and in ponds and lake are not likely to co-occur, these uses were not combined. For glyphosate, all non-dietary sources of post-application exposure to turf were combined to obtain a screening level estimate of potential exposure which could be used for the aggregate assessment.

All of the MOEs are greater than 100 ( ≥ 5,800) and, therefore, do not exceed HED's LOC (see Table 5.0.1). It should be noted that there is a lawn renovation use of glyphosate that may be applied at a much higher application rate than the assessed turf rate (1.62 lb ae/acre). However, since non-dietary exposure is not expected to result from the lawn renovation use, an assessment

is not needed.Glyphosate Human-Health Risk Assessment D372052

Page 22 of 27 Table 5.0.1: Exposure Potential for Adult and Child Short-term Aggregate Risk Estimates 1

.

Exposure Scenario Exposure (mg/kg/day) MOE Combined Exposure (mg/kg/day) 2 Combined

MOE 3

Incidental oral hand-to-mouth post-app. exposure from contacting treated turf 0.0242 7,230

Incidental oral post-application exposure from ingestion of treated soil 8.13 x 10 -5 >10 6 Toddler –

Treated Turf
Incidental oral post-application exposure from object-to-mouth 0.00605 28,900 0.03025 5,800

Toddler –

Swimmer Incidental oral post-application exposure from contacting treated water 0.023 7,600

-- --

Adult –

Swimmer Incidental oral post-application exposure from contacting treated water 0.00493 36,000

-- --

1 Source of information: Memo, J.R. Tomerlin, 29-Sep-06, D321992.

2 Combined exposure (mg/kg/day) = Dose Hand-to-mouth + Dose soil ingestion + Dose Object-to-mouth

. 3 Combined MOE = NOAEL (175 mg/kg/day) ÷ Combined exposure (dose) (mg/kg/day).

Spray Drift: HED notes that 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 glyphosate. 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 at http://www.epa.gov/ opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. 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 risks associated with drift. HED notes that residential exposure to glyphosate resulting from the turf uses do not exceed HED's LOC (see above) and it is unlikely that spray drift from the registered agricultural uses will result in exposures higher than these.Glyphosate Human-Health Risk Assessment D372052

Page 23 of 27 6.0 Aggregate Risk Assessment

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Based on the registered/proposed agricultural and residential uses, HED conducted short-term (food, water, residential incidental oral) and chronic (food and water) aggregate risk assessments.

Short-Term Aggregate Risk Assessment: Based on the proposed/registered uses, HED anticipates short-term incidental oral exposure to young child ren (swimmer and turf nondietary ingestion) and adults (swimmer). The short-term aggregate assessment combines dietary exposure with the single highest potential residential exposure.

For young children, short-term aggregate exposure includes chronic dietary (food and water) and incidental oral ingestion exposure resulting from the turf use (highest exposure of all possible scenarios). For adults, short-term aggregate exposure includes chronic dietary exposure (food and water) and incidental oral ingestion exposure resulting from the aquatic use (highest exposure of all possible scenarios). Table 6.0.1 is a summary of the short-term aggregate exposures and risk estimates (the populations included represent those with the highest dietary exposures). Since the aggregate MOEs are ≥ 720, short-term aggregate exposure to glyphosate

does not exceed HED's LOC. HED notes that sin ce the short-/intermediate-term incidental oral endpoints are identical, the short-term risk assessments are protective of intermediate-term

exposure.

Table 6.0.1: Short-Term Aggregate Exposure. Exposure (mg/kg/day) Population Dietary 1 Incidental Oral 2 Combined Aggregate. MOE 3

General U.S. populati on 0.089832 0.00493 0.094762 1,800

Children 1-2 years old 0.212275 0.03033 0.242525 720

Adults 20-49 years old 0.072633 0.00493 0.077563 2,300

1 See Table 4.6.1.

2 See Table 5.0.1

3 Aggregate MOE = 175 mg/kg/day (s hort-term incidental oral NOAEL) ÷ combined exposure (mg/kg/day).

Chronic Aggregate Risk Assessment: Because HED does not anticipate significant chronic residential exposure as a result of the proposed/registered glyphosate uses, aggregate chronic risk assessment takes into consideration dietary (food and water) exposure only. The chronic aggregate exposure and risk estimates do not exceed HED's LOC ( ≤ 12% cPAD; see Section 4.6).Glyphosate Human-Health Risk Assessment D372052

Page 24 of 27 7.0 Cumulative Risk Characterization/Assessment

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 for glyphosate and any other substances; and glyphosate does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that glyphosate does not have 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 Pathway

Based on the glyphosate toxicological database, HED concluded that short-/intermediate/longterm dermal and inhalation risk assessments are unnecessary. Therefore, occupational handler/applicator and post-application assessments are not required.

Based on an acute toxicity review for the formulated products (D295196, B. Backus, 2-Feb2004), there is some question as to whether the proposed 4-hour REI is appropriate. RD should ensure that 4-hour REI is acceptable.

9.0 Data Needs and Label Requirements

9.1 Toxicology

• Acute and Subchronic neurotoxicity studies.

• Immunotoxicity study.

9.2 Residue Chemistry

● Revised Section F: HED request a revised Sec tion F deleting the proposed sweet corn forage tolerance, specifying a tolerance of 3.5 ppm for residues of glyphosate in/on corn, sweet, kernel plus cob with the husk removed, and specifying a tolerance of 0.10 ppm for residues of glyphosate and N -acetyl-glyphosate in/on poultry meat.

9.3 Occupational and Residential Exposure

● Based on an acute toxicity review for the formulated products (D295196, B. Backus, 2-Feb2004), there is some question as to whether the proposed 4-hour REI is appropriate. RD should ensure that 4-hour REI is acceptable.

Attachment 1: Chemical Names and Structures. Attachment 2: Toxicity Profile.

RDI: RABI review (25-Aug-2010) T. Bloem:S10945:PY1:(703)-605-0217(7509P)Glyphosate Human-Health Risk Assessment D372052

Page 25 of 27 Attachment 1: Chemical Names and Structures.

Compound Structure

Glyphosate

N

-(phosphonomethyl)glycine P O

OH
OH N H

OH O

N

-Acetyl-glyphosate

N

-acetyl- N -(phosphonomethyl)glycine

AMPA

(aminomethyl)phosphonic acid P O

OH
OH NH

2

N

-Acetyl-AMPA

[(acetylamino)methyl]phosphonic acid P O

OH
OH N H CH

3

O P O

N O O C 3 H

O O H H O HGlyphosate Human-Health Risk Assessment D372052

Page 26 of 27 Attachment 2: Toxicity Profile.

Acute Toxicity Profile: Test Substance

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral 41400601 LD 50 > 5,000 mg/kg IV

870.1200 Acute dermal 41400602 LD 50 > 5,000 mg/kg IV

870.1300 Acute inhalation None The requirement for an acute

inhalation LC 50 study was

waived None

870.2400 Acute eye irritation 41400603 Corneal opacity or irritation clearing in 7 days or less III

870.2500 Acute dermal irritation 41400604 Mild or slight irritant IV

870.2600 Skin sensitization 41642307 Not a sensitizer None

Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type Results

870.3100 90-Day oral toxicity (Mouse) NOAEL = 1500 mg/kg/day in males and females LOAEL = 4500 mg/kg/day in males and females based on decreased body weight].

870.3100 90-Day oral toxicity (Range finding) NOAEL = not established LOAEL = 50 mg/kg/day in males and females based on possible increased phosphorus and potassium values.

870.3150 90-Day oral toxicity (Rat) - Aminomethyl phosphoric acid - glyphosate plant

metabolite NOAEL = 400 mg/kg/day in males and females LOAEL = 1200 mg/kg/day in males and females based on body-weight loss and histopathological lesions of the urinary bladder.

870.3200 21/28-Day dermal toxicity (Rabbit) NOAEL = 1000 mg/kg/day in males and females LOAEL = 5000 mg/kg/day based on slight erythema and edema on intact and abraded skin of both sexes, and decreased food consumption in females.

870.3485 28-Day inhalation toxicity (rat) NOAEL = 0.36 mg/L (HDT); LOAEL not established based on 6 hours/day, 5 days/week for 4 weeks

870.3700a Prenatal developmental in rodents (Rat) Maternal NOAEL = 1000 mg/kg/day LOAEL = 3500 mg/kg/day based on based on inactivity, mortality, stomach hemorrhages and reduced body-weight gain. Developmental NOAEL = 1000 mg/kg/day LOAEL = 3500 mg/kg/day based on increased incidence in the number of fetuses and litters with unossified sternebrae and decreased fetal body weight.

870.3700b Prenatal developmental in (Rabbit) Materna l NOAEL = 175 mg/kg/day LOAEL = 350 mg/kg/day based on based on mortality, diarrhea, soft stools, and nasal discharge. Developmenta l NOAEL = 350 mg/kg/day (HDT)

LOAEL = not established.Glyphosate Human-Health Risk Assessment D372052

Page 27 of 27 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type Results

870.3800 Reproduction and fertility effects, 3-generation (Rat) Parental/Systemic NOAEL = 30 mg/kg/day (HDT) Reproductive NOAEL = 30 mg/kg/day (HDT) Offspring NOAEL = 10 mg/kg/day LOAEL = 30 mg/kg/day based on focal dilation of the kidney in male F3b pups.

870.3800 Reproduction and fertility effects, 2-generation (Rat) Parental/Systemic NOAEL = 500 mg/kg/day in males and females LOAEL = 1500 mg/kg/day in males and females based on soft stools, decreased body-weight gain and food consumption. Focal dilation of the kidney observed at 30 mg/kg/day in the 3-generation study was not observed at any dose level in this study. Reproductive NOAEL = 1500 mg/kg/day (HDT) in males and females Offspring NOAEL = 500 mg/kg/day in males and femalesLOAEL = 1500 mg/kg/day in males and females based on decreased bodyweight gain during lactation.

870.4100b Chronic toxicity (dog) NOAEL = 500 mg/kg/day in males and females (HDT)

LOAEL = not established.

870.4300 Carcinogenicity (Mice) NOAEL = 750 mg/kg/day in males and females LOAEL = 4500 mg/kg/day in males and females based on significant decreased body-weight gain in both sexes, hepatocy te necrosis and interstitial nephritis in males, and increased incidence of proximal tubule epithelial basophilia and hypertrophy in the kidney of females. No evidence of carcinogenicity

870.4300 Chronic/Carcino-genicity (Rat) NOAEL = 362 mg/kg/day in males, 447 mg/kg/day in females LOAEL = 940 mg/kg/day in males, 1183 mg/kg/day in females based on decreased body-weight gain in females, d ecreased urinary pH in males, increased

incidence of cataracts and lens abnormalitie s in males, and increased absolute and relative (to brain) liver weight in males. No evidence of carcinogenicity

Gene Mutation

870.5265 Non-mutagenic when tested up to 1000 ug/plate, in presence and absence of

activation in S . typhimurium strains TA98, TA100, TA1535 and TA1537.

Gene Mutation

870.5300 Non-mutagenic at the HGPRT locus in Chinese hamster ovary cells tested up to cytotoxic concentrations or limit of solubility, in presence and absence of

activation.

In Vivo Cytogenetics - Bone

Marrow 870.5385 Non-mutagenic in rat bone marrow chromosome assay up to 1000 mg/kg in both sexes of Sprague Dawley rats.

870.5550 Rec - Assay and Gene Mutation Assay There was no evidence of recombination in the rec-assay up to 2,000 ug/disk

with B. subtilis H17 (rec+) and M45 (rec-). Negative for reverse gene mutation, both with and without S-9, up to 5,000 ug/plate (or cytotoxicity) with E.coli

SP2hcrA and S. typhimuarium TA98, TA100, TA1535, TA1537, and TA1538.

870.7485

Metabolism and pharmacokinetics (Rat) Absorption was 30-36% in males and females. Glyphosate was excreted unchanged in the feces and urine (97.5% minimum). The only metabolite present in the excreta was AMPA. Less th an 1% of the absorbed dose remained in the carcass, primarily bone. Repeat dosing did not alter metabolism, distribution, and excretion.