Glyphosate Human

- Health Risk Assessment D 398547

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### 1 .0 Executive Summary

Background: Glyphosate 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 (i ncluding 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, canola, aspirated grain fractions (AGF), and livestock commodities at 0.1

- 310 ppm. The Glyphosate Reregistration Eligibility Decision (RED) document was issued September 1993. The most recent glyphosate human

- health ri sk assessment was conducted o n 29

- Nov

- 2011 (D387535, T. Bloem)

The Interregional Research Project No. 4 (IR

- 4) re quested a Section 3 Registration modifying the currently registered application scenario for carrot, sweet potato, and the oilseeds ( crop group ( CG ) 20). IR

- 4 also proposed translation of the wheat forage/hay tolerance to teff forage/hay and proposed upda ting the CG definitions for bulb vegetable (CG 3

- 07), fruiting vegetable (CG 8

- 10), citrus fruit (CG 10

- 10), pome fruit (CG 11

- 10), and berry (CG 13

- 07). Section 2.2.2 includes a summary of the petitioner proposed tolerances.

Hazard Characterization : Glyphosate is categorized as having low acute toxicity for the oral, dermal, and inhalation routes , since all studies are in Toxicity Catego ries III or IV. It is a mild eye irritant (Toxicity Category III), slight skin irritant (Toxicity Category IV), and is not a dermal sensitizer.

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). A second chronic feeding/carcinogenicity study in rats tested at higher dietary levels, and a lowest

- observed

- adverse

- effect level (LOAEL) was identified at 20,000 parts per million (approximately 940 mg/kg/day) based on decreased body

weight gains in fema les and an 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 mice or rats. In a chronic t oxicity study in dogs, no systemic effects were found in all examined parameters.

No significant reproductive and developmental toxic effects were found. On the basis of developmental studies in rats and rabbits and reproductive findings in rats, there was no evidence of increased susceptibility of offspring. Neurotoxicity has not been observed in any of the acute, subchronic, chronic, developmental, or reproductive studies performed with glyphosate.

Since the last risk assessment, the neurotoxicity screening battery tests, and i mmunotoxicity study have been submitted. Preliminary review shows no effects up to the highest dose tested for both the acute and subchronic durations for the neurotoxicity st udies. The preliminary review of the immunotoxicity study also shows no effects up to the highest dose tested.Glyphosate Human

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### Food Quality Protection Act (FQPA) Safety Factor (SF): The RAB 1 risk assessment team recommends that the FQPA SF be reduced to 1 x . This r ecommen dation is based on the

c onsiderations described in the subsequent sections.

● The toxicol ogy database for glyphosate is adequate for characterizing glyphosate toxicity and quantific ation of risk for dietary and occupational uses. T he following acc eptable studies are available for evaluation: d evelopmental toxicity study in rats and rabbits ; t wo

- generation reproduction study in rats

. ● There is no evidence of neurotoxicity in any of the toxicology studies conducted.

● There is no quantitative or qu alitative evidence of increased susceptibility of rat or rabbit fetuses
to in utero exposure in developmental studies.

● The dietary exposure analysis is conservative as it assumed tolerance level residues and 100% crop treated. The residential exposure analysis is also considered conservative as it is based on the 2012 Residential SOPs.

Residential and Non

- Occupational Exposure and Risk Assessment: The proposed use s are not anticipated to result in residential exposure. However, glyphosate is currently registered for application to turf (including golf courses and residential lawns) and for aquatic application

, and residential exposure may occur as a result of these uses. These uses have been reassessed in this document to reflect (1) the HED’s Residential Standard Operating Procedures (SOPs; 2012) , (2) updates to HED’s inputs for aquatic/swimmer assessments, and (3) updated body weight information

. Based on the registered residential use patterns, there is a potential for short

- term der mal and inhalation exposure to residential handlers (mixing, loading, and applying) and short

- term dermal, inhalation, and incidental oral exposure from post

- application activities. Since short

- and intermediate

- term dermal or inhalation endpoints were n ot selected, a quantitative exposure risk assessment was not completed for these routes of exposure. However, children may have short

term post

- application incidental oral exposures from hand

- to

- mouth behavior on treated lawns and swimmers (adult and chil dren) may have short

- term post

- application incidental oral exposures from aquatic uses. Based on the soil half

- life for glyphosate, intermediate

- term soil ingestion was also considered. The resulting MOEs were all ≥1,100 and, therefore, do not exceed HED ’s level of concern (LOC).
Dietary (food and water) Risk Assessment : A chronic dietary risk assessment was conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID , ver. 3.16) which incorporates consumption data from United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008). Acute and cancer dietary risk assessments were not conducted since a n appropriate endpoint attributable to a single dose was not identified for the general U.S. population or any population subgroup and g lyphosate is classified as not likely to be a human carcinogen, respectively

. The chronic analysis assumed tolerance

- level residues , 100% crop treated, and DEEM (ver 7.81) default processing factors for all commodities

, and modeled drinking water estimates (direct application to water scenario)

. The resulting chronic risk estimates (food and water) were ≤13% c hronic population adjusted dose (c PAD ) and are not of concern to HED (children (1

- 2 years old) were the most highly exposed population).Glyphosate Human

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### Aggregate Risk Assessment : In accordance with the FQPA, HED must consider and aggregate pesticide exposures and r isks 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) , intermediate

- term (food, water, resid ential incidental oral)

, and chronic (food and water) aggregate risk assessments. The resulting aggregate exposures are all less than HED’s LOC

. Occupational Risk Assessment : Based on the proposed uses, there is the potential for occupational handler and post

- application dermal and inhalation exposure; however, no dermal or inhalation points of departure ( PODs ) were selected for glyphosate. Therefore, a quantitative occupation al exposure assessment was not conducted.

Human Studies: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include the 2012 Residential SOPs (Lawn/Turf) , are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descripti ons of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

.

2.0 HED Recommendations

Provided the petitioner submits revised Sections B and F, HED concludes that the toxicological

, residue chemistry, and oc cupational/residential exposure databases support an unconditional registration and establishment of the tolerances listed in Table 2.2.2 for residues of glyphosate.

2.1 Data Deficiencies

Prior to Registration: Revised Section F

- See Section 2.2; Revised Section B

- See Section 2.3.

As a Condition of Registration: None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Glyphosate is currently registered for application to a wide variety of crops

. HED concludes the currently

- available tolerance enforcement method is suitable for enforcement of the tolerances recommended here

.

2.2.2 Recommended Tolerances

Based on the available data, HED concludes that the tolerance s listed in Table 2.2.2, for residues of glyphosate per se , are appropriate (40 CFR §180.364(a)(1)). With the establishment of the tolerances listed in Table 2.2.2 , the following tolerances should be deleted: vegetables, root and tuber, crop group 1, except sugar beet; vegetable, bulb, group 3; vegetable, fruiting, group 8; fruit, citrus, group 10; fruit, pome, group 11; berry group 13; borage, seed; cotton, undelintedGlyphosate Human

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### seed; crambe, seed; flax, meal; flax, seed; jojoba seed; lesquerella, seed; meadowfoam, seed; mustard seed; rapeseed, seed; saff lower, seed; sesame, seed; sunflower, seed; cranberry; grape; juneberry; kiwifruit; lingonberry; salal; and strawberry.

There are no Canadian, Codex, or Mexican maximum residue limits for residues of glyphosate in/on carrot or sweet potato or for CGs 1, 3

- 07, 8

- 10, 10

- 10, 11

- 10, or 13

- 07; therefore, harmonization is not an issue for these crops or CGs. There are Codex and Canadian maximum residue limits for the following oilseed crops: Codex (glyphosate only)

- cotton seed at 40 ppm, sunflower seed at 7 ppm, and canola seed at 20 ppm; Canada (combined residues of glyphosate and aminomethyl phosphonic acid (AMPA) )

- canola seed at 10 ppm and flax at 3 ppm.

HED recently co nsulted the Canadian Pesticide M anagement Regulatory Agency (PMRA) concerning the canola seed tolerance and PMRA indicat ed that they are willing to increase the canola seed tolerance to 20 ppm (D394964, T. Bloem, 15

- Nov

- 2011). Therefore, the HED

recommended tolerance value for canola seed will be harmonized with Canada and Codex (it i s noted that the tolerance expressions are different ) . Based on the residue data and use pattern for the remaining oilseed crops, HED conclu des that the HED

- recommended 40

- ppm tolerance for CG 20 (except canola) is appropriate; with the establishment of t his tolerance th e U

. S

. and Codex cottonseed tolerance will be harmonized. Based on the oilseed residue data, harmonization with the Canadian flax and Codex sunflower seed tolerances is not possible.

Table 2.2.2

. Tolerance Summary

.

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments
vegetables, root and tuber, group 1, except sugar beet 6 not recommended Based on the magnitude of the residue following wiper application, HED concludes that separate carrot and sweet potato tolerances should be established. vegetables, root and tuber, group 1, except carrot, sweet potato, and sugar beet -- 0.20

C arrot

-- 5.0
sweet potato

-- 3.0

oilseeds, group 20 40 not recommended In order to maintain harmonization with Canada and Codex and due to the introduction of DuPontTM Optimum® GLY Canola and the resulting change in the canola seed tolerance expression, HED concludes that maintaining the current canola seed tolerance is appropriate. oilseeds, group 20, except canola

-- 40

vegetable, bulb, group 3

- 07 0.2 0.20

HED concludes that the commodity definition should change and/or the tolerance value should be revised to reflect HED policy concerning significant figures. vegetable, fruiting, group 8

- 10 1 0.1 not recommended vegetable, fruiting, group 8

- 10 (except okra) 1

-- 0.10 fruit, citrus, group 10

- 10 0.5 0.50 fruit, pome, group 11

- 10 0.2 0.20 berry and small fruit, group 13

- 07 0.2 0.20 teff, forage 100 100 The proposed tolerances are adequate. teff, hay 100 100

1 Tolerance are currently established in/on crop group ( CG ) 8 at 0.1 ppm and in/on okra at 0.5 ppm; note that okra wa s not included in CG 8 but is included in CG 8

- 10.Glyphosate Human

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### 2.2.3 Revisions to Petitioned

- For Tolerances

The commodity definitions and/or tolerance values recommended by HED in Table 2.2.2 differ from that proposed by the petitioner for the following reasons: (1 ) certain crops were excluded f r o m crop group definitions due to the magnitude of the residue in t hese crops relative to the other crops in their group (carrot, sweet potato, and sugar beet; okra) or to maintain harmonization with Codex and Canada (canola) and (2) tolerance values were changed to conform with HED policy concerning significant figures ( CG 3

- 07, CG 8

- 10, CG 10

- 10, CG 11

- 10, and CG 13

- 07).

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Revised Section B specifying the following: (1) oilseeds CG 20

- both the Roundup Ultra® and Roundup WeatherMAX ® labels should indicate that only a single harvest

- aid application is permitted and should indicate that for canola, the harvest

- aid application pertains to only those varieties which are not tolerant to glyphosate; (2) bulb vegetables CG 3

- 07

- the Round up Ultra® and Roundup WeatherMAX ® supplemental labels concerning application to bulb vegetables include statements concerning application to nonbearing ginseng and rutabaga which should be removed; (3) pome fruit CG 11

- 09

- the Roundup Ultra® and Roundup W eatherMAX ® supplemental labels concerning application to pome fruit include statements concerning application to berries, citrus, and tree nuts which should be removed; and (4) berry and small fruit crop group 13

- 07

- in order to conform with the current s trawberry (representative crop for subgroup 13

- 07G) label instructions, both the Roundup Ultra® and Roundup WeatherMAX ® labels should be revised to indicate a maximum yearly application rate to subgroup 13

- 07G crops of 6.0 lb ae/acre and should indicate a 30

- day plantback interval (PBI) for all nonlabeled crops following application to 13

- 07G crops (excluding cranberry).

2.3.2 Recommendations from Occupational Assessment

None.

2.3.3 Recommendations from Residential Assessment

None.Glyphosate Human

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### 3.0 In troduction

Glyphosate is a non

- selective herbicide that acts via blocking the ac tivity of the EPSPS enzyme

. EPSPS is produced only by green plants and is involved in the synthesis of the amino ac ids tyrosine

, tryptophan , and phenylalanine

. 3.1 Chemical Identity

The chemical structure and nomenclature for glyphosate is presented in Table 3.1

.

T able 3 .1

. Test Compound Nomenclature.

Compound

Common name Glyphosate Company experimental name DPX

- B2856
IUPAC /CAS name N

- ( phosphonomethyl)glycine CAS registry number 1071

- 83

- 6



### 3.2 Physical/Chemical Characteristics

T he physicochemical properties of technical grade glyphosate are presented in Table 3 .2.

T able 3 .2

. Physicochemical Properties of the Technical Grade Test Compound: Glyphosate. Melting point 189.5 ± 0.5 °C

The Pesticide Manual, 13 th Edition pH 1.9 at 20 °C Density 1.705 g/cm 3 at 20 °C Water solubility 10.5 g/L at 20 °C

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 1.31 x 10 - 2 mPa at 25 °C The Pesticide Manual, 13 th Edition
Dissociation constant, pK a 0.8 (1 st phosphonic), 2.3 (carboxylate), 6.0 (2 nd phosphonic), 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 ) European Commission: Glyphosate 6511/VI/99

- final, 1/21/02 UV/visible absorption spectrum ε = 0.086 (295nm)Glyphosate Human

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### 3.3 Proposed Application Scenario

The petitioner submitted proposed supplemental labels for Roundup Ultra® and Roundup WeatherMAX ® concerning wiper application to carrot and sweet potato and harvest

- aid application to all oilseed crops (currently harvest

- aid application is only permitted for the following oilseed crops: cotton, safflower, and sunflower). The petitioner a lso updated these labels to reflect the most recent commodity definitions for the following CGs: bulb vegetables CG 3

- 07; fruiting vegetables CG 8

- 09; citrus fruit CG 10

- 09; pome fruit CG 11

- 09; stone fruit CG 12

- 10; and berry CG 13

- 07. T able 3.3.1 is a summary of the proposed end

- use products and Table 3.3.2 is a summary of the proposed application scenarios.

HED concludes that the proposed labels are adequate provided the following are addressed (revised Section B is requested): (1) oilseeds CG 20

- both the Roundup Ultra® and Roundup WeatherMAX ® labels should indicate that only a single harvest

- aid application is permitted and should indicate that for canola, the harvest

- aid application pertains to only those varieties which are not tolerant to glyp hosate; (2) bulb vegetables CG 3

- 07

- the Roundup Ultra® and Roundup WeatherMAX ® supplemental labels concerning application to bulb vegetables include statements concerning application to nonbearing ginseng and rutabaga which should be removed; (3) pome fr uit CG 11

- 09

- the Roundup Ultra® and Roundup WeatherMAX ® supplemental labels concerning application to pome fruit include statements concerning application to berries, citrus, and tree nuts which should be removed; and (4) berry and small fruit crop group 13

- 07

- in order to conform with the current strawberry (representative crop for subgroup 13

- 07G) label instructions, both the Roundup Ultra® and Roundup WeatherMAX ® labels should be revised to indicate a maximum yearly application rate to subgroup 13

- 07G crops of 6.0 lb ae/acre and should indicate a 30

- day PBI for all nonlabeled crops following application to 13

- 07G crops (excluding cranberry).

Table 3.3.1

. Summary of Proposed End

- Use Products. Trade Name EPA Reg. No. concentration Form

. Label Date Target Crops Target Pests

Roundup Ultra® 524

- 475 glyphosate as the isopropylamine salt; 4 lbs ai/gallon; 3 lbs ae/gallon water

soluble liquid not provided root and tuber vegetables (CG 1)

bulb vegetable crops (CG 3

- 07) fruiting vegetables (CG 8

- 10) citrus (CG 10

- 10) pome fruits (CG 11

- 10) berry (CG 13

- 07) oilseed crops (CG 20) numerous annual and perennial grasses and broadleaf weeds Roundup WeatherMAX® 524

- 537 glyphosate as the potassium salt; 5.5 lbs ai/gallon; 4.5 lbs ae/gallon water

soluble liquid not provided carrot

sweet potato root and tuber vegetables (CG 1) bulb vegetable crops (CG 3

- 07) fruiting vegetables (CG 8

- 10) citrus (CG 10

- 10) pome fruits (CG 11

- 10) berry (CG 13

- 07) oilseed crops (CG 20)Glyphosate Human

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Page 10 of 28 Table 3.3.2

. Summary of Proposed Directions for Use. App. Timing, Type, and Equip. Formulation

( EPA Reg. No. ) App. Rate

(lb a e / acre ) Max. No.

App. per Season Max. Seasonal

App. Rate (lb ai/ acre ) PHI

(days) Use Directions and Limitations

carrot

post

- emergent; wiper or sponge bar applicators Roundup

WeatherMAX® (EPA Reg. No. 524

- 537) -- 2

-- 7 - Applications are to be made with a 33% solution of the formulated product (by volume).

- The first application can be made 60 days before harvest and the second application mad e 7 days before harvest.

- Wiper contact should be a minimum of 2 inches above the desirable vegetation.

- Weeds should be 6 inches above the desirable vegetation.

- Applicators should be operated at a ground speed of no greater than 5 miles per hour.

- Bett er results may be made when two applications are made in opposite directions.

- Do not add a surfactant to the solution when using a wiper applicator. sweet potato

post

- emergent; wiper or sponge bar applicators Roundup

WeatherMAX® (EPA Reg. No. 524

- 537) -- 5

-- 7 - Applications are to be made with a 33% solution of the formulated product (by volume).

- RTI (retreatment interval) of 14 days.

- Wiper contact should be a minimum of 2 inches above the desirable vegetation.

- Weeds should be 6 inches above the des irable vegetation.

- Applicators should be operated at a ground speed of no greater than 5 miles per hour.

- Better results may be made when two applications are made in opposite directions.

- Do not add a surfactant to the solution when using a wiper applica tor. oilseed crops (CG 20) 1 : Borage; c alendula; c astor oil plant; Chinese tallow tree; c rambe; c uphea; e chium; e uphorbia; e vening primrose; f lax seed; g old of pleasure; h are's ear mustard; j ojoba; l esquerella; lunaria; m eadowfoam; m ilkweed; m ustard seed; n iger seed; o il radish; p oppy seed; r apeseed (canola varieties) ; r ose hip; s afflower; s esame; s tokes aster; s unflower; s weet rocket; t allowwood; t ea oil plant;

v ernonia ; and cultivars, varieties, and/or hybrids of these.

preharvest harvest

- aid application; broadcast spray; ground and aerial application 1 Roundup

WeatherMAX® (EPA Reg. No. 524

- 537) Roundup Ultra ® (EPA Reg. No. 524

- 47 5) safflower

-

2.25 1 sunflower

- 0.77 1

cotton

- 1.55 1 all others

- 1.12 1 not indicated see “Use Directi on and Limitations” column 7 - Use sufficient water volume to ensure thorough coverage of foliage (3

- 40 GPA for ground and 3

- 15 GPA for aerial).

- If no harvest

- aid application is made, then the maximum seasonal application rate is 6.0 lbs

ae /acre. If a harvest

- aid application is made, then the following maximum seasonal application rates apply: safflower

- 4.50 lbs ae/acre (2.25 lbs ae/acre as harvest aid); sunflower

- 1.54 lbs ae/acre (0.77 lbs ae/acre as harvest aid); cotton

- 6.0 lbs ae/ acre (1.55 lbs ae/acre as harvest aid); and all others

- 2.62 lbs ae/acre (1.12 lbs ae/acre as harvest aid).
1 Preplant, at

- planting, pre

- e mergence, and post

- emergence (application to row middles) application are currently permitted for oilseed crops and harvest

- aid application to cotton, sunflower, and safflower are also currently permitted. The proposed use is to allow harvest

- aid applicat ion to all oilseed crops (CG 20; except Buffalo gourd). Since the difference for the proposed use and the registered use concerns only harvest

- aid application, only the application rate for harvest

- aid application are included in the table.Glyphosate Human

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### 3.4 Antic ipated Exposure Pathway

Based on the toxicological database, s hort

- / intermediate

- / long

- term dermal and inhalation risk
assessment s and acute dietary risk assessments are considered unnecessary (see Section 4.0 )

. Since dermal and inhalation endpoints were not selected, a quantitative occupational exposure assessment is unnecessary

. However, the proposed / registered agricultural and residential uses may result in chronic dietary (food and water) exposure and short

- /intermediate

- term incidental oral exposure

.

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.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 accord ing 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 NHANES/WWEIA and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and catego rized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances wa rrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further conside rations 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 specif ic subgroups.

It is noted that glyphosate is registered for direct application to water with fish (0.25 ppm) and shellfish (3.0 ppm) tolerances established ( 180.364(a)(1)). Although these tolerances were incorporated into the dietary exposure analysis

, t he employed consumption database does not consider consumption levels associated with subsistence fishing. Making the conservati ve assumption that an adult (60

- kg default body weight) will consume

, on a chronic basis

, 100 grams/day of fish and 100 grams/d ay of shellfish

, and assuming tolerance

- level residues , the resulting exposure occupies <1% of the cPAD. Therefore, HED concludes that exposure to glyphosate from subsistence fishing is less than HED’s LOC

.Glyphosate Human

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### 4.0

. Hazard Characterization and Dose

- Respo nse Assessment

4.1

. Toxicology Studies Available for Analysis

The hazard database for glyphosate is complete and is adequate for endpoint selection

. Since the last risk assessment, the neurotoxicity screening battery tests, and i mmunotoxicity study have been submitted, and are pending formal review. This hazard characterization also incorporates the modifications to the listing of the doses in the subchronic mouse and rat oral and rat dermal studies which were previously not documented corre ctly ( TXR # 0055772, Dykstra, W. et al., 22

- J an

- 1996 ).

4.2

. Absorption, Distribution, Metabolism, & Elimination (ADME)

In the rat metabolism study, absorption was estimated to be 30

- 36% in males and females following a single 10 mg/kg oral dose. Glypho sate was excreted unchanged in the feces and urine (97.5% minimum). Through the oral route the urine accounted for 31.2

- 33.4 % of the administered dose in males, and 24% of the administered dose in females. The feces accounted for 65.9

- 68.1% of the admini stered dose in males, and 75.1% of the administered dose in females. 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 seven d ays post dosing . Repeated dosing did not significantly alter absorption, metabolism, distribution, and excretion.

4.2.1

. Dermal Absorption

There is no dermal absorption study available for glyphosate.

4.3

. Toxicological Effects

Glyphosate is categor ized as having low acute toxicity following oral, dermal, and inhalation exposure, since all studies are in Toxicity Categor ies III or IV. It is a mild eye irritant (Toxicity Category III), slight skin irritant (Toxicity Category IV), and is not a dermal sensitizer.

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). A second chronic feeding/carcinogenicity study in rats tested at higher dietary levels, and a lowest

- observed

- adverse

- effect level (LOAEL) was identified at 20,000 parts per million (approximately 940 mg/kg/day) based on decreased body

weight gains 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 mice or rats. In a chronic toxicity study in dog s, no systemic effects were found in all examined parameters.

No significant reproductive and developmental toxic effects were found. On the basis of developmental studies in rats and rabbits and reproductive findings in rats, there was no evidence of increased susceptibility of offspring. Neurotoxicity has not been observed in any of the acute, subchronic, chronic, developmental, or reproductive studies performed with glyphosate.Glyphosate Human

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Page 13 of 28 

### Since the last risk assessment, the neurotoxicity sc reening battery tests, and i mmunotoxicity study have been submitted. Preliminary review shows no effects up to the highest dose tested for both the acute and subchronic durations for the neurotoxicity studies. The preliminary review of the immunotoxicity study also shows no effects of to the highest dose tested.

4.4. Safety Factor for Infants and Children (FQPA Safety Factor)

The RAB 1 risk assessment team recommends that the FQPA SF be reduced to 1 x . This

recommen dation is based on the c onsideratio ns described in the subsequent sections.

4.4 .1

. Completeness of the Toxicology Database

The toxicol ogy database for glyphosate is adequate for characterizing glyphosate toxicity and quantific ation of risk for dietary and occupational uses . The followi ng acceptable studies are available for evaluation: Developmental toxicity stud ies in rats and rabbits Two

- generation reproduction study in rats

4.4 .2

. Evidence of Neurotoxicity

There is no evidence of neurotoxicity in any of the toxicology studies con ducted.

4.4 .3

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

There is no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses
to in utero exposure in developmental studies. A focal tubular dilation of the kidneys was observed in a n older three

- generation reproductive study on rats at the 30

- mg/kg/day level [highest dose tested (HDT)], however a two

- generational reproductive study on rats d id not obse rve 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 lev el well below this effect.

4.4 .4

. Residual Uncertainty in the Exposure Database

The dietary exposure analysis is conservative as it assumed tolerance level residues and 100% crop treated. The residential exposure analysis is also considered conservative as it is based on the 2012 Residential SOPs.Glyphosate Human

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### 4.5. Toxicity Endpoint and Point of Departure Selections

A summary of the toxicological doses and endpoints for glyphosate used in human he alth risk assessment are summarized in table 4.5.4.

4.5.1

. 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 toxicologic al endpoint attributable to a single exposure (dose), including fetal 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 developmenta l toxicity study in rabbits was used to select the endpoint for establishing the chronic RfD (cRfD) of 1.75 mg/kg bw/day which was derived from a maternal NOAEL of 175 mg/kg/day and a 100

- fold factor that included a 10x

- UF for inter

species extrapolations , 10x

- UF for intra

- species variations, and a 1x FQPA SF . The maternal L OAEL was 350 mg/kg/day based on mortality, diarrhea, soft stools, and nasal discharge. 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

- term incidental oral endpoint. The maternal NOAEL was175 mg/kg/day based upon mortality, diarrhea, soft stools, and nasal discharge seen at the LOAEL of 350 mg/kg/day. The level of concern (LOC) is 100 based upon a 100

- fold factor that included a 10x

- UF for inter

- species extrapolations, 10x

- UF for intra

- species variations, and a 1x FQPA SF . 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 the offspring LOAEL of 1500 mg/kg/day (decreased body

- weight gain during lactation for both sexes).

Dermal Absorption: There is no dermal absorption study available for glyphosate. Furthermore

, a dermal absorption factor was not calculated due to lack of dermal toxicity as well as the absence of any developmental effects, or any other notable effects through the oral route.

Short

- , Intermediate

- a nd 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 relevan t to dermal endpoint selection.

Short

- , Intermediate

- and Long

- Term Inhalation: Short

- , intermediate

- and long

- term inhalation endpoints were not selected based on the absence of hazard in the 28

- day inhalation toxicity study in rats. Additionally, th ere were no developmental or reproductive toxicity concerns relevant to inhalation endpoint selection.Glyphosate Human

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### 4.5.2

. Recommendation for Combining Routes of Exposures for Risk Assessment

Based upon the common endpoints and common route of exposure, the chroni c dietary endpoint can be aggregated to the short

- and intermediate

- term incidental oral endpoints.

4.5.3

. Cancer Classification and Risk Assessment Recommendation

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 (October 1991, TXR# 0008898) . 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).

4.5.4

. Summary of P ODs and Toxicity Endpoints Used in Hum an Risk Assessment

Table 4. 5.4

. Summary of Toxicological Doses and Endpoints 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 population 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 inhalation risks is not required. Cancer (oral, dermal, inhalation) Classificatio n: Group E; no evidence of carcinogenicity; risk assessment not required.

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

observed adverse

- effect level, PAD = population

- adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of con cern, HDT = highest dose tested, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies)

.Glyphosate Human

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### 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

Table 5.1 is a summary of the conclusion made by HED concerning the residues of concern in primary crops, livestock, rotational crops, and drinking water.

Table 5.1

. Residues of Concern for Tolerance Expression and Risk Assessment.

Matrix Residues I ncluded in Risk Assessment Residues I ncluded in Tolerance Expression primary crops (excluding soybean and field corn) glyphosate glyphosate 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 not applicable



### Primary Crops: Metabolism studies conducted with non

- transgenic corn, cotton, soybeans, and wheat were previously submitted and reviewed. Based on these data, HED concluded that the residue of concern in non

- transgenic plants is glyphosate (Memo, R. Perfetti, 19

- Oct

- 199 2; RED, R. Perfetti, 27

- Oct

- 1992; Memo, R. Perfetti, 17

- Mar

- 1994). Metabolism studies have also been submitted on glyphosate

- tolerant canola (RT73; D242628, T. Bloem, 30

- Nov

- 1998) and glyphosate

- tolerant field corn (Roundup Ready ® 

### field corn; D217539, G. Kramer, 14

- Mar

- 1996). The glyphosate

- tolerant canola and field corn varieties were genetically modified to express the EPSPS gene derived from Agrobacterium sp. (strain CP4) which codes for an EPSPS protein that is not inhibited by glyphosate. The glyphosate

- tolerant canola and corn were also genetically engineered to express the oxireductase gene which converts glyphosate to the non

- herbicidal AMPA (aminomethyl phosphonic acid). Metabolism in these varieties of transgenic canola and

corn was essen tially the same as the non

- transgenic plants. Therefore, it was concluded that the terminal residue to be regulated, in non

- transgenic plants and transgenic corn and canola modified to express the Agrobacterium sp. EPSPS and oxireductase genes, is glyphos ate.

Subsequent to these decisions, HED approved DuPont requests permitting the commercialization of Optimum GAT soybean, Optimum GAT field corn , and Optimum ® 

### GLY Canola. These soybean, field corn, canola varieties were genetically engineered to expr ess the gat 4601 or gat 4621 genes ( derived from Bacillus licheniformis ; soil bacterium) which confer tolerance to glyphosate via conversion of parent to the non

- herbicidal N

- acetyl

- glyphosate. The Optimum GAT field corn was also engineered to express the zm

- hra gene (modified version of maize acetolactate synthase (ALS) gene) which 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 con cern in soybean, field corn, and canola for tolerance expression and risk assessment should change from glyphosate to the combined residues of glyphosate and N

- acetyl

- glyphosate (expressed in glyphosate equivalents; D346713, T. Bloem, 12

- Mar

- 2008; D357880, T. Bloem, 29

- Oct

- 2008; D361315, T. Bloem, 14

- Jan

- 2010; D394964, T. Bloem, 15

- Nov

- 2011).

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 HED Metabolism Assessment Review Committee ( MARC ) determined that theGlyphosate Human

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### 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 GAT 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 g oat 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

- glyphosat e, 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)

. Rotational Crops : A c onfined rotational crop stud y ha s been previously submitted/ reviewed which employed an application rate of 3.71 lb ae/acre and carrot, lettuce

, and barley as rotational crops (PBIs of 30, 119

- 125, and 364 days; MRIDs 415432

- 01 and

- 02, A. Abramovitch, 14

- Oct

1992)

. G lyphosate residues were <0.01 ppm in/on all rotational crops except for barley grain from the 125

- day PBI plot wh ich had a glyphosate residue of 0.018 ppm. Based on these data, HED concluded that residues in rotational crops will be insignificant provided the labels specify a 30

- day PBI for all nonlabeled crops ( D200041, G. Kramer, 12

- May

- 1994; field rotational crop study has not been submitted).

5.2 Food Residue Profile D39 8861 , T. Bloem, 14

- Nov

- 2012



### Magnitude of the Residue

- Proposed Primary Crops: Provided a revised Section B i s submitted, HED concludes that the proposal to update the commodity members for the following CGs to reflect current HED policy is acceptable and the tolerances from the old CGs may be translated to the new CGs: bulb vegetables CG 3

- 07; fruiting vegetabl es CG 8

- 09; citrus fruit CG 10

- 09; pome fruit CG 11

- 09; stone fruit CG 12

- 10; and berry CG 13

- 07. In addition, the petitioner prop osed the translation of the 100

- ppm cereal grain CG 16 (except field corn forage/stover) tolerance to teff forage and hay. B ased on similar morphological, cultural practices, taxonomical characteristics, and application scenarios for teff and the small grains, HED concludes that this translation is acceptable (Chemistry Science Advisory Council (ChemSAC); min_542.02

- May

- 2012)

. The petitioner is also proposing the expansion of the carrot and sweet potato application scenario to include

- over

- the

- top wiper application and submitted adequate carrot and sweet potato magnitude of the residue data depicting this application scenario. Based on these data and the Organization of Economic Cooperation and Development (OECD) tolerance calculation procedure, HED concludes that the carrot and sweet potato tolerances listed in Table 2.2.2 are appropriate. A revised Section F is requested.

Finally, the petitioner is proposing the establishment of an oilseed CG 20 tolerance (40 ppm; glyphosate only) and is proposing harvest

- aid application to all CG 20 crops. The representative crops for CG 20 are canola (subgroup 20A), sunflower (subgroup 20B), and cotton (subgroup 20C) with glyphosate tolerances established in/on the seeds of these crops as follows: canola seed

- 20 ppm (combined glyphosate and N

- acetyl

- glyphosate), sunflower/safflower seed

- 85 ppm (glyphosate only), and cotton seed

- 40 ppm (glyphosate only). Tolerances are alsoGlyphosate Human

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Page 18 of 28 

### established in/on several other CG 20 crops as follows: borage

- 0.1 ppm, crambe

- 0.1 ppm, flax

- 4.0 ppm, meadowfoam

- 0.1 ppm, mustard

- 0.1 ppm, safflower

- 85 ppm, and sesame

- 0.1 ppm. These tolerances r eflect preemergent and postemergent (row middles using shielded sprayers or wiper equipment) application for all as well as harvest

- aid application for sunflower (0.77 lb ae/acre), safflower (2.25 lb ae/acre), and cotton (1.55 lb ae/acre) and over

- the

- top application to canola and cotton (glyphosate

- tolerant varieties).

Based on reevaluation of the sunflower/safflower seed harvest

- aid data using the OECD tolerance calculation procedure and in order to maintain harmonization with the currently

established Canadian (canola seed) and Codex (cotton seed and canola seed) tolerances, HED concludes that the oilseed tolerances listed in Table 2.2.2 are appropriate.

Magnitude of the Residue

- Livestock : HED concludes that for the following reasons the proposal s associated with the current petition will not have a significant effect on the livestock dietary burdens and the currently

- established livestock tolerances remain appropriate: (1) the additional crops included in the updated CG definitions are not consi dered significant feed commodities; (2) the proposal to extend the harvest

- aid application scenario to all oil seed crops (CG20) will not have a significant effect on the livestock dietary burdens as harvest

- aid application to cotton, sunflower, and safflo wer is currently registered; and (3) the increase in the carrot (carbohydrate concentrate (CC)) tolerance to will not have a significant impact on the livestock dietary burdens as a 30

- ppm tolerance in/on the grain of several small grains (CC) is currently established.

Magnitude of the Residue

- Rotational Crops : HED previously concluded that a 30

- day PBI was appropriate for all non

- labeled crops (D200041, G. Kramer, 12

- May

- 1994 )

. Provided a revised Section B is submitted specifying a 30

- day PBI for al l non

- labeled crops following application to 13

- 07G crops (excluding cranberry), the proposed labels will conform with this requirement.Glyphosate Human

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### 5.3 Drinking Water Residue Profile D 398549 , J. Hetrick, 12

- Oct

- 201 2


### 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 ch emical 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. Based o n the low vapor pressure of glyphosate, volatilization 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, HE D concluded that glyphosate is the only residue of concern in drinking water.

Estimated Drinking Water Concentrations (EDWCs) : In support of the current assessment, EFED provided the following EDWCs for glyphosate ( D398549, J. Hetrick, 16

- Oct

- 2012):

s urface source water: daily peak

- 153.7 μg/L and annual average

- 8.11 μg/L; ground water concentrations are not expected to exceed 2.03 μg/L. The surface water estimates were generated using the index reservoir and the direct application to water applic ation scenario (3.75 lbs ae/acre) . The ground water estimate is based on monitoring data from the National Water

Quality Assessment Program (NAWQA ).

5.4 Dietary Risk Assessment D398863 , T. Bloem, 14

- Nov

- 20 1 2


### A chronic dietary risk assessment was conducted using DEEM

- FCID (ver. 3.16) which incorporates consumption data from USDA NHANES/WWEIA (2003

- 2008). Acute and cancer dietary risk assessments were not conducted since a n appropriate endpoint attributable to a single dose was not identified for the general U.S. population or any population subgroup and g lyphosate is classified as not likely to be a human carcinogen, respectively

. The chronic analysis assumed tolerance

- level residues , 100% crop treated, and DEEM (ver 7.81) default processing fact ors for all commodities

, and modeled drinking water estimates (direct application to water scenario)

. The resulting chronic risk estimates (food and water) were ≤13% cPAD and are not of concern to HED (children (1

- 2 years old) were the most highly exposed population). Table 5.4 is a summary of the chronic dietary exposure estimates.

Table 5.4

. Summary of Chronic Dietary Exposure and Risk. Population Subgroup cPAD (mg /kg/day) Exposure (mg/kg/day) %cPAD General U.S. Population

1.75 0.088331 5.0 All Infants (< 1 year old) 0.1 34620 7.7 Children 1

- 2 years old 0. 226241 13 Children 3

- 5 years old 0.210251 12 Children 6

- 12 years old 0.146472 8.4 Youth 13

- 19 years old 0.087318 5.0 Adults 20

- 49 years old 0.073213 4.2 Adults 50

- 99 years old 0.059852 3.4 Females 13

- 49 years old 0.067888 3.9
1 The bolded %cPAD represents the population with highest risk.Glyphosate Human

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### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization D398862, L

. Venkateshwara, 30

- Oct

- 2012



### The proposed use s are not anticipated to result in residential exposure. However, glyphosate is currently registered for application to turf (including golf courses and residential lawns) and for aquatic application

, and residential exposure may occur as a result of these uses. These uses have been reassessed in this document to reflect (1) the HED’s Residential Standard Operating Procedu res (SOPs; 2012) , (2) updates to HED’s inputs for aquatic/swimmer assessments, and (3) updated body weight information

. 6.1 Residential Handler Exposure

Based on the registered residential use patterns, there is a potential for short

- term dermal and i nhalation exposures to homeowners who mix and apply products containing glyphosate (residential handlers). However, since short

- and intermediate

- term dermal or inhalation endpoints were not selected, a quantitative exposure risk assessment was not comple ted.

6.2 Post

- Application Exposure

Post

- application dermal and inhalation assessments were not quantitatively assessed since short

and intermediate

- term dermal or inhalation endpoints were not selected. However, based on the registered use patterns, c hildren 1 to <2 years old may have short

- term post

- application incidental oral exposures from hand

- to

- mouth behavior on treated lawns and swimmers (adults and children 3 to <6 years old) may have short

- term post

- application incidental oral exposures from a quatic uses. Based on the soil half

- life for glyphosate, intermediate

- term soil ingestion was also considered for children 1<2 years old. It is noted that the lifestage s selected for risk assessment are considered protective for the exposures and risks f or any other potentially exposed lifestages.

Table 6.2.1 presents the post

- application incidental oral MOE values calculated for children 1 to <2 years old after applications of glyphosate to turf. Table 6.2.2 presents the post

- application incidental o ral ingestion MOE values calculated for adults and children 3 to <6 years old after aquatic applications of glyphosate. The p ost

- application MOEs are ≥1,100 and, therefore, do not exceed HED’s level of concern for any of the scenarios assessed.

The inci dental oral scenarios for the turf assessment (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 these scenarios would be overly

- conservative because of the conservative nature of each individual assessment. Therefore, none of the incidental oral scenarios were combined

.Glyphosate Human

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Page 21 of 28 Table 6 .2.1

. Post

- application Incidental Oral Risk Estimates for Application of Glyphosate to Turf

. Lifestage Post

- application Exposure Scenario Dose (mg/kg/day) Short

- term MOEs 4 Intermediate

- term MOEs 4

Children 1 to <2 year old Turf

- sprays Hand to Mouth 1 0.1565 1,100 NA Object to Mouth 2 0.00481 36,000 NA Incidental Soil Ingestion 3 3.4E

- 04 510,000

1 Hand

- to

- Mouth = Hand residue loading (mg/cm 2 )*fraction hand surface area mouthed/event (0.127/event)*typical surface area of one hand (150 cm 2 )*exposure time (1.5 hrs/day)*number of replenishment intervals/hr (4 intervals/hr)*(1

- (1

- saliva extraction factor (0.5)^number of hand

- to

- mouth contact events per hour (13.9 events/hr); Hand Residue L oading = fraction of ae on hands compared to total surface residue from dermal TC study (0.06)*dermal exposure (mg))/typical surface area of one hand (150 cm 2 ).
2 Object

- to

- Mouth = ((Object Residue (μg/cm 2 )*CF1 (1.0E

- 3 mg/μg)*Object Surface Area Mouthed /Event (10

cm 2 /event))*(Exposure Time (1.5 hrs/day)*#Replenishment Intervals/hr (4))*(1

- ((1

- Extraction by Saliva (0.48))^(#Object

- to

Mouth Events/hr (8.8 events/hr)/#Replenishment intervals/hr))))/Body Weight (11kg). 3 Soil Ingestion = (Soil Residue (7.0746975 μg/g) *Ingestion Rate (50 mg/kg/day) *CF(0.000001))/Body Weight (11 kg).
4 MOE = NOAEL/Daily Dose (mg ae kg/day); Oral NOAEL = 175 mg/kg/day. LOC is for MOEs <100

Table 6 .2.2

. Post

- Application Swimmer Risk Estimates for Aquatic Application of Glyphosate

.

Exposure Scenario Application Rate (lb ae /acre ) 1 Maximum Concentration

in water (mg/L) 2 Exposure(Dose); oral mg/kg bw/day) 3 Short

- term MOE 4 Ingestion of water,, Adult

- male 3.75 1.38 1.36E

- 03 129,000 Ingestion of water, Children 3 to <6 years old 1.06E

- 02 17,000

1 Application rate from registered labels for aquatic weed control using glyphosate IPA salt (ex. label = EPA Reg. No. 524

- 343; max rate = 7.5 pints/A containing 4 lb acid equivalent [ae ] glyphosate/gal. x 1 gal./4 pints = 3.75 lb ae/A.
2 Maximum concentration in water (top 1 ft.) = 3.75 lb ae/A x 1A/43,560 ft 2 x 454,000 mg/lb x 1/ft x ft 3 /28.32 L = 1.38 mg/L. 3 PDR, incidental oral exposure = concentration, C w (mg/L) x ingestion rate, IgR (L/hr) x exposure time, ET (hrs/d) x 1/BW (adult

- male=80 kg; children (3 to <6 years old ) = 19 kg)
4 MOE = NOAEL/PDR; short

- term incidental oral NOAEL = 175 mg/kg bw/d. LOC is for MOEs <100.



### 6.3 Residential Risk Estimates for Use in Aggregate Asses sment

Table 6. 3 reflects the residential risk estimates that are recommended for use in the aggregate

assessm ent for glyphosate

. The recommended residential exposure for use in the adult aggregate assessment reflects incidental oral exposures from post

- application exposure to treated aquatic

areas. The recommended short and intermediate

- term residential exposure for use in the ch ildren 1 to <2 years old aggregate assessment reflects incidental oral exposures from post

- application exposure to outdoor treated turf.

Table 6

. 3

. Recommendations for the Residential Exposures for the Glyphosate Aggregate Assessment. 1
Lifestage Post

- application Exposure (mg/kg/day) 2 Residential Post

- application Total Exposure (mg/kg/day) Residential Post

application MOE 3 Dermal Inhalation Oral short

- term adult male not applicable 0.00136 0.00136 129,000 children 1

- 2 years old 0.1565 0.1565 1,100 intermediate term adult male not applicable not applicable children 1

- 2 years old 0.00034 0.00034 510,000
1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.
2 Post

- application exposure represents high

- end incidental oral exposure for the relevant exposure duration.
3 Residential Post

- application MOE = Incidental oral NOAEL / Residential Post

- application total exposure

.Glyphosate Human

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Page 22 of 28 

### 6.4 Spray Drift and Residential Bystander Post

- applicat ion Inhalation Exposure

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 m itigation 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 risk estimates associated with drift.

6.5 Residential Bystander Post

- Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for glyphosate at this time primarily because there is no inhalation POD . However, volatilization of pesticides may b e a source of po st

- 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 (FIFRA) Scientific Ad visory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The 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 p rocedures are developed and/or an inhalation POD is selected for glyphosate , the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for glyphosate

.Glyphosate Human

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### 7

. 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

- and intermediate

term (food, water, residential incidental oral) and chronic (food and water) aggregate risk
assessments. Acute and cancer aggregate risk assessments were not conducted since a n appropriate endpoint attributable to a single dose was not i dentified for the general U.S. population or any population subgroup and g lyphosate is classified as not likely to be a human carcinogen, respectively

.
Short

- Term Aggregate Risk Assessment: Based on the proposed/registered uses, HED anticipates short

- t erm residential exposure to young children ( swimmer and turf incidental oral ingestion) and adults (swimmer incidental oral ingestion ). T he 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 includ es chronic dietary exposure (food and water) and incidental oral ingestion exposure resulting from the aquatic use (highest exposure of all possible scenarios). Table 7

. 0 .1 is a summary of the short

- term aggregate exposures and risk estimates. Since the aggregate MOEs are ≥ 45 0 , short

- term aggregate exposure to glyphosate does not exceed HED's LOC. HED notes that the lifestage s selected for short

- term aggregate risk assessment are considered protective for the exposures and risks for any other potentially exposed lifestage.

Table 7.0 .1

. Short

- Term Aggregate Exposure

.

Population Exposure (mg/kg/day) Aggregate MOE 2 Dietary 1 Incidental Oral 1 Combined General U.S. pop ulation 0.088331 0.00136 0.089691 2000 Children 1

- 2 years old 0.226241 0.1565 0.382741 450
1 See Table 5.4 (dietary) and Table 6.3 (incidental oral).
3 A ggregate MOE = 175 mg/kg/day (short

- term incidental oral NOAEL) combined exposure (mg/kg/day )

. 

### Intermediate

- Term Aggregate Risk Assessment: Based on the proposed/registered uses, HED anticipates intermediate

- term residential exposure to only young children (turf incidental oral ingestion).

The intermediate

- term aggregate assessment includes chronic dietary (food and water) and incidental or al ingestion exposure resulting from the turf use (highest exposure of all possible scenarios). Table 7.0.2 is a summary of the intermediate

- term aggregate exposures and risk estimates. Since the aggregate MOE is 770, intermediate

- term aggregate exposure to glyphosate does not exceed HED's LOC. HED notes that the lifestage selected for intermediate

- term aggregate risk assessment is considered protective for the exposure and risk for any other potentially exposed lifestage.

Tabl e 7.0.2

. Intermediate

- Term Aggregate Exposure

.

Population Exposure (mg/kg/day) Aggregate. MOE 2 Dietary 1 Incidental Oral 1 Combined Children 1

- 2 years old 0.226241 0.00034 0.22658 770
1 See Table 5.4 (dietary) and Table 6.3 (incidental oral).
2 A ggregate MOE = 175 mg/kg/day (short

- term incidental oral NOAEL) combined exposure (mg/kg/day )

.Glyphosate Human

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Page 24 of 28 

### 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 ( ≤1 3 % cPAD ; see Section 5. 4 ).

8 .0 Cumulative Exposure/Risk Characterizat ion
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 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 not assumed that glyphosate has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determ ine 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 cumulat ing effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9 .0 Occupational Exposure/Risk Characterization

Based on the proposed uses, there is the potential for occupational handler and p ost

- application dermal and inhalation exposure; however, no dermal or inhalation PODs were selected for glyphosate. Therefore, a quantitative occupational exposure assessment was not conducted.

10.0 References

CPRC memorandum

- October 1991, TXR# 0008898 Residue chemistry summary memorandum

- D394964, T. Bloem, 14

- Nov

- 2012 EDWCs

- D398549, J. Hetrick, 12

- Oct

- 2012 Dietary exposure memorandum

- D398863, T. Bloem, 14

- Nov

- 2012 Occupational/residential exposure memorandum

- D398862, L. Venkateshwara, 30

- Oct

- 2012 Most recent human

- health risk assessment

- D387535, T. Bloem, 29

- Nov

- 2011

Attachment 1: Chemical Names and Structures

. Attachment 2: Toxicity Profile Tables

.

RDI: RAB1 review ( 14

- Nov

- 20 1 2 ) T. Bloem:S10945:PY1:(703)

- 605

- 0217(7509P)Glyphosate Human

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Page 25 of 28 

### Attachment 1: Chemical Names and Structures

.

C ompound S tructure Glyphosate

N

- (phosphonomethyl)glycine

N

- Acetyl

- glyphosate

N

- acetyl

- N

- (phosphonomethyl)glycine

AMPA

(aminomethyl)phosphonic acid

N

- Acetyl

- AMPA

[(acetylamino)methyl]phosphonic acid P O

O H O H N O H O O

C H 3Glyphosate Human

- Health Risk Assessment D 398547

Page 26 of 28 

### Attachment 2: Toxicity Profile Tables

.

Acute Toxicity Profile

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

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

870.1200 Acute dermal [rabbit] 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 [rabbit] 41400603 Corneal opacity or irritation clearing in 7 days or less III

870.2500 Acute dermal irritation [rabbit] 41400604 Mild or slight irritant IV

870.2600 Skin sensitization [guinea pig] 41642307 Not a sensitizer None

Subchronic, Chronic , and Other Toxicity Profile

.

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

870.3100 90

- Day Oral Toxicity

(Mice) 00036803 (1979)

Acceptable/guideline 0, 5000, 10000, 50000 ppm (0, 944/ 1530, 1870/ 2740, 9710/ 14800 mg/kg/day [M/F]) NOAEL = 1870/2740 mg/kg/day [M/F] LOAEL = 9710/14800 mg/kg/day [M/F] based on decreased body weight.

870.3100 90

- Day oral toxicity

range finding (Rat) 40559401 (1987)

Acceptable/guideline 0, 1000, 5000, 20000 ppm (0, 63, 317, 1267 mg/kg/day) NOAEL = 1267 mg/kg/day LOAEL = not established.

870.3150 90

- Day oral toxicity

(Rat)

- Aminomethyl phosphoric acid

- glyphosate plant metabolite 00241351 (1979)

Acceptable/guideline 0, 400, 1200, 4800 mg/kg/day [M/F] NOAEL = 400 mg/kg/day [M/F] LOAEL = 1200 mg/kg/day [M/F] based on body

weight loss and histopathological lesions of the urinary bladder.

870.3200 21

- Day dermal toxicity

(Rat) 00098460 (1982)

Acceptable/guideline 0, 100, 1000, 5000 mg/kg/day 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.

870.3465 28

- Day inhalation

toxicity (rat) 00137704 (1983)

Acceptable/ guideline 0, 0.05, 0.16, 0.36 mg/L NOAEL = 0.36 mg/L (HDT) LOAEL not established based on 6 hours/day, 5 days/week for 4 weeks

870.3700 a Prenatal

developmental in rodents (Rat) 00046362 (1980)

Acceptable/guideline 0, 1000, 3500 mg/kg/day 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) 00046363 (1980)

Acceptable/guideline 0, 175, 350 mg/kg/day 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.

870.3800 Reproduction and

fertility effects, 3

- generation (Rat) 00105995 (1981)

Acceptable/guideline 0, 10, 30 mg/kg/day 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.Glyphosate Human

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Page 27 of 28 Subchronic, Chronic , and Other Toxicity Profile

.

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

870.3800 Reproduction and

fertility effects, two

generation (Rat) 41621501 (1990)

Acceptable/guideline 0, 2000, 10,000 or 30,000 ppm (0, 250, 500 and 1500 mg/kg/day) 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 females LOAEL = 1500 mg/kg/day in males and females based on decreased body

- weight gain during lactation.

870.4100a Chronic toxicity (dog) 00153374 (1985 ) Acceptable/guideline 0, 20, 100, and 500 mg/kg/day [M/F] NOAEL = 500 mg/kg/day [M/F] LOAEL = not established.

870.4200 Combined Chronic

Toxicity/Carcinogenici ty (rat) 41643801, 41728701 (1990 )

Acceptable/guideline 0, 2000, 8000, 20000 ppm 0, 362/447, 940/1183 mg/kg/day [M/F] NOAEL = 362/447 mg/kg/day [M/F] LOAEL = 940/1183 mg/kg/day[M/F] based on decreased body

- weight gain in females, decreased urinary pH in males, increased incidence of cataracts and lens abnormalities in males, and increased absolute and relative (to brain) liver weight in males. No evidence of carcinogenicity

870.4300 Carcinogenicity

(mouse) 41643801, 41728701 (1990 )

Acceptable/guideline 0, 1000, 5000, 30000 ppm 0, 150, 750, 4500 mg/kg/day [M/F] NOAEL = 75 0 mg/kg/day [M/F] LOAEL = 450 0 mg/kg/day [M/F] based on significant decreased body

- weight gain in both sexes, hepatocyte necrosis and interstitial nephritis in males, and increased incidence of proximal tubule epithelial basophilia and hypertrophy in the kidney of females. No evidence of carcinogenici ty

870.5265 Gene Mutation 00078620 (1978) Acceptable/ guideline Non

- mutagenic when tested up to 1000 ug/plate, in presence and absence of activation in S . typhimurium strains TA98, TA100, TA1535 and TA1537.

870.5300 Cytogenetics 00132683 (1983) Acceptable/ guideline 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.

870.5385 In Vivo Cytogenetics

-

Bone Marrow 00251737 (1983 )

Acceptable/guideline 0, 2000, 8000, 20000 ppm 0, 362/447, 940/1183 mg/kg/day [M/F] 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 00078619 (1978)

Acceptable/guideline 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.

870.6200a Acute neurotoxicity

screening battery 44320610 (1996)

Classification: Pending 0, 500, 1000, 2000 mg/kg [M/F] Preliminary NOAEL = 2000 mg/kg/day [M/F] Preliminary LOAEL was not observed.

870.6200b Subchronic

neurotoxicity screening battery 44320612 (1996)

Classification: Pending 0, 2000, 8000, 20000 ppm (0, 155.5/ 166.3, 617.1/ 672.1, 1546.5/ 1630.6 mg/kg/day [M/F]) Preliminary NOAEL = 1546.5/1630.6 mg/kg/day [M/F] Preliminary LOAEL was not observed.Glyphosate Human

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Page 28 of 28 Subchronic, Chronic , and Other Toxicity Profile

.

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

870.7485 Metabolism and

pharmacokinetics (rat) 40767101,40767102 (1988)

Acceptable/guideline 10 mg/kg 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 than 1% of the absorbed dose remained in the carcass, primarily bone. Repeat dosing did not alter metabolism, distribution, and exc retion.

870.7800 Immunotoxicity 48934207 (2012) Classification: Pending 0, 500, 1500, 5000 ppm (0, 150, 499, 1448 mg/kg/day [F]) Preliminary NOAEL = 1448 mg/kg/day Preliminary LOAEL was not observed.