Glyphosate Human-Health Risk Assessment D372052

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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. 

PC 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). 
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Table of Contents 

1.0 EXECUTIVE SUMMARY 3

2.0 INGREDIENT PROFILE 9

2.1 SUMMARY OF REGISTERED/PROPOSED USES 9

2.2 STRUCTURE AND NOMENCLATURE 10

3.0 HAZARD CHARACTERIZATION 11

3.1 HAZARD PROFILE 11

3.2 FQPA CONSIDERATIONS 13

3.3 ENDOCRINE DISRUPTION 13

3.4 DOSE-RESPONSE ASSESSMENT 14

3.5 RECOMMENDATION FOR AGGREGATE EXPOSURE RISK ASSESSMENTS 15

4.0. DIETARY EXPOSURE/RISK CHARACTERIZATION 16

4.1 METABOLISM IN PRIMARY CROPS, LIVESTOCK, AND ROTATIONAL CROPS 16

4.2 ANALYTICAL METHODOLOGY 17

4.3 DRINKING WATER RESIDUE PROFILE 18

4.4 FOOD RESIDUE PROFILE 18

4.5 INTERNATIONAL RESIDUE LIMITS AND HED-RECOMMENDED TOLERANCES 19

4.6 DIETARY EXPOSURE AND RISK 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 TOXICOLOGY 24

9.2 RESIDUE CHEMISTRY 24

9.3 OCCUPATIONAL AND RESIDENTIAL EXPOSURE 24

ATTACHMENT 1: CHEMICAL NAMES AND STRUCTURES. 25

ATTACHMENT 2: TOXICITY PROFILE. 26
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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, group 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 cry3Bb1 gene from Bacillus thuringiensis (controls corn root worm and other 

Coleopteran species), 5-enolpyruvylshikimate-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 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 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, 
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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 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. 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 the 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 (UFDB) 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 [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 data 
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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 UFDB 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 intermediate-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 endpoints 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 toddlers 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-
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FCIDTM, 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 commodities 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 children (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. 
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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 dietary 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 toddlers, youths, and adults entering or playing on 

treated areas postapplication are evaluated. Further considerations are currently in development 

as OPP has committed resources and expertise to the development of specialized software and 

models that consider exposure to bystanders and farm workers as well as lifestyle and traditional 

dietary patterns among specific subgroups. 

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. 
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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 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 Nacetyl-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)
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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 variety 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 potassium 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 plants 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. 
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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 Glyphosate (PC code 471300)

Company experimental name DPX-B2856

IUPAC/CAS name N-(phosphonomethyl)glycine

CAS registry number 1071-83-6 

Table 2.2.2: Physicochemical Properties of Technical Grade Glyphosate.

Melting point 189.5 ± 0.5 °C 

pH 1.9 at 20 °C 

Density 1.705 g/cm3 at 20 °C 

Water solubility 10.5 g/L at 20 °C 

The Pesticide Manual, 13th 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, 13th Edition 

Dissociation constant, pKa

0.8 (1st phosphoric), 2.3 (carboxylate), 

6.0 (2nd phosphoric), and 11.0 (amine)

Knuuttila. 1979 Acta Chem. Scand. B 

33:623-626 

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

UV/visible absorption spectrum ε = 0.086 (295nm) 

European Commission: Glyphosate 

6511/VI/99-final, 1/21/02 
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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 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 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 dilation 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 fetal 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 not 
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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 the 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 alter 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 based 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 LD50 was greater than 5000 mg/kg in rats. Based on 

structural similarity with glyphosate, structure-activity 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

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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 UFDB 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 adverse 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 UFDB 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 proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

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

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

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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 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 developmental toxicity study in rabbits was used to select the 

endpoint for establishing the chronic RfD (cRfD) 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-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 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-term 
Glyphosate Human-Health Risk Assessment D372052

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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 Endpoints for Glyphosate for Use in Human-Health Risk 

Assessments1

. 

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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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) Classification: Group E; no evidence of carcinogenicity; risk assessment not required. 

1

 UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no-observed adverse-effect level, 

LOAEL = lowest-observed adverse-effect level, PAD = population-adjusted dose (a = acute, c = chronic) RfD = 

reference dose, MOE = margin of exposure, LOC = level of concern, 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. 
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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 Tolerance Expression and Risk Assessment.

Matrix Residues Included in Risk Assessment Residues Included 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 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 (D242628, 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 genetically 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 DuPont requests permitting the commercialization of 

OptimumTM GATTM soybean and OptimumTM GATTM field corn (D346713, T. Bloem, 12-Mar2008; D357880, T. Bloem, 29-Oct-2008; D361315, T. Bloem, 14-Jan-2010). OptimumTM

GATTM soybean was engineered to express the gat4601 gene (derived from Bacillus 

licheniformis; soil bacterium) and OptimumTM GATTM 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 gat4601 and the gat4621 

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 OptimumTM

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

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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 OptimumTM GATTM 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 in 

glyphosate 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 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 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 adequately 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, 
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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 CO2, although at a slower rate than parent glyphosate. 

Based on 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, 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 glyphosate 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 (SCIGROW)). 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 different application scenarios with highest maximum 

and mean residues attained under the application scenario performed in MRID 47589202; 
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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 field 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 expression 

should be changed with the tolerance value remaining the same (D346713, T. Bloem 12-Mar2008; D357880, T. Bloem, 29-Oct-2008). Therefore, 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 confined 

rotational 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 Tolerances 
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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-FCIDTM (ver. 2.03) which 

incorporates consumption data from USDA 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 DEEMTM (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. Population 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 3.9 
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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 intermediate-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 endpoints 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-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; 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.
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Table 5.0.1: Exposure Potential for Adult and Child Short-term Aggregate Risk Estimates1.

Exposure Scenario Exposure 

(mg/kg/day) MOE 

Combined 

Exposure 

(mg/kg/day)2 

Combined 

MOE3 

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 Toddler – 6 

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) = DoseHand-to-mouth + Dosesoil ingestion + DoseObject-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

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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 children (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 since 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 Dietary1 Incidental Oral2 Combined Aggregate. MOE3

General U.S. population 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 (short-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

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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 Section 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

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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

2

NH

N-Acetyl-AMPA 

[(acetylamino)methyl]phosphonic acid P

O

OH

OH

N

H

3

CH

O

P

O

N

O

H3C O

O

OH

HO H
Glyphosate Human-Health Risk Assessment D372052

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Attachment 2: Toxicity Profile. 

Acute Toxicity Profile: Test Substance 

Guideline No. Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral 41400601 LD50 > 5,000 mg/kg IV 

870.1200 Acute dermal 41400602 LD50 > 5,000 mg/kg IV 

870.1300 Acute inhalation None 

The requirement for an acute 

inhalation LC50 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) 

Maternal NOAEL = 175 mg/kg/day 

LOAEL = 350 mg/kg/day based on based on mortality, diarrhea, soft stools, and 

nasal discharge. 

Developmental NOAEL = 350 mg/kg/day (HDT) 

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

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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 females 

LOAEL = 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, 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 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, 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

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 than 1% of the absorbed dose remained 

in the carcass, primarily bone. Repeat dosing did not alter metabolism, 

distribution, and excretion.