EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: James A. Tompkins 703

- 305

- 5697

Monsanto Company

PP

- 0F7741

EPA has received a pesticide petition ( PP

- 0F7741 ) from Monsanto Company

, 1300 I St., NW., Suite 450 East, Washington DC 20052 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. 364 by establishing a tolerance for residues of glyphosate N

- (phosphonomethyl) glycine in or on the raw agricultural commodity corn, field , forage at 13 parts per million (ppm) to support the use of glyphosate in RHS seed corn production

. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted d a ta at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The qualitative nature of glyphosate residues in plants and
livestock is adequately u nderstood . The terminal residue to be regulated in nontransgenic plants and transgenic crops modified to express the Agrobacterium sp. EPSPS and oxireductase genes is glyphosate per se . For crops (currently soybeans and corn) that
have a t ransgenic variety engineered to express the microbial glyphosate acetyltransferase gene ( gat 4601), the combined residues to be regulated are glyphosate and N

- acetyl

glyphosate. The qualitative nature of the glyphosate residue will not be changed as a

resu lt of the proposed tolerance changes. Glyphosate herbicides are not applied directly to livestock, so the only potential exposure is via glyphosate residues in their diet. O n December 3, 2008

, EPA published a final rule (EPA

- HQ

- OPP

- 2007

- 0147; FRL

- 8385

- 7) amending section 180.364 to reflect that the terminal residue to be regulated in livestock ( and in soybean commodities and grain aspirated fractions) is glyphosate and its
metabolite N

- acetyl

- glyphosate

, expressed as glyphosate

.

2. Analytical method. Adequate enforcement methods are available for analysis of residues of glyphosate and its metabolite AMPA in or on plant and livestock
commodities. These methods include gas liquid chromatography (GLC)

, Method I in Pesticides Analytical Manual (PAM) II ( 0.05 ppm limit of detection)

, and High Performance Liquid Chromatography (HPLC) with fluorometric detection (0.0005 ppm limit of detection) . Use of the GLC method is discouraged due t o the lengthiness of the experimental procedure. The HPLC procedure has undergone successful Agency validation and was recommended for inclusion in PAM II. A gas chromatography/mass spectrometry (GC/MS) method for glyphosate in crops has also been validat ed by EPA’s2

Analytical Chemistry Laboratory (ACL). Thus, adequate analytical methods are available for residue data collection and enforcement of the proposed tolerance s for glyphosate.

3. Magnitude of residues. R esidue data submitted with this petition support the proposed tolerances for the agricultural commodities corn, field , forage at 13 ppm , to support the use of glyphosate in RHS seed corn production

. A ny secondary residues occurring in livestock commodities will be co vered by existing tolerances

.

B. Toxicological Profile The existing toxicity database for glyphosate i s complete , with the exception of an immunotoxicity study , which only recently became a requirement for pesticides under 40 CFR Part 158 (see section 9 following ) . There is high confidence in the quality of the existing studies and the reliability of the toxicity endpoints identified for use in risk

assessment. EPA has considered available information regarding the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.

1. Acute toxicity. T he nature of the acute toxic effects caused by glyphosate has been evaluated by the Agency

. Glyphosate is of low acute toxicity by oral, dermal, and
ocular routes of exposure, as all studies are in Toxicity Category III or IV. Acute oral toxicity of glyphosate in the rat and dermal toxicity in the rabbit are both greater than 5000 mg/kg (Toxicity Category IV) and any corneal opacity or irritation caused by glyphosate is temporary an d clears up in 7 or less days (Toxicity Category III)

. G lyphosate is a mild skin irritant (Toxicity Category IV) and is not a dermal sensitizer. The acute inhalation study for glyphosate was waived due to glyphosate being a
nonvolatile solid

. An acute dietary endpoint for use in hum an health risk assessments was not selected for the general population, since an appropriate endpoint attributable to a single exposure was not identified in the toxicology data base.

Table 1 Acute Toxicity Profile

- Test Substance

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

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

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

870.1300 Acute inhalation None The requirement for an
acute inhalation LC 50 study was waived None

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

870.2500 Acute dermal irritation 41400604 Mild or slight irritant IV3

Table 1 Acute Toxicity Profile

- Test Substance

870.2600 Skin sensitization 00137138 Not a sensitizer None

]

2. Genotoxic i ty. In vitro and in vivo genotoxicity studies have been conducted with g lyphosate

. S hort term assay s for genotoxicity consisting of a bacterial reverse mutation assay (Ames test), an in vitro assay for cytogenetic damage using Chinese hamster ovary cells, and in vivo cytogenic assay in rat bone marrow have been conducted on glyphosate. These studies all show a lack of genotoxicity

.

Table 2 Genotoxicity Profile

Guideline No./ Study Type Results

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 evide nce 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.

]
3. Reproductive and developmental toxicity. Developmental studies in rats and rabbits were conducted with glyphosate. In rabbits, a maternal NOAEL of 175 mg/kg/day was determined based on mortality, diarrhea, and nasal discharge at the LOAEL of 350 mg/kg/day. This was the lowest NOAEL of all major studies. The developmental NOAEL was 350 mg/kg/day (HDT)

.

In rats, developmental effects of unossified sternebrae and decreased fetal body weight
were observed at a LOAEL of 3500 mg/kg/day (HDT) which was also the LOAEL for maternal toxicity. The maternal NOAEL was 1

, 000 mg/kg/day based on mortality, decreased body weight gain, inactivity, red matting on nose, mouth, forelimbs, and head, decrease in total implantations/dam a nd nonviable fetuses/dam. The developmental
NOAEL in rats was 1000 mg/kg/day.4

No reproductive effects were observed in the multigeneration study and i n the 2

- generation rat reproduction study, the offspring and parental NOAELs were 500 mg/kg/day based on decreased pup body weight during lactation (offspring) and soft stools, decreased body weight and food consumption (parents) at the LOAEL of 1500 mg/kg/day. The reproductive NOAEL was greater than or equal to 1500 mg/kg/day (HDT).

In developmental st udies in rats and rabbits and reproductive findings in rates, developmental effects were only observed at materna lly toxic doses. There was no evidence of any increased susceptibility of the young to the effects of glyphosate in developmental and reproduc tive toxicity studies in rats or rabbits.

A developmental neurotoxicity study was not required.

Table 3 Reproductive and Developmental T oxicity P rofile

Guideline No./ Study Type Results

870.3700a Prenatal developmental in rodents (Rat) Maternal NOAEL = 1000 mg/kg/day LOAEL = 3500 mg/kg/day based on reduced activity, mortality, and reduced body weight gain.

Developmental NOAEL = 1000 mg/kg/day LOAEL = 3500 mg/kg/day based on increased incidence in the
number of fetuses and litters with unossified sternebrae and decreased fetal body weight.

870.3700b Prenatal developmental in (Rabbit) Materna l NOAEL = 175 mg/kg/day LOAEL = 350 mg/kg/day (HDT) 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,
2

- generation (Rat) Parental/Systemic NOAEL = 500 mg/kg/day in males and females LOAEL = 1500 mg/kg/day (HDT) in males and females based on soft stools, decreased body weight gain and f ood consumption.

Reproductive NOAEL 1500 mg/kg/day (HDT) in males and
females

Offspring NOAEL = 500 mg/kg/day (HDT) in males and females LOAEL = 1500 mg/kg/day in males and females based on decreased body weight gain during lactation.

]
4. Subchronic toxicity. In rodent feeding studies, g lyphosate showed a NO A EL of
500 mg/kg/day in a 90

- day mouse study and 1445 mg/kg/day (HDT) in a 90

- day rat study. In a 21/28

- day rabbit dermal toxicity study the NOAEL was 1000 mg/kg/day and5

the LOAEL was 5000 mg/kg /day based on slight erythema and edema on intact and
abraded skin of both sexes.

Table 4 Subchronic Toxicity Profile

Guideline No./ Study Type Results

870.3100
90

- Day oral toxicity (Mouse) NOAEL = 500 mg/kg/day in males and females
LOAEL = 2 500 mg/kg/day (HDT) in males and females based on decreased body weight gains

.

870.3100
90

- Day oral toxicity (Ra t ) NOAEL = 1445 mg/kg/day (HDT)
LOAEL = not established

870.3200
21/28

- Day dermal toxicity (Rabbit) NOAEL = 1000 mg/kg/day in males and females
LO AEL = 5000 mg/kg/day based on slight erythema and edema on
intact and abraded skin of both sexes.

]
5. Chronic toxicity. A chronic toxicity study in dogs showed no systemic effects found for all examined parameters in males and females at the highest dose tested, 500 mg/kg/day . Chronic feeding/carcinogenicity studies have been conducted in rodents with glyphosate and results show no evidence of carcinogenicity in mice or rats

. In the mouse, a NOAEL of 750 mg/kg/day in males and females was established based on significant decreased body weight gain in both sexes and hepatocyte necrosis in males at the LOAEL of 4500 mg/kg/day. In the rat, a NOAEL of 362 mg/kg/day in males and 447 mg/kg/day
in females based on decrea sed body weight gain in females and increased incidence of cataracts and lens abnormalities in males at te LOAEL of 940 mg/kg/day in males and 1183 mg/kg/day in females. Glyphosate has been classified as “a Group E” carcinogen

— no evidence of carcinogenic ity to humans

— based on the absence of carcinogenicity in mice and rats.

Table 5 Chronic Toxicity Profile

Guideline No./ Study Type Results

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 and hepatocyte necrosis in females. No evidence of carcinogenicity6

Table 5 Chronic Toxicity Profile

Guideline No./ Study Type Results

870.43 00
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, increased
incidence of cataracts and lens abnormalities in males. No evidence of carcinogenicity

]
6. Animal metabolism. In the rat metabolism study, absorption was estimated to
be 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 small amounts of AMPA. Less than 1% of the absorbed dose remained in the carcass, primarily the bone. Repeated dosing did not alter metabolism, distribution, and excretion

.

7. Metabolite toxicology

. The residue of concern for risk assessment purposes is glyphosate per se . The metabolite AMPA is not included in either the tolerance expression or the risk assessment. In a meeting of the HED Metabolism Committee held 8/19/92, the Committee determined t hat, based on toxicological considerations, AMPA need not be regulated and should be dropped from the tolerance expression (Memo, R. Perfetti, 10/10/92). Furthermore, in a meeting of the HED Metabolism Committee held 3/17/94, the Committee discussed wheth er 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 consi derations, AMPA need not be regulated regardless of levels observed in foods or feeds (Memo, R. Perfetti, 3/17/94)

.

8. Endocrine disruption

. EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone syste m. EPA also adopted EDSTAC’s recommendation that the Program also include evaluations of potential
effects in wildlife.

Glyphosate is on the EPA list of the initial 67 pesticide active ingredients and pesticide inert high production volume chemicals to be screened under the first phase of EPA’s Endocrine Disruption Screening Program (EDSP). This is not a list of “endocrine disruptors” or “potential endocrine disruptors ; ” it is simply a list of chemicals to be the first to go through EPA’s evaluation process. The process that EPA used to prioritize substances for screening did not include a determination of potential endocr ine activity of7

any of the substances , but rather the potential for exposure. Glyphosate

, a widely

- used herbicide with multiple uses

, was included on this list of initial active ingredients to be
tested because it met the exposure criteria

. Test orders were issued for glyphosate in January of 2010

, with a final submission due date of January 14, 2012

.

Glyphosate has undergone extensive testing, including a battery of acute, sub

- chronic,
and chronic tests

, and a number of developmental and reproductive studies, mammalian and wildlife, capable of detecting effects on endocrine mediated events. The results from these studies, along with other scientifically relevant information, provide reliable and functionally equivalent information to the Tier 1 screen ing assays and demonstrate that glyphosate is not an endocrine active substance.

9. Immunotoxicity

. EPA recently instituted a new data requirement for an immunotoxicity study under 40 CFR Part 158 for all food and non

- food use pesticides

. T he Agency does not currently have such a study for glyphosate. This data gap was
identified in the Human

- Health Assessment Scoping Document in Support of Registration Review for glyphosate which began in June 2009, not because of any concern that glyphosa te may be a toxicant to the immune system, but because of the new data requirement. A task force of glyphosate technical registrants in the U.S. is being
assembled to address this issue under the Registration Review process

. However, in lieu of any new d ata, the available glyphosate studies already provide a reasonable certainty that glyphosate is not immunotoxic.

C. Aggregate Exposure Aggregate exposure for glyphosate is the combination of chronic dietary exposure (food

+ drinking water) and short

- and intermediat e

- term non

- dietary oral exposure from residential (home lawn care) and recreational (golf, swimming) use exposure.

1. Dietary exposure. Tolerances have been established (40CFR 180.364) for the residues of glyphosate N

- (phosphonomethyl) g lycine resulting from the application of glyphosate, the isopr o pylamine salt of glyphosate, the ethanolamine salt of glyphosate, the dimethylamine salt of glyphosate, the ammonium salt of glyphosate, and the potassium salt of glyphosate in or on a variety of raw agricultural commodities , including meat and meat by

- products

. The dietary

- exposure database is adequate to support the existing registrations

. C hronic dietary risk

assessment s incorporate concentration estimates from the direc t application of glyphosate

to water

, which represents a worst

- case scenario

, as the drinking water component of the

assessment

.

The petitioner proposes to establish a tolerance for corn, field , forage at 13 ppm. The proposed tolerance revision is not expected to increase the dietary burden for livestock ; the existing tolerances for livestock commodities are sufficient. ]

i. Food. No toxicological endpoint attributable to a single does of glyphosate has
been identified ; therefore, a quantitative acute dietary exposure assessment is not

necessary.8

A dietary risk assessment was conducted by Monsanto using the Dietary Exposure Evaluation Model software ( DEEM

- FCIDTM ), Version 2. 16 , which incorporates food consumption data from the United States Department of Agriculture ( USDA ) 1994

- 1996
and 1998 Nationwide Continuing Surveys of Food Intakes by Individuals (CSFII). A conservative estimate of dietary exposure (Tier 1) was performed with the assumptions
that 100% of crop s with approved and proposed uses of glyphosate would be treated and that glyphosate residues would be present in each raw agricultural commodity at the
tolerance level

. Under these conservative assumptions and based on a chronic population adjusted dose (c PAD) for glyphosate of 1.75 mg/kg/day, t he chronic dietary exposure
estimates to glyphosate from food and drinking water is 5 % of the cPAD for the general U.S. population . The chronic dietary exposure estimate for the most highly exposed subpopulation ( ch ildren 1

- 2 years old ) is 12 % of the cPAD.

Glyphosate is classified as a not likely human carcinogen, so a cancer dietary exposure analysis was not performed

.

ii. Drinking water

. The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary exposure analysis and risk assessment for glyphosate in drinking water. Because the Agency does not have comprehensive monitoring data, drinking water concentration e stimates are made by reliance on simulation or modeling taking into account data on the physical characteristics of glyphosate. Further information regarding EPA drinking water models used in pesticide exposure assessment
can be found at h ttp://www.epa.go v/oppefed1/models/index.htm

.

Glyphosate is registered for aquatic use to control weeds in bodies of water . Therefore,

t he Agency estimated the concentration in surface water resulting from direct application of the maximum single application rate of 3.75 pounds of glyphosate free acid per acre to a water body 6 feet deep. Based on this maximum application rate, the estimated concentration for use in the drinking water assessment is 230 g/L (ppb). This estimat e is based on a dilution model that does not take into account degradation in the water body and partitioning into the water column

- sediment phases.

Based on the generic expected environmental concentration (GENEEC) and screening
concentration in groundwater (SCI

- GROW) models, the estimated environmental concentrations (EEC’s) of glyphosate for acute exposures are estimated to be 21 ppb for surface water and 0.0038 ppb for ground water. The EEC’s for chronic exposures are estimated to be 0.83 ppb for surface water and 0.0038 ppb for ground water, based on glyphosate treatment in crops.

2. Non

- dietary exposure

. Glyphosate is registered for broadcast and spot treatments on home lawns and gardens , including for turf renovation . Glyphosate products for homeowner use are packaged as ready

- to

- mix formulations and ready

- to

- use
sprayers and are very common in home and garden stores in the U.S. Glyphosate products are also used by lawn care operators (LCOs) for broadcast and spot treatment
weed control programs on homeowner lawns

. Glyph osate products are also registered for9

weed control in recreational areas, including parks and golf courses, and for control of aquatic weeds in lakes, ponds and reservoirs

. All recreational and residential exposu res assessed do not exceed the Agency’s level of concern (MOEs <100).

The term “residential exposure

, ” as used here, refers to non

- occu pational non

- dietary exposure (e.g., for lawn and garden weed control). A risk assessment was conducted using the following residential exposure assumptions: Based on the registered residential use patterns, there is a potential for short

- term dermal and inhalation exposures to
homeowners who apply products containing glyphosat e (residential handlers). Additionally, based on the results of environmental fate studies, there is also a potential
for short

- and intermediate

- term post

- application dermal exposures by adults and toddlers and incidental ingestion exposures by toddlers. However, since short

- and intermediate

term dermal and inhalation endpoints were not identified , no residential handler or post

application dermal assessment is required

. P ost

- application toddler assessment for incidental ingestion exposures was perform ed; r isk estimates ranged from 7,230 to greater than 10 6

.

Based on the registered uses of glyphosate in recreational areas and for aquatic weed
control , adult and child golfers are anticipated to have short

- term

, post

- application dermal exposure at golf courses and s wimmers (adults, children and toddlers) are anticipated to
have short

- term post

- application dermal and incidental ingestion exposures. However, since HIARC did not select dermal endpoints, no post

- application dermal assessment is

necessa ry

. P ost

- application incidental ingestion exposure assessment was performed for adult, children and toddler swimmers ; r isk estimates ranged from 7,610 to 35,500.

Spray drift is always a potential source of exposure to residents nearby to spraying operati ons , particularly 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.

D. Cumulative Effects 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 prod uce a toxic metabolite produced by other substances. For the purposes of this tolerance action, t herefore, EPA has not assumed that glyphosate has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to
determine w hich chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the final rule for Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997).10

E. Safety Determination

1. U.S. population. A c hronic dietary risk assessment of glyphosate was recently conducted using the current and the proposed new and increased tolerance s for sweet corn. The Tier 1 chronic dietary analysis for glyphosate is a conservative estimate of dietary exposure that uses tolerance level residues and 100% crop treated. No increase in exposure is expected due to the proposed change in the corn forage tolerance, to support the use of glyphosate in RHS seed corn production. Under this assumption, exposure to glyphosate from food and water will utilize only 5% of the chronic population adjusted dose (cPAD) for the general U.S. population . Based on its use pattern, chronic residential and recreational exposure to residues of glyphosate is not expected.

Based on the completen ess and reliability of the toxicity data and the conservative exposure assessment, it can be concluded that there is a reasonable certainty that no harm will result to the general U.S. population from chronic aggregate exposure to glyphosate
residues.

2. Infants and children

. FFCDA Section 408 provides that EPA shall apply an additional tenfold margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database

. EPA has previously evaluated the prenatal and postnatal sensitivity of glyphosate and the adequacy of the data base as indicated in the Reregistration Eligilibility Decision for glyphosate

. There is no evidence of increased susceptibility in rats and rabbits to in utero and/or postnatal exposure to glyphosate. EPA has concluded that t here is a complete toxicity data base for glyphosate and exposure data are complete or are estimated based on data that reasonably accounts for all potential exposures. EP A determined that the 10X safety factor to protect infants and children is not necessary as well as t he FQPA

. The use of generally high quality data, conservativ e models and/or assumptions in the exposure assessment, provide adequate protection of infants and children

.

Chronic dietary exposure to residues of current and proposed tolerances is estimated to utilize only 12% of the chronic population adjusted dose (cPAD) for children 1

- 2 years old, which is the population subgroup predicted to be most highly exposed.

Use of glyphosate on turf does present a potential short

- and intermediate

- term exposure for children 1

- 2 years old. The aggregate MOE for the total short

- and intermediate

- term food and residential aggregate exposure are greater than 100, and, therefore

, doe s not exceed the Agency’s level of concern.

Based on the completeness and reliability of the toxicity data and the conservative exposure assessment, it can be concluded that there is a reasonable certainty that no harm
will result to infant s and children from chronic, short

- and intermediate

- term aggregate exposure to glyphosate residues.11

F. International Tolerances

There are no International MRLs for corn forage, so this petition will not impact any International MRLs for glyphosate.