EPA Registration Division contact: Andrew Ertman; 703-308-9367

Interregional Research Project No. 4

PP No. 2E7979

EPA has received a pesticide petition (2E7979) from Interregional Research Project No. 4, Rutgers, The State University of New Jersey, 500 College Road East, Suite 201W, Princeton, NJ 08540 requesting, pursuant to secti on 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S. C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of glyphosate N-(phosphonomethyl) glycine in or on the raw agricultural commodity Vegetable, root and tuber, Group 1, except sugar beet at
6.0 parts per million (ppm) ,teff, forage and teff, hay at 100 ppm , and Oilseed Crops, Group 20 at 40 ppm , and convert Borage, seed, Crambe, seed, Jojoba, seed, Lesquerella, seed, Meadowfoam, seed, Mustard, seed and Se same, seed all at 0.1 ppm; Flax, seed at 4.0 ppm; Flax, meal at 8.0 pp m; Canola, seed and Rapes eed, seed at 20 ppm; Cotton, undelinted seed at 40 ppm and Safflower, seed and Sunflower, seed at 85 ppm to Oilseed, group 20 at 40 ppm. Also convert Vegetabl e, bulb, group 3 at 0.2 ppm to Vegetable, bulb, group 3-07 at 0.2 ppm. Convert Okra at 0.5 ppm and Vegetable, fruiting, group 8 at 0.1 ppm to Vegetable, fruiting, group 8-10 at 0.1 ppm. Convert Fruit, citrus, group 10 at 0.5 ppm to Fruit, citrus, gr oup 10-10 at 0.5 ppm. Convert Fruit, pome, group 11 at 0.2 ppm to Fruit, pome, group 11- 10 at 0.2 ppm. Convert Cranberry, Grape, Juneberry, Kiwifruit, Lingonberry, Salal, Strawberry a nd Berry group 13 at 0.2 ppm to Berry and small fruit, group 13-07 at 0.2 ppm . EPA has determined that the petition contains data or information regarding the elements se t forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the peti tion. 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 unders tood. The terminal residue to be regulated in nontransgenic plants and transgenic crops modified to express the Agrobacterium sp. EPSPS and oxireductase genes is glyphosat e per se. For certain crops (currently only soybeans and corn) that have a transgenic variety engineered to e xpress the microbial glyphosate acetyltransferase gene (gat4601), the combined residues to be regulated are glyphosate and N-acetyl-glyphosate. The crops being cons idered here do not currently have an acetyltransferase gene inserted. The qualitati ve nature of the glyphosate residue will not be changed as a result of the proposed tolera nce changes. Glyphosate herbicides are not applied directly to livestock, so the only potential exposure is vi a glyphosate residues in their diet. On December 3, 2008, EPA publis hed a final rule (EPA-HQ-OPP-2007-0147; FRL-8385-7) amending section 180.364 to reflec t that the terminal residue to be regulated in livestock (and in soybean co mmodities and grain aspirated fractions) is glyphosate and its metabolite N -acety l-glyphosate, expressed as glyphosate.

2. Analytical method. Adequate enforcement methods ar e available for analysis of2

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; High Performance Liquid Chromatography (HPLC) with fluorom etric detection, 0.0005 ppm LOD (limit of detection); and gas chromatography/mass sp ectrometry (GC/MS) method for glyphosate in crops has also been validated by EPA’s Analytical Chemistry Laboratory (ACL). Thus, adequate analytical methods are av ailable for residue data collection and enforcement of the proposed tolerances for glyphosate.

3. Magnitude of residues. Data on the magnitude of glyphosate residue in carrot and sweet potato are being submitted along with the Petition to support the proposed

amendment of the tolerance fo r root and tuber vegetables, Crop Group 1. No new residue data were generated to support the establishm ent of the proposed tolerance for teff forage and hay, or for establishment of a group tolerance for oilseed crops, Crop Group 20. However, data from two additional glyphosate residue studies conducted outside the U.S. on oilseed rape are being submitted along with th is petition to further support the increase in the oilseed crop group tolerance. A ny secondary glyphosate residues occurring in

livestock commodities will be co vered by existing tolerances.

B. Toxicological Profile

EPA has evaluated the available toxic ity data and considered its validity, completeness, and reliability as well as the relationship of the resu lts of the studies to human risk. The toxicity database is comp lete with the exception of recently-required

studies on acute and subchr onic neuorotoxicity and i mmunotoxicity. There is no evidence of neurotoxicity in any of the t oxicology studies. Accordingly, although an

acute and subchronic neurotoxi city studies are now require d as part of new data requirements, EPA does not believe that conduc ting these studies will result in a lower POD than that currently used for overall ri sk assessment, and therefore, a database uncertainty factor is not needed to account for lack of these studies EPA has also considered available information concerning th e variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.

1. Acute toxicity. Glyphosate is of low acute toxi city following oral, dermal, and inhalation exposure. It is a mild eye irritant , slight skin irritant , and is not a dermal sensitizer in guinea pigs. Inhalation risk assessments ar e not required based on the low toxicity of the formulation products (toxi city category III or IV) and the physical characteristics of the technical product. An acute dose and endpoint for assessing acute risk have not been selected for any populati on subgroups because no effect that could be attributed to a single exposure (dose) was obs erved in oral toxicity studies including the developmental toxicity studi es in rats and rabbits.

Table 1 Acute Toxicity Profile - Test Substance

Guideline

No. Study Type MRID(s) Results Toxicity Category3

Table 1 Acute Toxicity Profile - Test Substance

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 M ild or slight irritant IV

870.2600 Skin sensitization 00137138 Not a sensitizer None

2. Genotoxicty. In vitro and in vivo genotoxicity st udies have been conducted with glyphosate. Short term assays for genotoxicity consisting of a bacterial reverse mutation assay (Ames test), an in vitro assay for cy togenetic 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 concentra tions 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 w ith 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. Acceptable d evelopmental toxicity studies in the rat and rabbit are available, as is an acceptable 2-generation reproduction study4

in the rat. No significant reproductive and developmental toxic effects were found. A focal tubular dilation of the kidneys was observed in a 3-generation reproductive study on rats at the 30-mg/ kg/day high dose treatment level (HDTL); however, a 2-generational reproductive study on rats did not observe the same effect at the 1,500-mg/ kg/day HDTL, nor were any adverse reproductive effects observed at any dose level. EPA 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 HDTL (3,500-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 HDTL (350-mg/kg/day). In the rabbit, developmental toxicity was not 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.

A developmental neurotoxicity study was not required.

Table 3 Reproductive and Deve lopmental Toxicity Profile

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 w ith 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) base d 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 food 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 ga in during lactation.5

4. Subchronic toxicity. In rodent feeding studies, glyphosate showed a NOAEL of 500 mg/kg/day in a 90-day mouse study a nd 1445 mg/kg/day (HDT) in a 90-day rat study. In a 21/28-day rabbit dermal toxici ty study the NOAEL was 1000 mg/kg/day and the LOAEL was 5000 mg/kg/day based on slig ht 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 = 2500 mg/kg/day (HDT) in males and females based on decreased body weight gains.

870.3100 90-Day oral toxicity (Rat) NOAEL = 1445 mg/kg/day (HDT)

LOAEL = not established

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

5. Chronic toxicity. A chronic feeding/carcinogeni city study in rats found no systemic effects in any of the paramete rs examined (body weight, food consumption, clinical signs, mortality, c linical pathology, organ weights, and histopathology). In a second chronic feeding/carcinogeni city study in rats tested at higher dietary levels, a

lowest observed-adverse-effect le vel (LOAEL) was identified at 940- milligrams/kilograms/day (mg/kg/day) & 1,183-mg/kg/day (male/female) based on decreased body-weight gains in females and increased incidence of cataracts and lens abnormalities, decreased urinary pH, increase d absolute liver weight, and increased relative liver weigh t/brain weight in males. No evid ence of carcinogenicity was found in rats or mice. In a chronic toxicity stu dy in dogs, no systemic effects were found. Glyphosate has been classified as “a Group E” carcinogen—no evidence of carcinogenicity to humans—based on the abse nce 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.6

Table 5 Chronic Toxicity Profile

Guideline No./ Study Type Results

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 carcinogenicity

870.4300

Chronic/Carcinogenicity (Rat) NOAEL = 362 mg/kg/day in males, 447 mg/kg/day in females LOAEL = 940 mg/kg/day in male s, 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, dist ribution, and excretion.

7. Metabolite toxicology

. The residue of concern for ri sk assessment purposes for crops that do not contain a glyphosate acetylt ransferase gene, and which the crops being considered in this Petition do not, is gl yphosate 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 that, 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 whether uses that result in significantly higher residues of AMPA in plants and livestock commodities in the future would require that AMPA be re introduced into the tolerance expression of glyphosate. The Committee determined that , based on toxicologi cal considerations, AMPA need not be regulated regardless of le vels 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 system. EPA also adopted EDSTAC’s recommendation that the Program also include evaluations of potential effects in wildlife.7

Glyphosate is on the EPA list of the initial 67 pe sticide 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 endocrine activity of 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 for glyphosate were issued January 14, 2010, with test data to be submitted beginning January 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 screening assays and demonstrate that glyphosate is not

an endocrine active substance.

C. Aggregate Exposure

Aggregate exposure for glyphosate is the combination of chronic dietary exposure (food + drinking water) and short- and inte rmediate-term non-dietary oral exposure from residential (home lawn care) and recr eational (golf, swimming) use exposure.

1. Dietary exposure. In evaluating dietary exposure to glyphosate, exposure under the petitioned-for tolerances as well as all existing glyphosate tolerances in 40 CFR

180.364 were considered.

i. Food. Quantitative acute dietary exposure and risk assessments are performed for a food-use pesticide if a t oxicological study has indicated the possibility of an effect of concern occurring as a result of a 1-day or single exposure. No such effect has been identified in the toxicologi cal studies for glyphosate; th erefore, a quantitative acute dietary exposure assessment is unnecessary.

A chronic dietary exposure assessment was c onducted using the food consumption data from the United States Department of Agricu lture Continuing Survey of Food Intake by Individuals (USDA CSFII) (1994–1996 and 1998). The chronic analysis assumed tolerance-level residues, 100 percent crop treated (PCT), and Dietary Exposure Evaluation Model (DEEM (version 7.81)) defau lt processing factors and incorporated glyphosate drinking water monitoring data.

EPA has concluded that glyphosate does not pose a cancer risk to humans; therefore, a dietary exposure assessment for the purpos e of assessing cancer risk is unnecessary.

ii. Drinking water. Monitoring data from the United States Geological Survey (USGS) National Water-Quality Assessment Program (NAWQA) was used to calculate drinking water exposure. For chronic dietary risk assessment, the water concentration8

value of 13.5 parts per million (ppm) was used to assess the contribution to drinking

water.

2. Non-dietary exposure

. The term ‘‘residential exposure’’ is used to refer to nonoccupational, non-dietary exposur e (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). The agricultural use on root and tuber vegetables, teff and oilseed crops is not an ticipated to result in residential exposure. However, residential exposure is anticipated from the registered broadcast and spot treatment to residential lawns, gardens, a nd recreational areas including parks and golf courses. Based on the registered residential use patterns, there is a potential for shortterm and intermediate-term dermal and i nhalation exposures to homeowners who mix and apply products containing glyphosate. Since short- and intermediate-term dermal and inhalation endpoints were not selected, no residential handler/applicator exposure assessment was conducted. Post-application de rmal and inhalation exposure assessments

were not conducted since short- and interm ediate-term dermal and inhalation endpoints were not selected. Based on registered use patterns, toddlers may have short-term postapplication incidental oral exposure from hand-to-mouth, object to mouth, and soil ingestion behavior on treated lawns and swi mmers may have short- term post-application incidental oral exposures from treated surface water. Exposures and risks from these scenarios were assessed because an app licable endpoint was identified. Further information regarding EPA standard assump tions and generic inputs for residential exposures may be found at http://www.ep a.gov/pesticides/trac/ science/trac6a05.pdf.

D. Cumulative Effects

Section 408(b)(2)(D)(v) of FFDCA require s that, when considering whether to establish, modify, or revoke a tolerance, the Agency must consider ‘‘available information’’ concerning the cumulative effect s of a particular pesticide’s residues and

‘‘other substances that have a common m echanism of toxicity.’’ EPA has not found glyphosate to share a common m echanism of toxicity with any other substances, and glyphosate does not appear to produce a toxi c 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 toxic ity with other substances. For information regarding EPA’s efforts to determine whic h chemicals have a common mechanism of toxicity and to evaluate the cumulative effect s of such chemicals, see EPA’s Web site at http://www.epa.gov/pesticides/cumulative.

E. Safety Determination

Based on conservative risk assessments, EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to glyphosate residues.

1. U.S. population. A chronic dietary risk assessment of glyphosate was conducted using the current and the proposed new and increased tolerances for all root and tuber vegetables included in Crop Group 1, except sugar beet, and all oilseed crops included in Crop Group 20, except cottonseed. Since it is proposed that tolerances for the animal feed9

commodities teff forage and teff hay be made the same as the current tolerance for Crop Group 16, Forage, Fodder and Straw of Cereal Grains, no additional residue exposure would be expected through the consumption of meat.

The Tier 1 chronic dietary analysis for glyphos ate is a conservative estimate of dietary exposure that uses tolerance level residues and 100% crop treated. Under this assumption, exposure to glyphosate from food and water will utilize only 5.3% 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 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 the general U.S. population from chronic aggregate exposure to glyphosate residues

.

2. Infants and children

. Section 408(b)(2)(C) of FFDCA provides that EPA shall apply an additional tenfold (10X) 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 on toxicity and exposure unless EP A determines based on reliable data that a different margin of safety will be safe for in fants and children. This additional margin of safety is commonly referred to as the FQPA SF. In applying this provision, EPA either retains the default value of 10X, or uses a different additional safety factor when reliable data available to EPA support th e choice of a different factor.

There is no quantitative or qualita tive 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 3-generation repr oductive study on rats at the 30-mg/kg/day HDTL; however, a 2-generationa l reproductive study on rats did not observe the same effect at the 1,500-mg/kg/day HDTL, nor were any adverse reproduc tive effects observed at any dose level. A clear NOAEL was establis hed and the chronic reference dose was set at a level well below (

׽ 17-fold) this effect. Therefore, the endpoints selected for risk assessment are protective of the effects seen in the 3-generation rat reproduction study.

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

EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQ PA SF were reduced to 1X. That decision is based on the following findings:

- The toxicity database is complete with the exception of recently-required studies on

acute and subchronic neuorotoxi city and immunotoxicity. There is no evidence of neurotoxicity in any of the toxicology studies. Accordingly, although an acute and subchronic neurotoxicity studies are now required as part of new data requirements, EPA

does not believe that conducti ng these studies will result in a lower POD than that currently used for overall risk assessment, and therefore, a database uncertainty factor is

not needed to account for lack of these studies.

- The toxicology database for glyphosate does no t show any evidence of treatment-related effects on the immune system. The overall weight of evidence suggests that this chemical10

does not directly target th e immune system. Accordingl y, although an immunotoxicity study is required as a part of the new da ta requirements in the 40 CFR part 158 for conventional pesticide registration, EPA doe s 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 data base uncertain ty factor is not needed to account for lack of this study.

- There is no quantitative or qualitative evidence of increased susceptibility of rats or

rabbit fetuses to in utero exposure in developmental studies.

- The dietary analysis of exposure to glyphosat e is conservative as it assumes tolerance

level residues and 100 PCT. EPA made conser vative (protective) assumptions in the water modeling used to assess exposure to glyphosate in drinking water. EPA used similarly conservative assumptions to assess post-application exposur e of children as well as incidental oral exposure of toddlers.

Based on the exposure assumptions, chronic exposure to glyphosate from food will utilize 12.5% of the cPAD for children 1–2 year s old, the population group receiving the

greatest exposure.

F. International Tolerances

Several countries (EU, Australia, Israel , Russia and others) have established a group tolerance or maximum residue limit (MRL) for glyphosate in or on all or some of the root and tuber vegetable crops listed in Cr op Group 1 in the U.S.; all of them are at or less than 0.1 ppm. The same is true for so me or all of the oils eed crops listed in Crop Group 20 in the U.S. There are no internati onal tolerances for glyphosate in or on teff forage and hay.