EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Kathry n Montague 703
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– 1243 Interregional Research Project #4. 9F7639 EPA has received a pesticide petition ( 9F7639 ) from Sy ngenta Crop Protection, In c., P.O. Box 18300, Greensboro, NC 27419 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 b y establishing a tolerance for residues of diquat dibromide in or on the raw agricultural commodities of canola (seed) at 1.0 parts per million (ppm) and canola (meal) 3.0 ppm . EPA has determined that the petition contains data or information regarding the elements set fo rth 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 petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The metabolism of diquat in plants is adequatel y understood. The residue of concern in plants is diquat per se. No further plant metabolism data are necessary for this proposed use. 2. Analytical method. An adequate anal ytical method, extraction with sulfuric acid with high performance liquid chromatography detection, is available for enforcement purposes. Analy tical methods for enforcing these tolerances have been published in the Pesticide Anal ytical Manual , Vol. II (PAM II). 3. Magnitude of residues. Magnitude of the residue data in support of the proposed tolerances based upon the new use of diquat dibromide on canola have been submitted with this petition. B. Toxicological Profile 1. Acute toxicity
. Diquat dibromide is not acutely toxic via the oral (Toxicity Category I II) and inhalation (Toxicity C ategory

I II) routes of exposure. D iquat dibromide is moderatel y to severel y toxic via the dermal route of exposure (Toxicity Category I I). D iquat dibromide is not a dermal irritant (Toxicity C ategory

IV) or a dermal sensitizer. Results from the eye acute toxicity s tudy s how that Diquat dibromide is Toxicity

Category II. Slight to severe eye irritation was seen following acute exposure.2

2. Genotoxicty
. Diquat dibromide tested negative for mutagenicity in a bacterial gene mutation (Ames) assay . D iquat dibromide showed no gene mutation response in a mammalian cell line (mouse ly mphoma) at doses below cy totoxiclevels. S imilarly , diquat dibro mide was not clastogenic in cultured human ly mphocy tesbelow cy

totoxic levels. There was no evidence of clastogenicity in somatic cells (mouse bone marrow) or germinal cells (mouse spermatogonia) or unscheduled DNA sy nthesis (UDS) in rat hepatocy tes in a s eries of in vivo studies. 3. Reproductive and developmental toxicity
. i. Two
- Generation Reproduction Study
- Rat. Diquat was fed at dose levels equivalent to 0, 16, 80, or 400/240 ppm of diquat cation (MRID 41531301). There was evidence of toxicity in both adults and offspring at 400/240 ppm of diquat. Al ow incidence of toxicity w as seen at 80 ppm in the adult rats only
. B ased on these findings, the No Observable Adverse Effect Level (NOAEL) and Lo west Observable Adverse Effect Level (L OAEL) for par ental systemic toxicity are 16 ppm (0.8 mg/kg/day) and 80 ppm (4 mg/kg/day), respectively , expressed as diquat cation. T he NOAEL and LOAEL for reproductive/developmental toxicity are 80 ppm (4 mg/kg/day) and 400/240 ppm (12 mg/kg/day). ii. Prenatal Developmental Toxicity S tudy
- Rabbit. Diquat dibromide was administered by g avage at dose levels of 0, 1, 3 or 10 mg/kg/day (MRID 41198901). The maternal toxicity N OAELw as 1 mg/kg/day , based on maternal body
- weight loss during gestation day s (GD) 7
- 10 and dec reased food consumption during dosing (GD 7
- 10) at the LOAEL of 3 mg/kg/day
. The developmental toxicity N OAEL was 3 mg/kg/day , based on an increased incidence of friable and/or mottled livers and poorer ossification, as evidenced by m inor skeletal alterations at the LOAEL of 10 mg/kg/day
. iii. Prenatal Developmental Study
- Rat. Diquat was administered by o ral gavage at dose levels of 0, 4, 12 or 40 mg/kg/day (MRID 41198902). The maternal toxicity N OAEL was 4 mg/kg/day , based on decreased maternal body
- wei ght gain and food consumption during dosing at the LOAEL of 12 mg/kg/day
. At the highest dose tested (40 mg/kg/day), one dam died, the dams lost weight during the first three day s of dosing, there was an increased incidence of subdued appearance and piloer ection, and a slightl y lower gravid uterine weight. The developmental toxicity

NOAEL was 12 mg/kg/day , based on decreased fetal body w eight (91% of control), decreased litter weight, an increased incidence of hemorrhagic kidney , and poorer ossification compared to the control at the developmental LOAEL of 40 mg/kg/day
. iv. Prenatal Developmental Toxicity S tudy
- Mouse. In a developmental toxicity study ( MRID 00061637), mice were administered diquat dibromide via gavage at dose levels of 0, 1,2 and 4 mg/kg/day (expressed as cation) from gestation day s 6 through 15. The maternal toxicity N OAEL was 1 mg/kg/day , based on clinical signs, deaths, and macroscopic lesions in the gastrointestinal tract and lungs at the maternal toxicity LOAEL of 2 mg/kg/day
. The developmental toxicity N OAEL was 2 mg/kg/day , based on decreased fetal body

w eight (88% of control) and an increased incidence of overall skeletal alterations at 4 mg/kg/day
. 4. Subchronic toxicity
. i. Repeated Dose Dermal
- Rat. Technical diquat dibromi de was administered at doses of 0, 5, 20, 40, or 80 mg/kg body w eight/day3

(mg/kg
- bw/day) (MRID 40308101). The NOAEL and LOAEL for sy stemic toxicity ( for both sexes) was 5 mg/kg/day and 20 mg/kg/day , respectivel y. ii. Subchronic Inhalation
- Rat. Exposure at doses of 0, 0.49, 1.1, 3.8 μg/L via the inhalation route resulted in increased lung weights, lung/body w eight and lung/brain weight; mottling and reddening of the lungs; and lung lesions (multifocal chronic interstitial pneumonia and alveolar macrophage s) in females; however all effects except the latter were reversible (MRID 40301701). As econd inhalation study w ith rats showed no effects on any of the parameters examined at a dose of 0.1 μg/l (microgram per liter) (MRID 40640801). Based on both studi es, the NOAEL and LOAEL for inhalation exposure is 0.1 μg/l and 0.49 μg/l, respectively
. 5. Chronic toxicity
. i. Two
- Year Rat Study
. Ac hronic feeding carcinogenicity study ( MRID 00145855) was conducted on rats. D oses were diets containing 0, 5, 15, 7 5, or 375 ppm of diquat cation. There was no treatment - related increase in tumor incidence in either sex. The NOAEL was 15 ppm (males 0.58 mg/kg/day , females 0.72 mg/kg/day), based on eye lesions (total cataracts) at the LOAEL of 75 ppm (males 2.91 mg/kg/day

and females 3.64 mg/kg/day)

. ii. C hronic Oral Toxicity S tudy
- Dog. A chronic toxicity

s tudy ( MRID 41730301) was conducted with diets contaioning 0, 0.5, 2.5 or 12.5 mg/kg/day , expressed as diquat cation. The NOAELi s 0.5 mg/kg/day , based on unilat eral cataracts in females and decreased epididy mides weights in males at the LOAELo f 2.5 mg/kg/day
. At the high
- dose level (12.5 mg/kg/day), bilateral cataracts, inflammatory

l esions in the large intestine, and increased absolute and relative kidney weights were observed in all dogs, and decreased relative adrenal and epididy mides weights were observed in males. iii. Carcinogenicity Study
- Rat. Ina

c ombined chronic toxicity /carcinogenicity study

( MRID 00145855, 00155474, 41085601) male and female rats were fed diets containing 0, 5, 15, 75, and 375 ppm diquat dichloride (0, 0.19, 0.58, 2.91, and 14.88 mg/kg/day f or males and 0, 0.24, 0.72, 3.64 and 19.44 mg/kg/day f or females) for 104 weeks. There was no treatment - related increase in tumor incidence in either sex. The NOAEL was 15 ppm (0.58 mg/kg/day f or males and 0.72 mg/kg/day f or females), based on eye lesions (total cataracts) at the LO AELof 75 ppm (2.91 mg/kg/day for males and 3.64 mg/kg/day f or females). iv. Carcinogenicity Study ( feeding)
- Mo use. In a carcinogenicity

s tudy ( MRID 42219801, 42880701, 42905901, 42919501), diquat dibromide was administered in diet for 104 weeks to mice at 0, 30, 100 and 300 ppm (0, 3.56, 11.96 and 37.83 mg/kg/day f or males and 0, 4.78, 16.03, and 48.27 mg/kg/day for females). The systemic NOAELis 30 ppm (3.5 mg/kg/day f or males and 4.78 mg/kg/day for females)

. The sy stemic LOAEL is 100 ppm (11.96 mg/kg/day f or males and 16.03 mg/kg/day

f or females), based on clinical signs (eye discharge in males, subdued behavior in females, and decreased body w eight/body

w eight gain in males. D iquat dibromide is not carcinogenic in male or female CD
- 1 mice.
6. Animal metabolism
. The reregistration requirements for animal metabolism have been fulfilled. T he qualitative nature of the residue in animals is adequatel y understood based on acceptable poultry , ruminant, and fish metabolism studies. There are no animal feed items associated with this proposed use.4

7. Metabolite toxicology
. The qualitative nature of the residu e in plants is adequatel y understood based on an acceptable potato metabolism study and rat bioavailability

s tudy
. The terminal residue of concern in plants is diquat per se. The qualitative nature of the residue in animals is adequately understood.
8. Endocrine disruption . There is no evidence of endocrine effects in the database supporting registration of diquat dibromide. C. Aggregate Exposure 1. Dietary exposure. Tier I acute and Tier III chronic dietary exposure evaluations were completed for diquat using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM
- FCIDTM, version 2.16) from Exponent. The Tier Iacute exposure ass essment included tolerance values for root and tuber vegetables (Crop Group 1), leafy vegetables (Crop Group 4), brassica vegetables (Crop Group 5), seed and pod vegetables, dry shelled peas and beans except soy bean (Crop Subgroup 6C), foliage of legume ve getables (Crop Group 7), fruiting vegetables (Crop Group 8), cucurbit vegetables (Crop Group 9), citrus fruit (Crop Group 10), pome fruit (Crop Group 11), stone fruit (Crop Group 12), small and berry fruit, tree nuts (Crop Group 14), cereal grains (Crop Group 15), foliage of cereal grains (Crop Group 16), grasses (Crop Group 17), avocado, cotton, fish, shellfish and sugarcane plus a proposed preharvest desiccant use on canola. Percent of crop treated values were conservativel y estimated to be 100% for the p roposed use. The Tier III chronic exposure assessment included secondary residues from all animal commodities based on theoretical balanced diets, tolerance values for residues arising from all treated irrigation water uses (including fish and shellfish) and field residue values for potatoes, alfalfa, sorghum, so ybean, bananas (imported), coffee (imported), dry peas, dry beans, lentils and preharvest desiccant use on canola. Drinking water estimates were incorporated directl y into the dietary

exposure asses sment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water. All consumption data for these assessments were taken from the USDA’s Continuing Survey of Food Intake by individuals (CSFII) with the 1994
- 96 consumption database and the Supplemental CSFII children’s survey

(1998) consumption database. i. Food. Acute Risk. The acute dietary risk assessment was performed for all population subgroups with an acute reference dose of 0.75 mg/kg
- bw/day based on a No Observed Adverse Effect L evel (NOAEL) of 75 mg/kg
- bw/day from an acute neurotoxicity

study in rats an d an uncertainl y factor of 100X. The 100X safety factor includes intra
- and interspecies variations. No additional FQPA safety factor was applied. For the purpose of the aggregate risk assessment, the exposure value was expressed in terms of margin of e xposure (MOE), which was calculated b y dividing the NOAEL b y the exposure for each population subgroup. In addition, exposure was expressed as a percent of the acute reference dose (% aRfD). Acute exposure to the U.S. population resulted in a MOE of 14,0 66 (0.7% of the aRfD of 0.75 mg/kg
- bw/day).5

Acute exposure to the most sensitive subpopulation (children 1 to 2 ye ars old) resulted in a MOE of 11,119 (0.9% of the aRfD of 0.75 mg/kg
- bw/day). Chronic Risk. The chronic dietary risk assessment was perfo rmed for all population subgroups with a chronic reference dose of 0.005 mg/kg
- bw/day based on a chronic toxicity study in dogs with a NOAEL of 0.5 mg/kg
- bw/day and an uncertainly

factor of 100X. The 100X safety factor included intra
- and interspecies variations. No additional FQPA safety

factor was applied. For the purpose of the aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated b y dividing the NOAEL b y the exposure for each populati on subgroup. In addition, exposure was expressed as a percent of the reference dose (%RfD). Chronic exposure to the U.S. population resulted in a MOE of 14,549 (0.7% of the cRfD of 0.005 mg/kg
- bw/day). Chronic exposure to the most exposed sub
- population (children 1 to 2 ye ars old) resulted in a MOE of 4,674 (2.1 % of the cRfD of 0.005 mg/kg
- bw/day). Cancer Risk. Carcinogenicity studies in rats and mice provided no evidence of increased tumor incidence and diquat dibromide was classified as a Category E (evidence of non
carcinogenicity

to humans) by

the HED Reference Dose/Peer Review Committee. ii. Drinking water. Estimated Drinking Water Concentrations (EDWCs) are made by reliance on simulation or modeling taking into account data on the physical c haracteristics of diquat dibromide. As reported in a 2002 Revised Tier I Drinking Water and Aquatic Ecological Exposure Assessment document, EFED recommended using the MCL G/MCLof 20 μg/L (ppb) from the EPA
- Office of Water (OW) compliance monitoring dat a to assess both acute and chronic exposure from aquatic uses of diquat. Using the Tier I model, FIRST (v 1.0), EFED estimated the drinking water concentration (EDWC) for surface water ranged from 6.3

– 13.2 ppb for acute (peak) exposure and 0.2

– 0.4 ppb for chronic exposure based on the use pattern for trees, vines, small fruits, and vegetables. For acute and chronic EDWCs from aquatic uses, EFED recommended use of the MCLof 20 ppb. The use of the MCL for chronic drinking water exposure estimates repre sents a highl y conservative approach an individual would not be exposed to the maximum allowed concentration value on a chronic basis. Acute Exposure from Drinking Water. The acute EDWC of 20 ppb (surface and groundwater

– terrestrial and aquatic diquat dibromide uses) was used to calculate the acute drinking water exposure values for the U.S. Population and population subgroups. Acute exposure (food and water) to the U.S. population resulted in a MOE of 100,671 (0.1% of the aRfD of 0.75 mg/kg/day). The most sensitive sub
- population was infants (<1 year old) with a MOE of 28,802 (0.4% of the aRfD of 0.75 mg/kg/day). Chronic Exposure from Drinking Water. The chronic EDWC of 20 ppb (surface and groundwater

– terrestrial and aquatic diquat dibromide use s) was used to calculate the chronic drinking water exposure values for the U.S. Population and population subgroups. Chronic exposure (food and water) to the U.S. Population resulted in a MOE of 1,186 (Benchmark MOE = 100; 8.4% of the cRfD of 0.005 mg/kg/day). The most sensitive sub
- population was infants (<1 ye ar old) with a MOE of 362 (Benchmark MOE6

= 100; 27.6% of the cRfD of 0.005 mg/kg/day).

1. Non

- dietary exposure. Diquat dibromide can be applied to turf and backyard ponds for general weed control and can be used around home and garden sites for weed control and landscape uses b y residential handlers. Diquat dibromide may be applied to turf at rates ranging from 0.25 lb a.i./A to 0.5 lb a.i./A. The residential exposure and risk assessments f or diquat dibromide were conducted using the applications to residential turf (both rates) because this use represents the upper
- bound estimates of exposure. Only short
- term exposures (1 to 30 days) are assessed for residential uses. A NOAELof 1 mg/kg/day was used for short
- term dermal exposure to diquat dibromide with a dermal absorption factor of 0.3%. A NOAEL of 1 mg/kg/day was also used for short
- term incidental non
- dietary oral exposure to diquat dibromide. Consistent with the approach reported in the HED assessment, short
- term inhalation exposure was not aggregated with dermal exposure for the adult handler because the NOAEL (0.024 mg/kg/day) for the inhalation exposure pathway is based on a distinct target organ effect (Diquat Dibromide HED Risk A ssessment for Tolerance Reassessment Eligibility

Document (TRED) DP Barcode: D281200). For adult handler and re
- entry

scenarios, the combined short
- term MOE for adults was calculated as 360. For post
- application exposures to treated turf, the combined sh ort - term MOE for children was 111 based on dermal and oral (hand
- to - mouth) exposure. Since the EPA’s Benchmark MOE for diquat dibromide is 100, the residential exposure for both adults and toddlers do not exceed EPA’s level of concern. D. Cumulative Ef

fects A cumulative risk assessment considering the potential risks from other pesticides or chemical compounds having a common mechanism of toxicity has not been included for this action because EPA has not determined based upon the available data that there are any other chemical substances that have a mechanism of toxicity common with that of diquat dibromide. E. Safety Determination 1. U.S. population. Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity

data, the acute aggregate (food plus water) exposure calculation for current and proposed uses of diquat dibromide provided a MOE of 12,342 ( 0.8% of the aRfD) for the U.S. population. The chronic aggregate exposure anal ysis (food and water) showed that exposure from all current and proposed diquat dibromide uses resulted in a MOE of 1,096 (9.1% of the cRfD) for the U.S. population. For short
- term exposures, the chronic dietary (food and water) exposure for the U.S. population was aggregated with the residential exposure (inhalation application) resulting in a short
- term aggregate MOE of 309. An intermediate
- term aggregate exposure anal ysis (f ood, water and residential) was not required for adults because residential lawn applications scenarios are not expected to occur for longer than a short
- term time frame. In summary , all aggregate MOEs (ranging from 12,342 to 309) assessed for the US population exceed the Benchmark MOE of 100 from the current and proposed uses for diquat dibromide.7

2. Infants and children . Using the conservative assumptions described in the exposure section above, and based on the completeness and reliability of the to xicity data, the acute aggregate (food plus water) exposure calculation for current and proposed uses of diquat dibromide provided a MOE of 9,677 (1.0% of the aRfD) for children 1

– 2 ye ars old (the most sensitive population subgroup). The chronic aggregate exposure anal ys is (food and water) showed that exposure from all current and proposed diquat dibromide uses resulted in a MOE of 347(28.8% of the cRfD) for the most sensitive population subgroup (infants, <1 year old). A short
- term aggregate exposure anal ys is (food, water and residential) was determined for small children since they represent the worst case scenario with both dietary (food and water) exposure and two routes of non
dietary exposure (dermal and incidental oral) from turf residues. For sh ort - term exposures, the chronic dietary (food and water) exposure for children 1

– 6 years old was aggregated with the residential exposure resulting in a short
- term aggregate MOE of 103. An intermediate
- term aggregate exposure anal ys is (food, water and r esidential) was not required for children because residential lawn applications scenarios are not expected to occur for longer than a short
- term time frame. In summary , for all of the children’s subgroups assessed, the aggregate exposure MOEs were greater than the minimum required (benchmark) MOE of 100 for potential exposures that could arise from all current and proposed uses of diquat, including anticipated dietary exposure from food, water and all other types of non
- occupational exposures. F. International Tolerances The Codex Alimentarius Commission has established several maximum residue limits (MRL s) for diquat in/on various raw agricultural commodities. Additionally both Canada and Japan have established MRL s for diquat in/on various co mmodities.