Document ID: EPA-HQ-OPP-2009-0920-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-02-04T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Kathryn Montague 703-305 - 1243

Interregional Research Project #4.

9F7639

	EPA has received a pesticide petition (9F7639) from Syngenta Crop Protection, Inc., 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 by 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 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 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 adequately 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 analytical method, extraction with
sulfuric acid with high performance liquid chromatography detection, is available for enforcement purposes. Analytical methods for enforcing these tolerances have been published in the Pesticide Analytical 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 III) and inhalation (Toxicity Category III) routes of exposure.  Diquat dibromide is moderately to severely toxic via the dermal route of exposure (Toxicity Category II).  Diquat dibromide is not a dermal irritant (Toxicity Category IV) or a dermal sensitizer.  Results from the eye acute toxicity study show that Diquat dibromide is Toxicity Category II.  Slight to severe eye irritation was seen following acute exposure.

      
	2. Genotoxicty.  Diquat dibromide tested negative for mutagenicity in a bacterial gene mutation (Ames) assay.  Diquat dibromide showed no gene mutation response in a mammalian cell line (mouse lymphoma) at doses below cytotoxiclevels.  Similarly, diquat dibromide was not clastogenic in cultured human lymphocytesbelow cytotoxic levels.  There was no evidence of clastogenicity in somatic cells (mouse bone marrow) or germinal cells (mouse spermatogonia) or unscheduled DNA synthesis (UDS) in rat hepatocytes in a series 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.  A low incidence of toxicity was seen at 80 ppm in the adult rats only.  Based on these findings, the No Observable Adverse Effect Level (NOAEL) and Lowest Observable Adverse Effect Level (LOAEL) for parental systemic toxicity are 16 ppm (0.8 mg/kg/day) and 80 ppm (4 mg/kg/day), respectively, expressed as diquat cation.  The 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 Study - Rabbit. Diquat dibromide was administered by gavage at dose levels of 0, 1, 3 or 10 mg/kg/day (MRID 41198901).  The maternal toxicity NOAEL was 1 mg/kg/day, based on maternal body-weight loss during gestation days (GD) 7-10 and decreased food consumption during dosing (GD 7-10) at the LOAEL of 3 mg/kg/day.  The developmental toxicity NOAEL was 3 mg/kg/day, based on an increased incidence of friable and/or mottled livers and poorer ossification, as evidenced by minor skeletal alterations at the LOAEL of 10 mg/kg/day. iii. Prenatal Developmental Study - Rat. Diquat was administered by oral gavage at dose levels of 0, 4, 12 or 40 mg/kg/day (MRID 41198902). The maternal toxicity NOAEL was 4 mg/kg/day, based on decreased maternal body-weight 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 days of dosing, there was an increased incidence of subdued appearance and piloerection, and a slightly lower gravid uterine weight. The developmental toxicity NOAEL was 12 mg/kg/day, based on decreased fetal body weight (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 Study - 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 days 6 through 15.  The maternal toxicity NOAEL 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 NOAEL was 2 mg/kg/day, based on decreased fetal body weight (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 dibromide was administered at doses of 0, 5, 20, 40, or 80 mg/kg body weight/day (mg/kg-bw/day) (MRID 40308101).  The NOAEL and LOAEL for systemic toxicity (for both sexes) was 5 mg/kg/day and 20 mg/kg/day, respectively. 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 weight and lung/brain weight; mottling and reddening of the lungs; and lung lesions (multifocal chronic interstitial pneumonia and alveolar macrophages) in females; however all effects except the latter were reversible (MRID 40301701).  A second inhalation study with rats showed no effects on any of the parameters examined at a dose of 0.1 ug/l (microgram per liter) (MRID 40640801).  Based on both studies, the NOAEL and LOAEL for inhalation exposure is 0.1 ug/l and 0.49 ug/l, respectively.

      
	5. Chronic toxicity. i. Two-Year Rat Study.  A chronic feeding carcinogenicity study (MRID 00145855) was conducted on rats.  Doses were diets containing 0, 5, 15, 75, 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.  Chronic Oral Toxicity Study - Dog.  A chronic toxicity study (MRID 41730301) was conducted with diets contaioning 0, 0.5, 2.5 or 12.5 mg/kg/day, expressed as diquat cation.  The NOAEL is 0.5 mg/kg/day, based on unilateral cataracts in females and decreased epididymides weights in males at the LOAEL of 2.5 mg/kg/day.  At the high-dose level (12.5 mg/kg/day), bilateral cataracts, inflammatory lesions in the large intestine, and increased absolute and relative kidney weights were observed in all dogs, and decreased relative adrenal and epididymides weights were observed in males.  iii. Carcinogenicity Study - Rat.  In a combined 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 for males and 0, 0.24, 0.72, 3.64 and 19.44 mg/kg/day for 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 for males and 0.72 mg/kg/day for females), based on eye lesions (total cataracts) at the LOAEL of 75 ppm (2.91 mg/kg/day for males and 3.64 mg/kg/day for females). iv. Carcinogenicity Study (feeding) - Mouse.  In a carcinogenicity study (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 for males and 0, 4.78, 16.03, and 48.27 mg/kg/day for females).  The systemic NOAEL is 30 ppm (3.5 mg/kg/day for males and 4.78 mg/kg/day for females).  The systemic LOAEL is 100 ppm (11.96 mg/kg/day for males and 16.03 mg/kg/day for females), based on clinical signs (eye discharge in males, subdued behavior in females, and decreased body weight/body weight gain in males.  Diquat dibromide is not carcinogenic in male or female CD-1 mice.

      
	6. Animal metabolism. The reregistration requirements for animal metabolism have been fulfilled.  The qualitative nature of the residue in animals is adequately understood based on acceptable poultry, ruminant, and fish metabolism studies.  There are no animal feed items associated with this proposed use.

      
	7. Metabolite toxicology. The qualitative nature of the residue in plants is adequately understood based on an acceptable potato metabolism study and rat bioavailability study.  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 I acute exposure assessment 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 soybean (Crop Subgroup 6C), foliage of legume vegetables (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 conservatively estimated to be 100% for the proposed 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, soybean, bananas (imported), coffee (imported), dry peas, dry beans, lentils and preharvest desiccant use on canola. Drinking water estimates were incorporated directly into the dietary exposure assessment 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 Level (NOAEL) of 75 mg/kg-bw/day from an acute neurotoxicity study in rats and an uncertainly 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 exposure (MOE), which was calculated by dividing the NOAEL by 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 14,066 (0.7% of the aRfD of 0.75 mg/kg-bw/day).  Acute exposure to the most sensitive subpopulation (children 1 to 2 years 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 performed 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 by dividing the NOAEL by the exposure for each population 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 years 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 characteristics of diquat dibromide.  As reported in a 2002 Revised Tier I Drinking Water and Aquatic Ecological Exposure Assessment document, EFED recommended using the MCLG/MCL of 20 ug/L (ppb) from the EPA - Office of Water (OW) compliance monitoring data 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 MCL of 20 ppb. The use of the MCL for chronic drinking water exposure estimates represents a highly 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 uses) 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 year old) with a MOE of 362 (Benchmark MOE = 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 by 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 for 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 NOAEL of 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 Assessment 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 short-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 Effects

	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 analysis (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 analysis (food, 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.

	2. Infants and children. Using the conservative assumptions described in the exposure section 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 9,677 (1.0% of the aRfD) for children 1  -  2 years old (the most sensitive population subgroup).  The chronic aggregate exposure analysis (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 analysis (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 short-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 analysis (food, water and residential) 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 (MRLs) for diquat in/on various raw agricultural commodities. Additionally both Canada and Japan have established MRLs for diquat in/on various commodities.