Document ID: EPA-HQ-OPP-2007-0546-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-06-23T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (7/1/2007)

EPA Registration Division contact: Janet Whitehurst; (703) 305-6129

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

Syngenta Crop Protection, Inc., PO Box 18300, Greensboro, NC 27419

[0F7730]

	EPA has received a pesticide petition ([0F7730]) from Syngenta Crop Protection, Inc., PO 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.

(Options (pick one)
   
   	1. by establishing a tolerance for residues of

		Thiabendazole, [2-(4-thiazolyl)-1H-benzimidazole], (CAS Reg. No. 148-79-8) and its metabolite benzimidazole (free and conjugated), in or on  corn, field, forage (0.01 ppm),  corn, field, grain (0.01 ppm), corn, field, stover (0.01 ppm), corn, pop, forage (0.01 ppm),  corn, pop, grain (0.01 ppm), corn, pop, stover (0.01 ppm), corn, sweet, forage (0.01 ppm), corn, sweet, stover (0.01 ppm), corn, sweet, kernel plus cobs with husks removed (0.01 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 qualitative nature of the residues in plants is adequately understood based on soybean, sugar beet, and wheat metabolism studies.  The residues of concern in plants include   thiabendazole and benzimidazole, free and conjugated.]

	2. Analytical method. [Adequate analytical methodology is available for data collection enforcing of thiabendazole residues. The Pesticide Analytical Manual (PAM) Vol. II lists four spectrophotofluorometric methods (Methods I, A, B and C) for determining residues of  thiabendazole  per se in or on plant commodities, and one spectrophotofluorometric method (Method D) for determining residues of thiabendazole and 5-hydroxy-thiabendazole in milk.]

	3. Magnitude of residues. [Syngenta Crop Protection, Inc. has submitted complete residue data for Thiabendazole on corn (representing field corn forage, grain and stover,  pop corn forage, grain and stover and sweet corn forage, stover, and kernel plus cob with husks removed).]

B. Toxicological Profile

      	1. Acute toxicity.  [Thiabendazole has very low acute toxicity via oral and dermal (Category IV).   For acute inhalation, Thiabendozole is classified under Category II.   Thiabendazole is minimally irritating to the eye (Category III) and not irritating to skin (Category IV).  It is not a dermal sensitizer. ]

	2. Genotoxicty. [The available genetic toxicology studies on thiabendazole indicate that the compound is not mutagenic in bacteria or clastogenic in vitro in mammalian cells.  Thiabendazole did not cause DNA strand breaks in cultured rat hepatocytes and was negative for structural chromosome aberrations in rats.]

      	3. Reproductive and developmental toxicity. [In the rat development study, the observed  maternal and developmental LOAEL/NOAEL of 40/10 mg/kg/day was based on decrease in body weight and food consumption.  

In the mouse prenatal development toxicity study, there were reductions in maternal body weight at mid (100 mg//kg/day) and high dose (299 mg/kg/day) treatment groups. There were accompanying reductions in feed consumption in the HDT group. The mouse maternal and developmental LOAEL/NOEAL were 100/25 mg/kg/day, respectively.  

In a rabbit developmental study, decreased maternal body weight gains and decreased  food consumption were seen at HDT (600 mg/kg/day).  There was also decreased fetal body weight and increased resorptions at 600 mg/kg.  The rabbit maternal and developmental LOAEL/NOAEL were 600/150 mg/kg, respectively.  
In a 2-generation reproduction study in the rat, the parental systemic LOAEL was based on decreased body weight gain and food consumption seen at 30 mg/kg.  The NOEAL was 10 mg/kg. The offspring LOAEL was based on decreased body weight gain in offspring during lactation seen at 30 mg/kg. The reproductive LOAEL was >90 mg/kg.  The effects in the offspring were observed at higher dosages (90 mg/kg) than dosages (30 mg/kg) causing parental toxicity.  Therefore, there was no increased susceptibility.]

      	4. Subchronic toxicity. [In a 21 day dermal toxicity study in the rabbit, thiabendazole was administered dermally to rabbits. No systemic or dermal toxicities were noted at doses up to 1000 mg/kg/day. The systemic and dermal  NOEL was 1000 mg/kg.  

In a subchronic toxicity study, thiabendazole was administered to rats in the diet.  The NOEL of 10 mg/kg was based on reduced body weight gains and histopathological changes in the bone marrow, liver and thyroid.  

In another subchronic toxicity study, thiabendazole was administered to rats by gavage at doses of 0, 25, 100, or 400 mg/kg/day for 14 weeks .  The LOAEL for this study was 100 mg/kg/day. The NOEL of 25 mg/kg was based on histopathological changes of the liver, thyroid, kidneys, and spleen. 

In a subchronic toxicity study in dogs, thiabendazole was administered orally in capsules to four beagle dogs at dose levels of 0, 35, 75, or 150 mg/kg/day for 14 weeks.  The NOEL was150 mg/kg based on the increase of gallbladder epithelial cytoplasmic vacuolation.]

      	5. Chronic toxicity. [In a chronic toxicity study, thiabendazole was administered orally in capsules to four beagle dogs at dose levels of 0, 10, 40, or 160 mg/kg/day for 52 weeks.  The LOAEL for this study was 40 mg/kg based on increased liver weight, splenic erythropoiesis and hemosiderosis in both sexes. The LOAEL was 10 mg/kg. 

In a chronic toxicity and carcinogenicity study, thiabendazole was administered to rats in the diet at dose levels of 0, 10, 30, or 90 mg/kg/day for104 weeks.  The systemic LOAEL was 30 mg/kg based on increase in incidence of benign thyroid  follicular cell adenoma.  The NOAEL was 10 mg/kg.  

In a carcinogenicity study, thiabendazole was administered to 50 mice for 105 weeks.  There was an increase in mortality in all dose groups.  Body weight gains were significantly lower in high dose female and male. However, no treatment-related  increase in tumor incidence above background level was observed.]

	6. Animal metabolism. [The rat, goat and hen metabolism studies indicate that the qualitative nature of the residues in animals is adequately understood. The residue of concern in eggs, milk, and poultry and livestock tissue is thiabendazole and 5-hydroxy-thiabendazole (free and conjugated) and benzimidazole.

In a rat metabolism study, radio-labeled thiabendazole was administered to rats by gavage. Thiabendazole was readily absorbed by male and female rats following oral dosing.   Within 168 hours of dosing , over 89% of the dose was excreted in urine and feces.  The majority of the administered dose was recovered in the urine identified as the glucuronide conjugate of 5-hydroxythiabendazole and the sulfate conjugate of 5-hydroxy thiabendazole.  The data indicate that the renal excretion is the primary pathway for the elimination of thiabendazole from rats.  At the low dose level, it was shown that thiabendazole oxidizes to form 5-hydroxythiabendazole, followed by conjugation to form glucuronide and sufate conjugates of 5-hydroxythiabendazole. ]

	7. Metabolite toxicology. [The nature of residues in plants and animals is adequately understood. Residues of concern in plants include thiabendazole and its metabolite benzimidazole, free and conjugated.  The residue of concern in animal commodities are thiabendazole and 5-hydroxy-thiabendazole (free and conjugated) and benzimidazole.  No additional additional toxicologically significant metabolites were detected in any of the plant or animal metabolism studies. ]

	8. Endocrine disruption. [Thiabendazole does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system.  Developmental toxicity studies in rats and rabbits and a reproduction study in rats gave no indication that thiabendazole might have any effects on endocrine function related to development and reproduction. ]

C. Aggregate Exposure

	1. Dietary exposure. [Tier III/IV chronic dietary exposure evaluations were made for thiabendazole using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID[TM], version 2.16) from Exponent.  These exposure assessments included all registered uses (apple, avocado, banana, dry bean, dry peas, Brussels sprouts, cabbage, cauliflower, cantaloupe, carrot, citrus fruit, lentils, mango, mushroom, papaya, pear, potato, soybean, strawberry, sweet potato, and wheat) and a proposed use on corn (seed treatment). USDA-PDP monitoring data (1994  -  2005) was used for all crops except avocados, corn, mangos, papayas, and dry peas. The residue values for avocados, mangos and papayas were from field trials where the fruit was treated post-harvest at a rate selected to support the maximum use pattern specified on thiabendazole product labels. The residue values for dry peas and corn were from field trials where thiabendazole was applied as a seed treatment at the maximum use rate.  Residue values for dry peas were used for dry bean, cauliflower, and broccoli, as no residue data was available for these seed treatment uses.  Since PDP data, field trial data and current tolerance values reflect analysis for thiabendazole only, a correction factor was applied to wheat, soybean, sweet potato, cantaloupe and strawberry residue values to account for anticipated residues of benzimidazole which is a metabolite of thiabendazole.  Seed treatment data were reported as thiabendazole only as residues are not likely to be detectable from seed treated with thiabendazole.  Benzimidazole conversion factors and percent of crop treated values were taken from the EPA's September 7, 2000 dietary exposure assessment on thiabendazole (DP Barcode No. D267542).  Percent of crop treated values for mushrooms were provided by Syngenta.  Crop processing values for citrus oil and dry potato were empirically dervived and DEEM default processing values were used for all other crop commodities.  Tolerance values were used for all animal commodities.  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 Exposure: The acute dietary risk assessment was not performed since an endpoint of concern attributable to a single dose was not identified. ]
	

Chronic Exposure.  [The chronic assessment was run using DEEM-FCID(TM) software using the proposed tolerance value for corn seed treatment, the average field trial residue value for dry peas, avocado, mango and papaya, and the average USDA-PDP residue values for all other registered crops that are currently supported by the product labels.  The residue values for wheat, soybean, sweet potatoes, cantaloupes and strawberries were adjusted to account for residues of benzimidazole.  The chronic dietary risk assessment was performed for all population subgroups with a chronic reference dose of 0.1 mg/kg-bw/day based on a 2 year feeding/chronic/carcinogenicity study in rats with a NOAEL of 10 mg/kg-bw/day and an uncertainly factor of 100X.  The 100-fold safety factor includes 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 (non-cancer) exposure to the U.S. population resulted in a MOE of 6,953 (1.4% of the chronic RfD of 0.1 mg/kg-bw/day).  Chronic exposure to the most exposed sub-population (children 1 to 2 years old) resulted in a MOE of 1,647 (6.1% of the chronic RfD of 0.1 mg/kg-bw/day).  Since the Benchmark MOE for this assessment is 100 and since EPA generally has no concern for exposures above the Benchmark MOE or below 100% of the RfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic dietary (food only) exposure to residues arising from the current and proposed uses for thiabendazole. ]

Cancer.  [Thiabendazole has been classified as "not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis."  Therefore, no cancer risk assessment was performed for thiabendazole.]

	ii. Drinking water. [The Estimated Drinking Water Concentrations (EDWCs) of thiabendazole were determined for ground water using the Tier I SCI-GROW model and for surface water using the Tier I FIRST model which estimates pesticide concentrations in surface water.  EDWCs of thiabendazole from the currently registered uses plus the proposed seed treatment use on corn were determined.   Based on the SCI-GROW modeling results, the ground water EDWC for thiabendazole was 0.0104 ppb (chronic) based on the currently registered seed treatment use on dry peas.   Based on Tier I FIRST modeling for surface water, the currently registered dry peas use provided the highest chronic EDWC of 0.487 ppb (adjusted for 0.87 Percent Cropped Area, PCA).  Since the surface water chronic EDWC exceeds the ground water EDWC, the surface water value was used for risk assessment purposes and will be considered protective for any ground water concentration concerns. ]

 
Acute Exposure from Drinking Water:  [The acute exposure from drinking water was not performed since an endpoint of concern attributable to a single dose was not identified.]

Chronic Exposure from Drinking Water:  [The chronic EDWC of 0.487 ppb (0.000487 ppm) was input directly into the DEEM-FCID(TM) software as "water, direct and indirect, all sources" to model the chronic drinking water exposure.   Chronic drinking water exposure to the U.S. population resulted in a MOE of 974,206 (0.0% of the cRfD of 0.1 mg/kg-bw/day).  The most sensitive sub-population was all infants (<1 year old), with a MOE of 297,148 (0.0% of the cRfD of 0.1 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the Benchmark MOE or below 100% of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from all current and proposed uses of thiabendazole.]

	2. Non-dietary exposure. [There are no products containing thiabendazole that are currently registered for use by homeowners.  Thiabendazole-treated carpets and paints, can however, be used by homeowners.  In the 2002 EPA RED document, the Agency indicated that homeowners are not at risk from exposure to thiabendazole-treated carpets since the pesticide is applied to the backing of carpets during the manufacturing process and estimates are extremely conservative.  Due to thiabendazole's use profile, the Agency concluded that there is a low potential for residential exposure.  The low concentrations of thiabendazole incorporated in paints, adhesives, paper and carpet greatly reduces the potential for exposure.  Residential handlers using airless sprayer applicators and worst-case application rates resulted in a MOE of 1,010 (dermal plus inhalation).  In all cases, residential exposure is not expected to exceed EPA's level of concern (Benchmark MOE 100) and since EPA generally has no concern for exposures above the Benchmark MOE, Syngenta believes there is a reasonable certainty that no harm will result from residential exposure to residues arising from current uses for thiabendazole. ]

D. Cumulative Effects

	[Cumulative Exposure to Substances With a Common Mechanism of Toxicity.  Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity".  The Agency is examining whether and to what extent benzimidazole fungicidal pesticides share a common mechanism of toxicity.  Current information on the common mechanism of toxicity for benzimidazole fungicides is limited and the Agency's understanding of this relationship needs to be further developed.  As a result, the Agency has not determined if it would be appropriate to include them in a cumulative risk assessment with other benzimidazole fungicides or carcinogenic chemicals.  Therefore, for the purposes of this tolerance action, the EPA has not assumed that thiabendazole has a common mechanism of toxicity with other benzimidazole or carcinogenic chemicals.]

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 chronic aggregate (food plus water) exposure calculation for current and proposed uses of thiabendazole resulted in a MOE of 6,904 (1.4% of the chronic RfD of 0.1 mg/kg-bw/day) for the U.S. population.  Since the chronic aggregate MOE of 6,904 exceeds the chronic aggregate Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to the U.S. Population from chronic aggregate exposures arising from the current and proposed uses for thiabendazole.]

	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 chronic aggregate (food plus water) exposure calculation for current and proposed uses of thiabendazole provided a MOE of 1,643 for children 1 - 2 years old (the most sensitive population subgroup).  Since the chronic aggregate MOE of 1,643 exceeds the chronic aggregate Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to infants and children from chronic aggregate exposures arising from the current and proposed uses for thiabendazole.]

F. International Tolerances

	[The Codex Alimentarius Commission has established maximum residue limits (MRLs) for thiabendazole in/on various fruit, vegetable and animal commodities.  Codex MRLs for thiabendazole are currently expressed in terms of the parent for plant commodities and in terms of the sum of parent and 5-hydroxy-thiabendazole for animal commodities.  The tolerance expressions for U.S. tolerances includes residues of benzimidazole, as such, the U.S. tolerance definition is not compatible with Codex MRLs for plant commoditites. ]