Document ID: EPA-HQ-OPP-2010-0186-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-05-19T04:00Z

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

EPA Registration Division contact: Tony Kisch, (703) 308-9443

Nissan Chemical industries, Inc.

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from Nissan Chemical Industries, Inc., 3-7-1, Kanda Nishiki-cho, Chiyoda-ku, Tokyo, Japan 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 [3-[3-bromo-6-fluoro-2-methyl-H-indol-1-yl)sulfonyl]-N,N-dimethyl-1H  -  1,2,4-triazole-1-sulfonamide (amisulbrom) in or on grapes at 0.4 ppm and on raisins at 1.0 ppm. The proposed tolerance will be a tolerance on treated grapes and its processed products treated in Western Europe and imported into the U.S. There will be no U.S registration. 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. Metabolism studies were conducted with Thompson seedless grapes using [14]C amisulbrom labeled in both the indole and the triazole ring.
      
      Studies were conducted in both 2004 and in 2005 in California. 
      
      The 2004 study reflected application at the rate of 100 g a.i./ha or 0.089 lb a.i./A using a 20% SC formulation.
      
      Applications were made at 34, 24 and 14 days before harvest. Fruit were harvested at 0 and 7 days after the last application. Fruit and leaves were harvested at 14 days after last application. Additionally, some bunches of grapes were covered during amisulbrom application. The purpose of this was to assess translocation in the grape plant. 
      
      The 2005 grape study reflected application at the rate of 75g a.i./ha or 0.067 lb a.i./A using a 20% SC formulation. 
      
      Applications were made at 58, 48, 38 and 28 days before harvest. Fruit were harvested at 0 days after the last application. Fruit and leaves were harvested at 28 days after last application. 
      
      Samples from both metabolism studies were surface washed with acetonitrile on the day of sampling. The washed samples were extracted by homogenization with acetonitrile: water and the remaining solid residues combusted. The radioactivity from the washes, extracts and residues are the total residue in the plant.
      
      In the 2004 study, residues at 14 days after application were 0.289 ppm and 0.537 ppm for the [14]C indole and the[14]C triazole ring labeled amisulbrom respectively. Translocation was found to be a very minor route in the metabolism of amisulbrom in grapes. At both the 0 day and the 14 day harvest intervals, the major residue was amisulbrom per se; 84.3% from the indole ring label and 83.4% from the triazole ring label. There were 8 non-bridge cleaved metabolites, 2 bridge cleaved metabolites, up to 10 unidentified metabolites and polar metabolites. The levels of individual metabolites were between <=0.05% of the total radioactive residue (TRR) and 1.2% TRR (<=0.0005 ppm and 0.006 ppm). The potential residue of concern, 1,2,4-triazole was not detected in grape fruits treated with triazole-ring labeled amisulbrom.
      
      The residue level in the grape foliage was higher in the foliage than in the grape fruits; 6.08 and 9.19 ppm respectively from the [14]C indole and the[14]C triazole ring labeled amisulbrom. Amisulbrom comprised 3.54 ppm and 4.79 ppm respectively from the [14]C indole and the[14]C triazole ring labeled amisulbrom. Soxlet extraction, mild acidic and basic hydrolysis, EDTA extraction and enzyme hydrolysis were used to release the bound residue. There were 7 non-bridge cleaved metabolites, 3 bridge-cleaved metabolites and up to 13 unidentified metabolites and polar material. 
      
      In the 2005 study, residues at 28 days after application were 0.319 ppm and 0.231 ppm for the [14]C indole and the[14]C triazole ring labeled amisulbrom respectively. Translocation was found to be a very minor route in the metabolism of amisulbrom in grapes. At the 28 day harvest interval, the major residue was amisulbrom per se; 67.3% from the indole ring label and 69.8% from the triazole ring label. There were 6 non-bridge cleaved metabolites, 3 bridge-cleaved metabolites, triazole alanine, triazole acetic acid up to 18 unidentified metabolites and polar metabolites. The levels of individual metabolites were between <=0.05% of the total radioactive residue (TRR) and 5.1% TRR (<=0.0005 ppm and 0.012 ppm). The potential residue of concern, 1,2,4-triazole was not detected in grape fruits treated with triazole-ring labeled amisulbrom.
      
      The residue level in the grape foliage was much higher in the foliage than in the grape fruits; 3.02 and 3.58 ppm respectively from the [14]C indole and the[14]C triazole ring labeled amisulbrom. Amisulbrom comprised 1.07 ppm and 1.35 ppm respectively from the [14]C indole and the[14]C triazole ring labeled amisulbrom. Soxlet extraction, mild acidic and basic hydrolysis, EDTA extraction and enzyme hydrolysis were used to release the bound residue. There were 7 non-bridge cleaved metabolites, 4 bridge-cleaved metabolites, triazole acetic acid and up to 30 unidentified metabolites and polar material. The levels of the individual metabolites were between <=0.003 ppm and 0.213 ppm.
      
      The nature of the [3-[3-bromo-6-fluoro-2-methyl-1H-indol-1-yl)sulfonyl]-N.N-dimethyl-1H-1,2,4-triazole-1-sulfonamide] (ISO name-amisulbrom) residue in grapes is adequately understood. In summary, [amisulbrom] is metabolized as follows.
      
1.       Cleavage of the sulfonylamino side chain on the triazole ring
2.       Debromination
3.       Oxidation/hydroxylation
4.       Cleavage of the sulfonyl bridge between the indole and triazole ring
5.       Indole ring opening
      
      The plant metabolism data show that the amisulbrom itself translocates to a very small extent into the grape fruit. 77% of the residue in grapes has been identified. 70% of the residue in grape fruits is amisulbrom at the proposed 28 day PHI. The potential residue of concern, 1,2,4-triazole was not detected in grape fruits treated with triazole-ring labeled amisulbrom. 
      
      The nature of the residue in grapes, raisins and grape leaves is adequately understood. 
      
      The residue of toxicological concern is parent compound, amisulbrom [3-[3-bromo-6-fluoro-2-methyl-1H-indol-1-yl)sulfonyl]-N.N-dimethyl-1H-1,2,4-triazole-1-sulfonamide].

   1. Analytical method. The analytical method used to collect grape field and processing data is briefly described below.

      Grape Method. (Report No. NAS/490/042294):
      
      The method involves extracting the crop substrate with acetonitrile: water (80:20 v/v).  Clean-up was performed using solid phase extraction (SPE), prior to quantitation using tandem mass spectrographic detection (LC/MS/MS). The limit of quantitation is 0.01 ppm. The limit of detection is 0.0025 ppm.  
      
      Processing Method. (Report No. NAS/648/052518):
      
      The analytical method used to collect raisin, juice, and wine processing data is similar to the method used for grapes, but has a few minor modifications. The determination and quantitation of the amisulbrom is conducted using LC/MS/MS detection.  The limit of quantitation of the method for amisulbrom is 0.01 ppm.
      
      Independent Method Validation. (Report No. 0306-150):  
      
      The analytical method used for grape data collection (Report No. NAS/490/042294) was subjected to an independent laboratory validation. Untreated control grapes were fortified with amisulbrom at 0.01 ppm and 1.0 ppm.  The method was successfully validated  and the results are shown in the following table.
      
      Independent Laboratory Validation Grape Analytical Method
      
      Analyte
                              Fortification Level (ppm)
                                    Recovery (%)
      Amisulbrom
                                        0.01
                                        1.00
      85, 82, 84, 70, 73
      90, 97, 90, 87, 57
      
                                  Overall Mean = 82
                             Standard Deviation =  11.7
      
      
      Independent Laboratory Validation Analytical Method
      
                                          
                                          
                                     Amisulbrom
                                Procedural Recoveries
                                        
                                       
                                    Matrix
                            Range of Fortification
                                     (ppm)
                                          
                                          
                                          n
      Mean
                                          %
                                      Recovery
                                    Grapes
                                     0.01
      5
                                         79
      
                                      1.0
      5
                                         84
      
      
      Enforcement Method Conclusion:  An analytical method (LC/MS/MS) is available for enforcement.
      
      Multiresidue Method. Grapes and Raisins (Report No. 221C-103):
      
      Grapes and raisins were analyzed to evaluate the multiresidue methodology as presented in the Pesticide Analytical Manual (PAM), Volume I (1), for the determination of amisulbrom in a fortified nonfatty plant substrate. The analyses were performed by solvent extraction and gas chromatography. The decision tree outline for MRM testing was (Protocol C and Protocol E).
      
      Grapes were fortified at 0.05 ppm a.i. and 0.5 ppm a.i. Raisins were also fortified at 0.05 ppm a.i. and 0.5 ppm a.i.
      
      For grapes, the recoveries at 0.05 ppm and 0.5 ppm were for samples extracted with method 303 E5 and cleaned-up with C1 were 117% and 120% and 86% and 92% respectively.
      
      For raisins the recoveries at 0.05 ppm and 0.5 ppm were for samples extracted with method 303 E5 and cleaned-up with C1 were 97% and 107% and 85% and 89%  respectively.
      
      Amisulbrom is recovered by the FDA PAM I Protocols C and E.
       
   2. Magnitude of residues. Grapes. The magnitude and decline of amisulbrom residues were determined on grapes and on raisins, grape juice and on wine.
      
      Magnitude of the Residue-Grape Raw Agricultural Commodity Crop Field Trials
      
      Seven field trials were conducted in 2003 using various varieties of grapes. 
      
      Trial sites were located in Germany (2 sites), North France (2 sites), South France (1 site), and Spain (2 sites).  Grapes were harvested 0-28 days following four applications (10 day spray intervals) with a suspension concentrate (SC) formulation of amisulbrom.  The target application rate was0.067 lb a.i./A. (Report No. NAS/519/033985)
      
      Samples of grapes were analyzed for residues of amisulbrom, using a validated analytical method (Report No. NAS/490/042294).  The overall recoveries were 79% to 100% for amisulbrom.  The limit of quantitation was 0.01 ppm.   The samples were stored frozen 38 to 121 days from collection to extraction.
      
      The residues of amisulbrom ranged from 0.17 ppm to 0.34 ppm at a 0 day PHI and 0.03 to 0.10 ppm in grapes at the proposed 28 day PHI.
      
      Eleven field trials were conducted in 2004 using various varieties of grape.  Trial sites were located in Germany (2 sites), North France (3 sites), South France (3 sites), Italy (2 sites), and Spain (1 site).  Grapes were harvested 0-28 days following four applications (10 day spray intervals) with a suspension concentrate (SC) formulation of amisulbrom-.  The target application rate was 0.067 lb a.i/A. (Report No. NAS/636/043428)
      
      Samples of grapes were analyzed for residues of amisulbrom, using a validated analytical method (Report No. NAS/490/042294).  The overall recoveries were 79% - 100% for amisulbrom.  The limit of quantitation was 0.01 ppm.   The samples were stored frozen 28 to 137 days from collection to extraction.
      
      The residues of amisulbrom ranged from 0.10 ppm to 0.90 ppm at a 0 day PHI and 0.03 to 0.23 ppm in grapes at the proposed 28 day PHI.
      
      Magnitude of the Residue-Grape Processed Commodity Crop Field Trials (Report No. NAS/638/043430):
      
      Four processing studies were conducted using grapes grown in Germany (two studies) and Italy (two studies). Grapes were harvested 28 days after four applications of an SC formulation of amisulbrom.  
      
      For the first German trial, there were two plots for two treatments rates. There was also a control plot in the study. 
      
      For the this trial, the first plot reflected four treatments at the proposed application rate of   0.067 lb a.i./A. The amisulbrom residue at the 28 day PHI was 0.28 ppm to 0.32 ppm prior to processing. 
      
      For the second plot, there were four treatments at 2.5 x the proposed application rate. The residue at the 28 day PHI was 1.13 ppm to 1.43 ppm prior to processing. 
      
      At a second German trial, the application rate was 0.067 lb a.i./A. There was also a control plot. The amisulbrom residue at the 28 day PHI was 0.21 ppm to 0.29 ppm prior to processing.
      
      There were two Italian grape residue studies for processing. In both studies the application rate was 0.067 lb a.i./A There were also control plots in each study.
      
      In one Italian study, the amisulbrom residue at the 28 day PHI was 0.05 ppm to 0.07 ppm prior to processing.
      
      In the second Italian study, the amisulbrom residue was 0.09 ppm prior to processing at the 28 day PHI.
      
      Grapes were harvested at a 28 day PHI in all of the studies that were used for processing.
      
      Processing study summary: Grapes treated at the proposed application rate in the four studies reported an average amisulbrom residue of 0.19 ppm in grape fruits at the 28 day PHI and were 0.16 ppm at processing; 0.45 ppm in raisins, 0.035 ppm in fresh grape juice, 0.021 ppm in pasteurized grape juice and non-detectable (<0.0025 ppm) in wine. Residues of amisulbrom are not likely to concentrate in grape juice and wine. 
      
      Magnitude of the Residue in Grape and Grape Processed Commodities
      
      A tolerance of 0.4 ppm is needed for grapes and because residues concentrate in raisins, a tolerance of 1.0 ppm is needed for raisins.
      
      Magnitude of the Residue in Animals
      
      There are no livestock feed items associated with the crops for which tolerances are proposed. There will be no problem of secondary residues resulting in meat, milk, poultry and eggs from the proposed grape use.
      
B. Toxicological Profile

   1. Acute toxicity. Acute Toxicity. Several acute toxicology studies were conducted, and the overall results placed technical grade amisulbrom in toxicity Category IV.  These include the following studies in Category IV: acute oral toxicity (LD50  >5,000 mg/kg); acute dermal LD50 > 5,000 mg/kg rabbit; acute inhalation toxicity (LC50 >2.85 mg/L, rat). Primary eye irritation: not irritating.  Primary skin irritation: not irritating. Amisulbrom was not a dermal sensitizer. 
       
   2. Genotoxicity. All mutagenicity studies on amisulbrom were negative.  Tests run included, bacterial gene mutation assays, chromosomal aberration study in human lymphocytes, mammalian gene mutation in mouse lymphoma cells, in vivo/in vitro unscheduled DNA synthesis, and in vivo mouse micronucleus test (bone marrow). 
      
   3. Reproductive and developmental toxicity.  A developmental toxicity study in Han Wistar rats administered dosage levels of 0, 100, 300 and 1000 mg/kg/d in 22 mated females.  The maternal and developmental   toxicity no-observed effect level (NOEL) was 1000 mg/kg/day. Result: No adverse effect on pregnancy or embryo -fetal survival and development. 
      
      A developmental toxicity study in rabbits administered dosage levels of 0, 30, 100 and 300 mg/kg/day, 24 rabbits/dose. The maternal toxicity NOEL was 30 mg/kg/day was based on decreased body weights and food consumption at 100, 300 mg/kg/d. No fetal effects were observed. The fetal NOEL was 300 mg/kg/d.
      
      A two-generation developmental study in Wistar rats (28/sex) fed diets containing 0, 120, 600, 3,000 ppm,15,000 ppm (or approximately 9.8, 48.5, 240, 1200 mg/kg/d for males and  10.5, 53, 261, 1291 mg/kg/d for females.)  Results were: Decreased body weight gains, food consumption and increased liver and decrease in ovarian weights and delayed sexual maturation at 3,000, 15,000 ppm: Poor sexual performance in females at 15,000 ppm. Found with mechanistic studies to be due to decreased food consumption and decreased food consumption and decreased lactation in the dams. 
      
      NOEL for F1 and F2 adults: 600 ppm
      NOEL for reproductive performance: 15,000 ppm (males) and 3,000 ppm (females)
      
      
   4. Subchronic toxicity. A 13-week study was conducted in Wistar rats fed diets
      containing 0, 2,000, 6,300 ppm, or 20,000 ppm amisulbrom  (or approximately 0, 170.6, 
      525.0, 1715.8 mg/kg/day in males and 0, 186.6, 587.2 and 1880.4 mg/kg/day in females). 
      The NOEL was 2,000 ppm (170.6 mg/kg/day) in males and 6,300 ppm (587.2 mg/kg/day) in
      females. This was based on decreased body wt, food consumption, increased liver enzymes,
      non-specific toxicity at 6300 and 20,000 ppm. 
      
      A 13-week feeding study in mice was conducted with diets that contained 0, 800, 2,500 or 
      8,000 ppm amisulbrom (or approximately 0, 118.8, 400.3, 1280.2 mg/kg/day in males and 0, 
      163.4, 505.6 and 1638.4 mg/kg/day in females).  The NOEL was 800 ppm (118.8 
      mg/kg/day) in males and (164.4 mg/kg/day) in females. This was based on non-specific
      toxicity seen at 2500 and 8000 ppm. Liver weighs increased at those doses. 
      
      A 13- week dog study with beagle dogs (4/sex/dose) was conducted with diets that 
      contained 0, 100, 300 1,000 mg/kg/day amisulbrom by capsule. The NOEL was 300 
      mg/kg/day. This was based on non-specific toxicity seen at 1000 mg/kg/day in early weeks, 
      increased alkaline phosphatase in females. 
      
      An acute neurotoxicity study was conducted with CD rats; 10/sex/dose were dosed at levels of 0, 200, 2,000 mg/kg with a14-day observation period. The results showed no effects at any dose except decreased absolute brain weights at 2,000 mg/kg (no accompanying pathology). The NOEL was greater than 2,000 mg/kg with no evidence of acute neurotoxicity.
      
      Subchronic Neurotoxicity Study. Rats dosed at levels of 0, 300, 3,000, and 10,000 ppm (or approximately 0, 22.9, 246, 860 mg/kg/d for males and 0, 29, 313, 1132 mg/kg/d for females. The results were general toxicity-reduced body weight gains at 3,000 and 10,000 ppm.
      
      NOEL: General Toxicity: 300 ppm (22.9 mg/kg/d for males and 29.0 mg/kg/d for females)
      NOEL: Neurotoxicity: 10,000 ppm (860 mg/kg/d for males and 1132 mg/kg/d for females.
      
      A 21-day dermal study was conducted in rats at amisulbrom doses of 0, 100, 300, or 1,000 
      mg/kg/day. The NOEL was 300 mg/kg/day (males) and 1000 mg/kg/day (females). This was 
      based on decreased body weight gain, food efficiency at 1000 mg/kg/day in males: 
      Hyperplasia at dermal application site in females at 300 and 1000 mg/kg/day, males at 1000
       mg/kg/day.
      
   5. Chronic toxicity. Chronic Toxicity/Oncogenicity. A two-year chronictoxicity study was conducted in Han Wistar rats fed diets containing 0, 200, 2000, 10,000, and 20,000 ppm amisulbrom (0, 11.1, 112,, 568 and 1160 mg/kg/day for males and 0, 14.3, 147, 753, and 1503 mg/kg/day for females, respectively). A two-year carcinogenicity study was conducted in rats fed diets containing 2,000, 10,000, 20,000, ppm (0, 96.0, 496, 1008 mg/kg/day for males and 0, 129, 697, 1436 mg/kg/day for females, respectively). 
      
      Toxicity phase: Non-specific toxicity was seen in liver and kidney. NOEL: 200 ppm (11.1 mg/kg/d for males and 14.3 mg/kg/d for females.
      
      Carcinogenicity phase: Well tolerated at 2,000 ppm but exceeded MTD at 10,000 and 20,000 ppm with marked decreased weight gain and increased mortality. Target organs: liver, kidney, stomach, duodenum, caecum, thyroid and mesenteric lymph nodes.
      
      Treated-related tumors were seen in liver and stomach at 10,000 ppm and higher, with excess toxicity in liver and chronic inflammatory changes in forestomach.
      
      Liver tumors: Hepatocellular adenomas (0, 2, 10, 13 in males; 0, 1, 24, 28 in females) and carcinomas (0, 0, 1, 0 in males and 0, 0, 2, 1 in females).
      
      Stomach tumors: Squamous cell papillomas (0, 0, 1, 2 in males) and carcinomas (0, 0, 0, 1in females).
      
      A carcinogenicity study in CD-1 mice (78 weeks) was conducted. 50 mice/sex. Doses: 0, 100, 800, 4000, 8000 ppm amisulbrom (11.6, 97.8, 494, 1035 mg/kg/d males; 13.5, 121, 594, 1255 mg/kg/d, females). Results: Decrease body weight gain at 4,000 ppm (23 % males) and 8,000 ppm (37 % male, 13 % females). Non-specific toxicity at 800 ppm and higher.  Focal hepatic necrosis at 8,000 ppm in males.
      
      Results: Neoplastic: Heptacellular adenomas, non carcinomas in males at 800 ppm and higher (9, 12, 17, 23, 18) MTD exceeded at 4,000 and 8,000 ppm.
      
      NOEL: 100 ppm (11.6 mg/kg/d males, 13.5 mg/kg/d females).
      
      A one-year feeding study was conducted in beagle dogs fed diets containing 0, 10, 100, 300, 1000 mg/kg/day amisulbrom by gelatin capsules. There was no specific toxicity at 300, 1000 mg/kg/day, target was liver.  The NOEL was 100 mg/kg/day.
      
   6. Animal metabolism. Single and repeat dose study:  Han Wistar rats were used in the two studies.
      
      The route of metabolism of amisulbrom in the rat involves a complex series of reactions including cleavage of the sulfonylamino side chain on the triazole ring, debromination, oxidation/hydroxylation and limited cleavage of the sulfonyl bridge between the indole and triazole moieties.
      
   7. Metabolite toxicology. Metabolite IT-4
      
      IT-4: reverse mutation in four histidine-requiring strains of Salmonella typhimurium and one tryptophan-requiring strain of Escherichia coli. Negative.
      
      IT-4: Induction of micronuclei in the bone marrow of treated mice. Negative.
      
      IT-4: Acute oral toxicity in the female rat (acute toxic class method). Strain: hsd.BrHan: WIST. Acute oral toxicity: > 50 mg/kg, < 300 mg/kg.
      
   8. Endocrine disruption. No special studies investigating the potential estrogenic or other endocrine effects of amisulbrom have been conducted. However, the standard battery of required toxicology studies has been conducted. These include an evaluation of the potential effects on reproduction and development, and an evaluation of the pathology of the endocrine organs following repeated or long-term exposure to doses that far exceed likely human exposures. Based on these studies there is no evidence to suggest that amisulbrom has an adverse effect on the endocrine system.
      
   9. Immunotoxicity.  Subchronic (4-week) immunotoxicity study:  Rats dosed at levels of 0, 400, 2,000, and 10,000 ppm (0, 32.8, 157, and 732 mg/kg/day in males and 0,33.4, 167, and 823 mg/kg/day in females).  The results were general toxicity with reduced bodyweight gain in both sexes at 10,000 ppm.  There were no statistically significant changes in number of cells/spleen, PFC/106 
      
      NOEL:  General Toxicity 2,000 ppm  (157 mg/kg/day for males and 167 mg/kg/day for females).
      
      NOEL:  Immunotoxicity:  10,000 ppm (732 mg/kg/day for males and 823 mg/kg/day for females).
      
      Subchronic (4-week) immunotoxicity study.  Mice dosed at 0,250, 1000, 4000 ppm (0, 36.7, 164, or 595 mg/kg/day in males and 0, 48.7, 191, or 738 mg/kg/day in females).  General toxicity was noted in males at 4,000 ppm with reduced bodyweight gain.  There were no statistically significant changes in number of cells/spleen, PFC/106 cells, or PFC/spleen for any groups that received amisulbrom.
      
      NOEL:  General Toxicity:  1,000 ppm (164 mg/kg/day for males and 191 mg/kg/day for females).
      
      NOEL:  Immunotoxicity:  4,000 ppm (595 mg/kg/day in males and 738 mg/kg/day in females).
      
C. Aggregate Exposure

   1. Dietary exposure.
 
      i. Food. 
      
      The chronic ADI is 0.11 mg/kg/d with 100 fold safety factor.
      
      The acute NOEL was based on the findings from the rabbit developmental toxicity study.  The NOEL for general toxicity was 30 mg/kg/day in dams.  This was the lowest does from all short term studies.   The DEEM Model was used to evaluate risk from acute dietary exposure to amisulbrom using this reference dose and tolerance level residues. Using the Tier I assessment (the most conservative exposure) for the overall exposure for the overall U.S. population, the predicted acute exposure are estimated to be 0.4% of the aPAD (0.3 mg/kg/d with 100-fold safety factor) for the general U.S. population, 0.7% for all infants, 2.1% for children aged 1-2 years old (the most highly exposed subpopulation), and 1.4% for children aged 3-5 years old.. Acute dietary exposures below 100% of the aPAD are reasonably expected to result in no harm to exposed populations.
      
      The chronic NOEL was based on the findings of a combined chronic/carcinogenicity study with rats. The NOEL for general toxicity was 11.1 mg/kg/d for males. This was the lowest dose from all long term studies. The DEEM Model was used to evaluate risk from chronic dietary exposure to amisulbrom using this reference dose and tolerance level residues. Using the Tier I assessment (the most conservative exposure) for the overall exposure for the overall U.S. population, the predicted chronic exposure are estimated to be 0.2% of the cPAD (0.11 mg/kg/d) for the general U.S. population, 0.3% for all infants, 1.1% for children aged 1-2 years old (the most highly exposed subpopulation), and 0.7% for children aged 3-5 years old. Chronic dietary exposures below 100% of the cPAD are reasonably expected to result in no harm to exposed populations.
      
      ii. Drinking water. 
      
      There is no U.S. registration proposed for the use on grapes; therefore will be no residues of amisulbrom  in drinking water in the U.S.
      
   2. Non-dietary exposure. There will be no registered use of amisulbrom in the U.S. The proposed tolerances are to cover residues that could occur on imported grapes and grape products that are treated in Western Europe and imported into the U.S. No U.S. registration is involved with this petition. 
      
      There will be no other sources of exposure to amisulbrom than the dietary exposure.
       
D. Cumulative Effect 

      There are no registered uses for the chemical amisulbrom. There is no evidence to indicate that amisulbrom has any toxic effects on mammals that would be cumulative with those of any other chemicals.

E. Safety Determination

   1. U.S. population.

      This assessment documents a Tier I chronic and acute dietary assessment associated with proposed tolerance-level residues of amisulbrom on grapes and raisins. Tolerance-level residues and 100% crop treated were assumed for all commodities. The chronic and acute dietary exposures associated with the proposed import tolerances for amisulbrom have been demonstrated to be less than the cPAD (0.11 mg/kg/d) and aPAD (0.3 mg/kg/d). Exposures below the cPAD and the aPAD are not of concern. These dietary assessments are conservative because they include tolerance-level residues and 100% crop treated for all commodities. Actual exposures will be considerably lower than those estimated here because only import tolerances are being proposed for amisulbrom.

   2. Infants and children.
      
      Based on the above, it is concluded that reliable data support use of the standard 100-fold uncertainty factor and that an additional uncertainty is not needed to protect the health of infants and children. 
      
F.	International Tolerances International Tolerances. Harmonization of Tolerances: 

   	There are no Mexican, Canadian or Codex MRLs/tolerances; therefore, compatibility is not an issue at this time. There is a 3 ppm MRL for amisulbrom on grapes in Japan. The use pattern differs from the use pattern in Europe.  In the EU, a 0.3 ppm MRL has been proposed for grapes, but it has not yet been established.  
   
   	A temporary MRL of 0.01 mg/kg has been set in the U.K. and in Northern Ireland for the use of NC-224 20 SC on potatoes; however, since potatoes from the U.K. and Northern Ireland are not imported in the U.S., import tolerances for these commodities are not required