Document ID: EPA-HQ-OPP-2011-0113-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-08-29T04:00Z

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

EPA Registration Division contact: Shaja Joyner (703)308-3194

Taminco, Inc. 

1E7823

	EPA has received a pesticide petition (1E7823) from Taminco, Inc., Two Windsor Plaza, Suite 411, Allentown, PA requesting, 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 thiram in or on the raw agricultural commodity avocado at 8 parts per million (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 and chemical nature of residues of thiram in plants has been extensively evaluated and is adequately understood.

	2. Analytical method. Avocado samples were analyzed according to ALS Laboratory Group method MS 133.02 "The Determination of Mancozeb and/or other Ethylene-bis-dithiocarbamates (EBDCs) as CS2 in Plant Tissue by GC/MS". Detection and quantitation for thiram (as CS2) were conducted using a gas chromatograph (GC) equipped with a mass spectral detector for determination of CS2. The limit of quantitation (LOQ) was 0.05 ppm reported as carbon disulfide (CS2) evolved.
	
      3. Magnitude of residues.  Three residue trials on avocado, HAAS variety, were
conducted in the State of Michoacan, Mexico (NAFTA Region 18). This area is
representative of the avocado production area in Mexico from which avocadoes may be
imported to the United States. A formulation containing 80% w/w thiram was applied at
a rate of 2.4 kg a.i./hectare equivalent to 2.14 lb a.i/acre. The avocados were treated on 14
+- I days preharvest (PHI), 7 +- I days PHI and on the day of harvest (0 day PHI). Analytical results support the establishment of import tolerance of 8 ppm for whole avocado fruit. A tolerance for avocado pulp has not been proposed as no thiram residues were found in avocado pulp samples.

B. Toxicological Profile

                                          1.       Acute toxicity.  Acute toxicity. The acute oral LD50 was 2600 mg/kg (Toxicity Category III). The acute dermal LD50 was greater than 2000 mg/kg (Toxicity Category III). The acute inhalation LC50 for was 2: 3.46 mg/L (Toxicity Category III). Thiram is a moderate eye irritant, a very slight dermal irritant and a moderate skin sensitizer.
      
      In an acute neurotoxicity study, Sprague-Dawley rats were orally gavaged at 0,5, 150, and 600 mg/kg, and were subsequently evaluated in functional observational batteries (FOB) and motor function observations. Neuropathological evaluations were performed.  The Lowest Observed Adverse Effect Level (LOAEL) was 150 mg/kg based on FOB effects (lethargy, lower temperature, reduced startle response, no tail pinch response), reduced motor activity, and reduced brain weights. The No Observable Adverse Effect Level (NOAEL) for neurotoxicity was 5 mg/kg.
      	
                                          2.       Genotoxicty. Genotoxicity evaluations of thiram were negative in a mammalian cell gene mutation assay with Chinese Hamster V9 cells, a chromosomal aberrations assay in Chinese hamster ovary cells, an DNA repair study in cultured rat hepatocytes and an in vivo micronucleus study in mice.

      3. Reproductive and developmental toxicity. In a developmental toxicity study in rats, a maternal NOAEL was not achieved. The maternal LOAEL was 7.5 mg/kg/day based on reduced body weight gains and clinical signs of toxicity. The developmental NOAEL was 7.5 mg/kg/day.

      Pregnant female rabbits were dosed with thiram via gavage on gestation days 7 to 19. The NOEL for maternal and developmental toxicity was 10 mg/kg/day, the highest tested
      dose.

      Two multi generation studies with thiram were conducted in rats. In both studies, the rates were exposed over two generations. In the first study, the parental NOEL was 25 ppm, the reproductive NOEL was 50 ppm and the fetal NOEL was 50 ppm. The results from the second study showed a parental NOEL was 20 ppm, the reproductive NOEL was>180 ppm and the fetal NOEL was 20 ppm.

      A developmental neurotoxicity study was conducted in which female rats received diets containing 0, 20, 45 or 90 ppm thiram from gestation day 3 through postnatal day 20. The maternal systemic and neurotoxicity LOAEL was 90 ppm based on decreased body weight, body weight gain and food consumption, clinical signs of toxicity and FB findings. The maternal NOAEL was 45 ppm. The offspring systemic and neurotoxicity LOAEL was 45 ppm based on increased locomotor activity in females on PND 17. The offspring NOAEL was 20 ppm.

      4. Subchronic toxicity. Thiram was administered via the diet to rats for 13 weeks. The LOEL was 250 ppm based on effects on body weight, body weight gain, food consumption, hematologic and clinical chemistry parameters, organ weights and liver histopathologic findings. The NOEL was 50 ppm.

      In a subchronic neurotoxicity study, rats were exposed to thiram technical (98.76% a.i.) in their diet at doses of 0, 30, 125, or 500 ppm. The neurotoxicity LOAEL is 125 ppm, based on increased numbers of rearing events and elevated incidences of hyperactivity in females at weeks 8 and 13. The NOAEL was 30 ppm for females and 125 ppm for males.

      5. Chronic toxicity. In a combined chronic/oncogenicity study, Thiram technical was administered to albino rats in the diet for 104 weeks. The LOAEL was 119 ppm based on a reduction in body weight gain, changes in hematology and clinical chemistry parameters; and an increased incidence of bile duct hyperplasia. The NOAEL was 16.3 ppm.
      
      Thiram was administered to male and female beagle dogs via the diet for 52 weeks. The LOAEL was 90 ppm (2.6 rug/kg/day) based on elevated cholesterol levels and increases in liver-to-body weight ratio. The NOAEL was 30 ppm (0.84 mg/kg/day).

      6. Animal metabolism. Thiram is readily absorbed (via the oral route), distributed, extensively metabolized and eliminated primarily in the expired air and urine of rats within 24 hours following single or repeated oral administrations. No sex differences in metabolism were noted and very low levels were found in tissues (1.5-4.2%).

	7. Metabolite toxicology. No metabolites of toxicologic concern have been noted.

      8. Endocrine disruption.  No indication of potential endocrine effects have been seen in any of the toxicological studies including reproductive and developmental toxicity studies conducted with thiram.

C. Aggregate Exposure

	1. Dietary exposure. 
            i. Food. No additional dietary exposure is expected from this petition as no residues of thiram are found in the edible avocado pulp.

            ii. Drinking water. No additional water exposure is expected as this is an import tolerance petition.

      2. Non-dietary exposure.  Non-dietary exposure is not expected for this import tolerance

D. Cumulative Effects
      The USEPA is developing methodologies for assessing cumulative risks for chemicals having common mechanisms of toxicity. No available data indicate that the toxic effects produced by thiram would be cumulative with those ofany other chemical compounds.

E. Safety Determination

      1. U.S. population. The acute dietary exposure for the General U.S. Population was 23.3% of the ARID. The population group with the highest acute dietary exposure was Females 13-49 yrs. Total acute exposure for females 13-49 years was estimated to be 0.009522 mg/kg/day, equivalent to 68.0% of the ARID.

      Chronic dietary exposure for the General U.S. Population and the multiple population subgroups was 3.2% of the CRID.
	
      2. Infants and children. The acute dietary exposure for Infants and Children ranged from 27.4% to 50% of the ARID. The highest acute dietary exposure for Infants and Children was Children 1-2 years.
      
      Chronic dietary exposure for Infants and Children ranged from 4.2% to 9.2% of the CRID with the highest chronic dietary exposure for Children 1-6 years.

F. International Tolerances 
      Codex MRLS have been established for the Dithiocarbamates as the sum of residues of zineb, ziram, thiram, nickel bis(dimethyl dithiocarbamate), ferbam, propineb, polycarbamate, mancozeb, maneb and metirarn which are calculated as carbon disulfide. Applicable MRLs (Codex, February 2006) for thiram are apples (5 ppm), bananas (2 ppm), stone fruits (7 ppm) and strawberries (5 ppm).