


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

EPA Registration Division contact: PV Shah, 703-308-1846

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:

Aceto Corporation


[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from Exponent (1150 Connecticut Ave., NW Washington, DC 20036) on behalf of Aceto Corporation, EPA Company Number 33427-7, 4 Tri Harbor Court Port Washington, NY 11050 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)
   
   2. to establish an exemption from the requirement of a tolerance for

	Tin dioxide (also referred to as tin oxide in the EPA's Inert Finder Database), CAS No. 18282-10-5, for use in pre-harvest pesticide formulations as an inert ingredient in seed treatments with a maximum use rate of 40% in seed treatment formulations in accordance with 40 CFR §180.920.  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. Not applicable to this inert ingredient petition

	2. Analytical method. Not applicable to this inert ingredient petition

	3. Magnitude of residues. Not applicable to this inert ingredient petition


B. Toxicological Profile

	1. Acute toxicity. Tin dioxide is EPA Toxicity Category III for acute oral toxicity. Skin irritation and skin sensitization were not reported in humans from the use of low concentrations (0.3% to 0.5%) of tin dioxide as a cosmetic ingredient. No other relevant data were publically available on acute dermal toxicity, acute inhalation toxicity, skin irritation, eye irritation or skin sensitization.

	2. Genotoxicity. While studies were not available on tin dioxide, several in vitro and in vivo studies were conducted to determine the potential for genotoxicity with similar inorganic tin compounds that are applicable and described in World Health Organization (WHO), European Food Safety Agency (EFSA) and the Agency for Toxic Substances and Disease Registry (ATSDR) reviews.  Overall, inorganic tin is not considered to be genotoxic in vitro or in vivo.  

      3. Reproductive and developmental toxicity. While studies were not available on tin dioxide, several in vitro and in vivo studies were conducted to determine the potential for reproductive and developmental toxicity with similar inorganic tin compounds that are applicable and described in WHO, EFSA and ATSDR reviews. In a multigenerational study in rats with tin dichloride, the no observable adverse effect level (NOAEL) was 40 mg/kg/day. In rat developmental toxicity/teratogenicity studies conducted with inorganic tin compounds no effects were reported up to 635 mg (tin) /kg/day. No evidence of fetotoxicity or teratogenicity was seen in any study. 
      
	4. Subchronic toxicity. Available oral repeat dose subchronic studies conducted in rats and mice with inorganic tin compounds are described in WHO, EFSA and ATSDR reviews. Clear NOAELs were established for soluble inorganic tin, with the critical toxicological effects being decreased body weight gain and local gross pathological effects (distended cecum and reddened mucosal surface of the stomach).  The 13-week oral NOAEL in rats for tin dioxide was reported as 1000 ppm, estimated to be equivalent to 1000 mg/kg/day.  

	5. Chronic toxicity. No carcinogenic effects were observed in rat and mouse National Toxicology Program (NTP) carcinogenicity studies conducted by oral administration with tin(II) chloride.  The NOAEL was 60 mg/kg (tin)/day.

	6. Animal metabolism. While animal metabolism studies were not available on tin dioxide, several in vitro and in vivo studies were conducted to determine the potential for reproductive and developmental toxicity with similar inorganic tin compounds that are applicable and described in WHO, EFSA and ATSDR reviews.  In addition to evaluation of reproductive and developmental toxicity, these studies also provide information regarding metabolism of inorganic tin, indicating that bioavailability of inorganic tin in humans and animals via oral exposure is low.  Ingested tin is largely unabsorbed and excreted mainly in the feces, with additional slow elimination of the absorbed fraction in the urine.  



	7. Metabolite toxicology. There are no metabolites of toxicological concern. 

	8. Endocrine disruption. EPA did not report any information to suggest that tin dioxide would have any endocrine effects.  When the appropriate screening and/or testing protocols under the EDSP have been developed, tin dioxide may be subject to additional screening and/or testing to better characterize effects related to endocrine disruption.  This does not impact the current regulatory status of this material.

C. Aggregate Exposure

1. Dietary exposure. Based on the use pattern as a colorant in seed treatment coatings and the physical, chemical, and environmental properties of tin dioxide, significant crop residues are not likely. Possible food and water exposures to tin dioxide have been evaluated using the EPA Inerts Dietary Exposure Evaluation Model (I-DEEM), the primary screening model for predicting dietary exposure to inert ingredients in pesticide products. I-DEEM establishes a highly conservative estimate of dietary exposure for the food uses of an inert ingredient from both food and water.  I-DEEM, as developed by EPA, uses crop-specific residue data (i.e., maximum tolerances) for 57 active ingredients as surrogates for potential inert ingredient residue levels. I-DEEM estimates that inert ingredients are used on all crops, and that 100 percent of all crops are assumed to be "treated" with the inert ingredient. I-DEEM also assumes that the inert ingredient is present at a concentration of 50% in all the pesticide formulations. For tin dioxide, the only change to the I-DEEM default parameters was to change the concentration to 40% to reflect a maximum use rate. Based on the proposed use of the inert ingredient, chronic oral dietary points of departure are relevant for tin dioxide. No relevant acute effects were reported in the toxicological database for tin dioxide or inorganic tin compounds; therefore, an acute endpoint for risk assessment was not identified. The chronic reference dose was 0.6 mg (tin)/kg/day based on the POD of 60 mg (tin)/kg/day and total uncertainty factors of 100X (10X interspecies, 10X intraspecies, and 1X FQPA).

	i. Food. Food exposures of concern are not anticipated for tin dioxide up to the maximum concentration of 40% in pesticide formulations.  

	ii. Drinking water. Drinking water exposures of concern are not anticipated for tin dioxide up to the maximum concentration of 40% in pesticide formulations.  

	2. Non-dietary exposure. The occupational risk assessment endpoints are specific to dermal and inhalation exposure expected through use and incidental oral exposures.  The expected duration of occupational exposure is short to intermediate term.  Because appropriate duration testing data were available for tin dioxide, those data were used for the point of departure (POD) for inhalation and dermal exposure.  The endpoint selected for risk assessment was 500 mg/kg/day based on the 13-week oral NOAEL in rats with tin dioxide.  Based on the short to intermediate term risk assessment, occupational exposures are not anticipated to exceed the EPA's level of concern for tin dioxide up to the maximum concentration of 40% in pesticide formulations.  

D. Cumulative Effects The Agency has not made a common mechanism of toxicity finding for tin dioxide and it does not appear to produce a toxic metabolite that is produced by other substances.  For the purposes of this tolerance exemption petition, therefore, it is assumed that tin dioxide does not have a common mechanism of toxicity with other substances.

E. Safety Determination

Based on the current database of toxicology, environmental and ecotoxicological data provided herein for tin dioxide and supporting inorganic tin compounds, there are sufficient data to conduct the risk assessment and to demonstrate reasonable certainty of no harm as required by the Food Quality Protection Act (FQPA).  The FQPA safety factor for tin dioxide can be reduced from 10X to 1X because the toxicological database is complete, clear NOAELs exist for each study, and no sensitivity to offspring has been demonstrated.  

	1. U.S. population. Using a 40% cap in - pesticide formulations, the chronic dietary exposures are 25% of the cRfD for the U.S. Population.  

	2. Infants and children. Using a 40% cap in - pesticide formulations, the chronic dietary exposures are 94% of the cRfD for children 1-2 years of age, the most highly exposed sub-population.

F. International Tolerances
There are no known international tolerances established for tin dioxide or inorganic tin compounds.  Maximum limits of tin content in canned foods (200 mg/kg) and beverages (100 mg/kg) have been established by Codex to protect against possible local acute effects on the gastrointestinal tract in humans.  
