UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION April 3, 2015

Erin Tesch, Technical Advisor Silver Task Force North America c/o Technology Sciences Group, Inc. 1150 18th Street, NW – Suite 1000 Washington, DC 20036

Subject: EPA Response to Silver Task Force North America Position Paper Dated December 12, 2012

Dear Ms. Tesch:

Thank you for your October 10, 2012 letter and th e Silver Task Force North America (STFNA) document titled, “Position Paper on Registratio n Review of Silver Compounds, December 12, 2012.” Among other things, the STFNA position pape r asserted that, although there are several forms of silver active-ingredients under review (Table 1), the active comp onent of toxicological interest for risk assessment purpos es for all silver-based pesticid es is the silver ion. Based on that assertion, STFNA recommended that the US Environmental Protection Agency (EPA) consolidate the review of all s ilver-based pesticide products and issue a single data call-in (DCI) using the silver ion as the common test substanc e because the silver ion is the “biologically active moiety.” In addition, the STFNA requested that all generic data requirements (i.e., those that do not deal with product chemistry) be placed on hold until EPA determines which products will be evaluated under which case.

This letter responds to the “P osition Paper on Registration Re view of Silver Compounds, December 12, 2012.” In our response, EPA affirms the approach of assessing the risk for silver, silver ion, silver nitrate, silv er chloride, silver oxide, and silver sulfate separately from nanosilver, silver zeolite, and silver sodium hydroge n zirconium phosphate as stated in the Silver and Compounds Final Work Plan (FWP) on Page 13 “The current PWP [Preliminary Work Plan] and this FWP are not intended to examine ef fects of nanosilver, which will be addressed separately...” and on Page 18 “Each silver zeolite compound is thus considered separately for hazard and risk assessments....” However, EPA agr ees to the STFNA’s request to place certain DCI-imposed data requirements (OCSPP guidelines 835, 850, 870, and 875) on hold. The registrants who are subject to the affected DCI requirements will be informed by a “DCI Status2 letter” about this decision to put the particular data requirements on hold and to impose revised deadlines for certain other ex isting data requirements. Background EPA is currently reviewing the silver-based pestic ides listed in Table 1 to determine whether they continue to meet the Federal Insecticide, Fungicide, and Rodenticid e Act (FIFRA) standard for registration. Registration Re view was initiated for the Silv er and Compounds case in June, 2009, and a FWP for this case was issued in December, 2009. On February 29, 2012, EPA issued DCIs for silver, silver nitrate, silver ch loride, silver oxide, and si lver sulfate and on July, 6, 2012, EPA issued a DCI for silver ion. Regist ration Review for the Nanosilver case was initiated in July, 2012 with the posting of the PWP to the Nanosilver docket.

Table 1. Silver Active Ingredients Curren tly Undergoing Registration Review Case Chemical Name PC Code 4082 – Silver and Compounds Silver 072501 Silver ion 072501 Silver nitrate 072503 Silver chloride 072506 Silver oxide 129097 Silver sulfate 072511 Silver zeolite 221700 Silver sodium hydrogen zirconium phosphate 072560 5042 – Nanosilver N anosilver 072599

Risk Assessment Approach The STFNA position paper stated that while there were various silver-based materials in currently registered products and that these “...materials may differ in their mechanisms of action, the common and characteris tic element, release of silver ion, should predominate for initial risk assessment purposes.” In Attachment 2 of the position paper, STFNA categorized all the current registered silver products based on the mechanism of silver ion release, which included oxidation, dissolution and elution. Although STFNA provided additional information suggesting how pesticide usage relates to release of silver ions, there were no data provided quantifying the amount and form of silver released from each of the registrations identified in Attachment 2 of the position pape r. Notwithstanding the lack of data, but based on its analysis STFNA proposed that EPA should is sue a single DCI for all silver-based pest icides using silver ion alone as the common test substance.

The STFNA approach of classifying certain silve r-based pesticides based on the silver ion is consistent with EPA’s current risk assessment appr oach. For certain silver-based pesticides, the Antimicrobials Division Toxicity Endpoint Co mmittee met in 2004 and determined that once internalized in the body, the compou nd of interest is ionic silver, which is common to the silver salts, and that therefore, one toxi cology dataset can represent the hazard for the silver salts. This was the basis for combining silver, silver nitrate, s ilver chloride, silver oxide, silver sulfate, and silver ion as “Silver and Silver Salts” in the FWP for Silver and Compounds. However, for the3 reasons discussed in the following paragraphs, EPA has not concluded that the hazard of nanosilver or silver-based zeolites can be fully ch aracterized using only data for the silver ion. EPA issued the Nanosilver case separately from the Silver and Compounds case because the agency believes that because of the unique characteristics of nanosilver, products containing nanosilver may have different toxi city and / or fate profiles th an products containing only macroscaled silver or other silver ingredients. Thus , additional and different data are needed to determine whether the FIFRA standard for main taining registrations c ontaining nanosilver are met. This view on nanosilver is consistent with the 2009 FIFRA Scientific Advisory Panel (SAP) report on this issue, in which the SAP concl uded that nanosilver has unique physical and chemical properties and that the toxicity of nanosilver could di ffer from other forms of silver including the silver ion. 1 Notwithstanding this background, the STFNA position paper provided EPA with new and different journal articles than were considered by the 2009 SAP, and the STFNA position paper suggests that if the EPA were to consider the findings of these journal articles that the health and safety properties of nanosilver would be fully characterized using data for the silver ion alone. The agency is aware of no new data to suggest th at the SAP concerns are misplaced or that the hazard for the nanosilver in or released from use of a pesticide product can be fully characterized using silver ion hazard data only.

The EPA has determined that each zeolite-base d silver compound (silver zinc zeolite, silver copper zeolite and silver sodium hydrogen zircon ium phosphate) will be considered separately for antimicrobial pesticide hazard and risk assess ments. As stated in the STFNA proposal, EPA issued a letter to Gary Burin of Technology Sc iences Group on December 7, 2010 stating that it intends to bridge available toxicity data among antimicrobial zeolites manufactured from zeolite A instead of requiring toxicity data separately for each product containing zeolite A. However, there is no final conclusion regard ing extending this determination to bridge toxicity data for products containing zeolite X. At this time, the ag ency lacks sufficient in formation to determine if ionic silver is the only material of toxicological interest for silv er-based zeolites. Therefore, the agency has not determined if the hazard of silv er-based zeolites can be fully characterized using data for ionic silver alone. Because of this uncertainty, as stated in the Silver and Compounds FWP, EPA is requiring studies for silver-based zeo lites that are separate from silver salts. A DCI for silver-based zeolites has not been issued because EPA believes many silver-based zeolites may be incorrectly classified under the silver PC Code 072501 and therefore may need to be reclassified.

Re-Classification of the Form of Silver in Each Registration EPA greatly appreciates STFNA’s efforts regarding classifying s ilver-based pesticides by type (Attachment 2 of STFNA’s Position Paper) and plan s to use this information in guiding the reclassification process. In the event that EPA re-classifies a product, EPA will provide written notification to the registrant of each affected product and will pos t the information in the Silver Compounds and Nanosilver registration review public dockets. EPA will use the product chemistry data that were required in the DCIs issued in February and July, 2012 for assessment and to ensure that the form or forms of silver contained in each silver product is classified correctly.

1 FIFRA SAP. November 3-6, 2009: Assessment of Hazard and Exposure Associated with Nanosilver and other Nanometal Pesticide Products: A Consultation. http://www.epa.gov/scipoly/sap/

.4 All product-specific data requireme nts, including, but not lim ited to, particle size (OCSPP guideline 830.7520), must be submitted. The agency notes that many companies are deficient in responding to portions of the DCI, specifically the particle size da ta requirement. To avoid EPA issuance of a Notice of Intent to Suspend th e affected products pursuant to FIFRA section 3(c)(2)(B)(iv), the agency will request to rece ive from registrants within 90 calendar days measured from receipt of their “DCI Status letter ,” information that the agency determines will satisfy the overdue data requirement s identified in Tables 3 through 8.

Guidance Concerning the Particle Size Di stribution Data Requirement (GLN 830.7520) Because existing data indicate that particle si ze distribution may affect the hazard profile of metals as pesticide ingredients, EPA required info rmation about the particle size distribution of the silver-based active ingredie nt in these products. The agency intends to use particle size distribution data along with other product chemis try information to determine if each product(s) should be moved to the Nanosilv er Registration Review (Case No. 5042) or if the product(s) should remain in the case where they are currently included.

In response to requests for EPA guidance on determ ining the appropriate test method(s) to be used to fulfill this data requirement, EPA is providing the guidance below. EPA notes that there is no single method that is most appropriate fo r determining the particle size distribution of pesticide ingredients. The appropriate method de pends, among other things, on the particle sizes of the ingredient and whether th e ingredient is suspended in li quid, present as a dry powder, or contained within a solid matrix. The registrant must test the TGAI or MUP. Also, additional testing may be appropriate for nanomaterials . Refer to the discussion that follows on nanomaterial standards.

For liquid (and possibly solid powder) products:

a. If the material is in solution as a coll oid, use the Dynamic Light Scattering (DLS) technique for screening level size and size distribution. The identity of the capping agent used to limit the size of the nanomaterial should be submitted to the agency. b. If the material is produced as a solid pow der, use Dynamic Light Scattering (DLS) technique for screening leve l size and size distribution.

c. If the material is in solution as a colloid or produced as a solid powder and DLS is not sufficient, use Scanning Electron Micr oscopy (SEM) or Transmission Electron Microscopy (TEM).

For matrix composite products:

a. If the material produced is incorporated into a silica ma trix or any other polymeric matrix (to form a nanocomposite), use the X-Ray diffraction Method (XRD) to provide information on the structure of the entire material and a detailed position of each atom in the material. If more well-d efined particle size distribution data is needed, use SEM or TEM.

Standards Developed by ASTM and ISO for Nanomaterials Registrants are required to submit data which identify and characterize their product. The analytical techniques used for the characterizatio n of materials with la rger particles are not5 sufficient for the characterization of nanomaterials . Literature on nanomaterials indicates that one analytical technique may not suffice to identify and characterize a nanomaterial depending on the individual makeup of the product. The Amer ican Society for Testing Materials (ASTM) and the International Standards Organization (ISO) have develope d a number of standards for nanomaterials. OPP recommends the methods in Table 2.

Table 2: Methods Relevant to Nanometals (metal oxides) Standard Method ID/ Organization Information obtained from the Standard

ISO/TR 11360: 2010 Nanotechnologies guida nce for the classification and characterization of nanomaterials ISO/TS 11937: 2012 Nanotechnologies nanos cale titanium dioxide in powder form-characteristics and measurements ISO/TR 13329: 2012 Nanomaterials preparati on of material safety data sheet (MSDS) ISO/TS 17200-2013 Nanotechnologies nanop articles in powder formcharacteristics and measurements ISO/NP TS 19590 Nanoparticles detecti on and characteriza tion using singleparticle ICP-MS ASTM E2490-09 Standard Guideline for measurement of particle size distribution of nanomateri als in suspension by photon correlation spectroscopy ASTM E2834-12 Standard guide fo r measurement of particle size distribution of nanomaterials in suspension by nanoparticle tracing analysis (NTA) ASTM E2578-07(2012) Standard practice fo r calculation of mean sizes/diameters and standard deviations of particle size distributions ASTM E2859-11 Standard Guide fo r size and size measurement of nanoparticles using atomic force microscopy (AFM)

DCI Status Because proper product classification is essentia l to determine which products are subject to which data requirements, the agency is plac ing the generic data requirements guidelines 835, 850, 870 and 875 imposed by the referenced DCIs on hold until further notice. The specific data requirements affected by the hold are identified as such in Tables 3-8. These holds do not affect the product chemistry data requirements which still mu st be satisfied as stated in the referenced DCIs. Since, it is well past the initial due da te for fulfilling product chemistry data requirements in the DCI, any required information is due 90 ca lendar days after a letter is received by the registrant.6 Table 3 - Silver (GDCI-072501-1129) February 29, 2012 Guideline Requirement N umbe r Study Title Due Date 830.1600 Description of materials us ed to produce the product 90 days from receipt of letter 830.1620 Description of production process 90 days from receipt of letter 830.1650 Description of formulation process 90 days from receipt of letter 830.1670 Discussion of formation of impurities 90 days from receipt of letter 830.1700 Preliminary analysis 90 days from receipt of letter 830.1750 Certified limits 90 days from receipt of letter 830.1800 Enforcement analytical method 90 days from receipt of letter 830.1900 Submittal of samples 90 days from receipt of letter 830.6314 Oxidizing or reducing action 90 days from receipt of letter 830.6315 Flammability 90 days from receipt of letter 830.6316 Explodability 90 days from receipt of letter 830.6317 Storage stability of product 90 days from receipt of letter 830.6319 Miscibility 90 days from receipt of letter 830.6320 Corrosion characteristics 90 days from receipt of letter 830.6321 Dielectric breakdown voltage 90 days from receipt of letter 830.7520 Particle size, fiber length , and diameter distribution 90 days from receipt of letter 830.7840 Water solubility: Column elution method, shake flask method 90 days from receipt of letter7 835.1100 Activated sludge sorption isotherm On hold 850.1350 Mysid chronic toxicity test On hold 850.1400 Fish early-life stage toxicity test On hold 850.1735 Whole sediment: acute fr eshwater invertebrates On hold 850.1740 Whole sediment: acute marine invertebrates On hold 850.1850 Aquatic food chain transfer On hold 850.4225 Seedling emergence, Tier II On hold 850.4250 Vegetative vigor, Tier II On hold 850.4400 Aquatic plant toxicity test using Lemna spp. Tiers I and II On hold 850.5400 Algal toxicity, Tiers I and II On hold 850.6800 Modified Activated Sludge Respiration Inhibition On hold 870.3465 90-day inhalation toxicity On hold 875.1400 Inhalation exposure - indoor On hold 875.1700 Product Use Information On hold 875.2300 Indoor surface residue dissipation On hold 875.2700 Product Use Information On hold 875.3000 N on-dietary ingestion exposure On hold

Table 4 - Silver Sulfate (GDCI-072511-1130) February 29, 2012 Guideline Requirement N umbe r Study Title Due Date 830.7520 Particle size, fiber length , and diameter distribution 90 days from receipt of letter 830.7840 Water solubility: Column elution method, shake flask method 90 days from receipt of letter 835.1100 Activated sludge sorption isotherm On hold 850.1350 Mysid chronic toxicity test On hold 850.1400 Fish early-life stage toxicity test On hold 850.1735 Whole sediment: acute fr eshwater invertebrates On hold 850.1740 Whole sediment: acute marine invertebrates On hold 850.1850 Aquatic food chain transfer On hold 850.4225 Seedling emergence, Tier II On hold 850.4250 Vegetative vigor, Tier II On hold 850.4400 Aquatic plant toxicity test using Lemna spp. Tiers I and II On hold 850.5400 Algal toxicity, Tiers I and II On hold 850.6800 Modified Activated Sludge Respiration Inhibition On hold 870.3465 90-day inhalation toxicity On hold8 875.1400 Inhalation exposure - indoor On hold 875.1700 Product Use Information On hold 875.2300 Indoor surface residue dissipation On hold 875.2700 Product Use Information On hold 875.3000 N on-dietary ingestion exposure On hold

Table 5 - Silver Nitrate (GDCI-072503-1131) February 29, 2012 Guideline Requirement N umbe r Study Title Due Date 830.1600 Description of materials us ed to produce the product 90 days from receipt of letter 830.1620 Description of production process 90 days from receipt of letter 830.1700 Preliminary analysis 90 days from receipt of letter 830.1800 Enforcement analytical method 90 days from receipt of letter 830.1900 Submittal of samples 90 days from receipt of letter 830.7520 Particle size, fiber length , and diameter distribution 90 days from receipt of letter 830.7840 Water solubility: Column elution method, shake flask method 90 days from receipt of letter 835.1100 Activated sludge sorption isotherm On hold 850.1350 Mysid chronic toxicity test On hold 850.1400 Fish early-life stage toxicity test On hold 850.1735 Whole sediment: acute fr eshwater invertebrates On hold 850.1740 Whole sediment: acute marine invertebrates On hold 850.1850 Aquatic food chain transfer On hold 850.4225 Seedling emergence, Tier II On hold 850.4250 Vegetative vigor, Tier II On hold 850.4400 Aquatic plant toxicity test using Lemna spp. Tiers I and II On hold 850.5400 Algal toxicity, Tiers I and II On hold 850.6800 Modified Activated Sludge Respiration Inhibition On hold 870.3465 90-day inhalation toxicity On hold 875.1400 Inhalation exposure - indoor On hold 875.1700 Product Use Information On hold9 875.2300 Indoor surface residue dissipation On hold 875.2700 Product Use Information On hold 875.3000 N on-dietary ingestion exposure On hold

Table 6 - Silver Chloride (GDCI-072506-1132) February 29, 2012 Guideline Requirement N umbe r Study Title Due Date 830.7520 Particle size, fiber length , and diameter distribution 90 days from receipt of letter 830.7840 Water solubility: Column elution method, shake flask method 90 days from receipt of letter 835.1100 Activated sludge sorption isotherm On hold 850.1350 Mysid chronic toxicity test On hold 850.1400 Fish early-life stage toxicity test On hold 850.1735 Whole sediment: acute fr eshwater invertebrates On hold 850.1740 Whole sediment: acute marine invertebrates On hold 850.1850 Aquatic food chain transfer On hold 850.4225 Seedling emergence, Tier II On hold 850.4250 Vegetative vigor, Tier II On hold 850.4400 Aquatic plant toxicity test using Lemna spp. Tiers I and II On hold 850.5400 Algal toxicity, Tiers I and II On hold 850.6800 Modified Activated Sludge Respiration Inhibition On hold 870.3465 90-day inhalation toxicity On hold 875.1400 Inhalation exposure - indoor On hold 875.1700 Product Use Information On hold 875.2300 Indoor surface residue dissipation On hold 875.2700 Product Use Information On hold 875.3000 N on-dietary ingestion exposure On hold

Table 7 - Silver Oxide (GDCI-129097-1133) February 29, 2012 Guideline Requirement N umbe r Study Title Due Date10 830.1600 Description of materials us ed to produce the product 90 days from receipt of letter 830.1620 Description of production process 90 days from receipt of letter 830.1650 Description of formulation process 90 days from receipt of letter 830.1670 Discussion of formation of impurities 90 days from receipt of letter 830.1700 Preliminary analysis 90 days from receipt of letter 830.1750 Certified limits 90 days from receipt of letter 830.1800 Enforcement analytical method 90 days from receipt of letter 830.1900 Submittal of samples 90 days from receipt of letter 830.6314 Oxidizing or reducing action 90 days from receipt of letter 830.6315 Flammability 90 days from receipt of letter 830.6316 Explodability 90 days from receipt of letter 830.6317 Storage stability of product 90 days from receipt of letter 830.6319 Miscibility 90 days from receipt of letter 830.6320 Corrosion characteristics 90 days from receipt of letter 830.6321 Dielectric breakdown voltage 90 days from receipt of letter 830.7000 p H of water solutions or suspensions 90 days from receipt of letter 830.7100 Viscosity 90 days from receipt of letter 830.7200 Melting point/melting range 90 days from receipt of letter 830.7520 Particle size, fiber length , and diameter distribution 90 days from receipt of letter 835.1100 Activated sludge sorption isotherm On hold 850.1350 Mysid chronic toxicity test On hold11 850.1400 Fish early-life stage toxicity test On hold 850.1735 Whole sediment: acute fr eshwater invertebrates On hold 850.1740 Whole sediment: acute marine invertebrates On hold 850.1850 Aquatic food chain transfer On hold 850.4225 Seedling emergence, Tier II On hold 850.4250 Vegetative vigor, Tier II On hold 850.4400 Aquatic plant toxicity test using Lemna spp. Tiers I and II On hold 850.5400 Algal toxicity, Tiers I and II On hold 850.6800 Modified Activated Sludge Respiration Inhibition On hold 870.3465 90-day inhalation toxicity On hold 875.1400 Inhalation exposure - indoor On hold 875.1700 Product Use Information On hold 875.2300 Indoor surface residue dissipation On hold 875.2700 Product Use Information On hold 875.3000 N on-dietary ingestion exposure On hold

Table 8 - Silver Ion (GDCI-072500-1194) July 6, 2012 Guideline Requirement N umbe r Study Title Due Date 830.1600 Description of materials us ed to produce the product 90 days from receipt of letter 830.1620 Description of production process 90 days from receipt of letter 830.1650 Description of formulation process 90 days from receipt of letter 830.1670 Discussion of formation of impurities 90 days from receipt of letter 830.1700 Preliminary analysis 90 days from receipt of letter 830.1750 Certified limits 90 days from receipt of letter 830.1800 Enforcement analytical method 90 days from receipt of letter 830.1900 Submittal of samples 90 days from receipt of letter 830.6314 Oxidizing or reducing action 90 days from receipt of letter12 830.6315 Flammability 90 days from receipt of letter 830.6316 Explodability 90 days from receipt of letter 830.6317 Storage stability of product 90 days from receipt of letter 830.6319 Miscibility 90 days from receipt of letter 830.6320 Corrosion characteristics 90 days from receipt of letter 830.6321 Dielectric breakdown voltage 90 days from receipt of letter 830.7520 Particle size, fiber length , and diameter distribution 90 days from receipt of letter 830.7840 Water solubility: Column elution method, shake flask method 90 days from receipt of letter 835.1100 Activated sludge sorption isotherm On hold 850.1350 Mysid chronic toxicity test On hold 850.1400 Fish early-life stage toxicity test On hold 850.1735 Whole sediment: acute fr eshwater invertebrates On hold 850.1740 Whole sediment: acute marine invertebrates On hold 850.1850 Aquatic food chain transfer On hold 850.4225 Seedling emergence, Tier II On hold 850.4250 Vegetative vigor, Tier II On hold 850.4400 Aquatic plant toxicity test using Lemna spp. Tiers I and II On hold 850.5400 Algal toxicity, Tiers I and II On hold 850.6800 Modified Activated Sludge Respiration Inhibition On hold 870.3465 90-day inhalation toxicity On hold 875.1400 Inhalation exposure - indoor On hold 875.1700 Product Use Information On hold 875.2300 Indoor surface residue dissipation On hold 875.2700 Product Use Information On hold 875.3000 N on-dietary ingestion exposure On hold

A copy of this letter will be pl aced in the Silver Compounds and Nanosilver registration review public dockets (EPA-HQ-OPP-2009-0334 and EP A-HQ-OPP-2011-0370, respectively). If you have any questions regarding this letter, please contact SanYvette Williams, DVM, the chemical review manager (CRM) of these cases. Any questions should be directed to her in writing either by email at williams.sanyvette@epa.gov or by USPS letter.13 CC: Lance Wormell, Chief, Regulatory Mana gement Branch II, An timicrobials Division John Hebert, Chief, Regulatory Manageme nt Branch I, Antimicrobials Division Rose Kyprianou, Reevaluation Team Leader, Antimicrobials Division Seiichi Murasaki, Acting Product Manager 33, Antimicrobials Division SanYvette Williams, Chemical Review Manager, Antimicrobials Division Sincerely,

Jennifer L McLain, Acting Director Antimicrobials Division (7510P) Office of Pesticide Programs