1 of 57 Registration of NSPW-L30SS

EPA Response to Comments Receiv ed for Docket: EPA-HQ-OPP-2012-0594

The public comment period was open from August 27 until September 26, 2013 and a total of ten public comment submissions were received as of November 8, 2013. All public comments were assigned a docket number and are include d in this document grouped as follows:

 Citizens – Two public comment submissions from Citizens

 Trade Associations – Three public comment submissions from Trade Associations (Copper Development Association, Silv er Nanotechnology Working Group, Silver Task Force North America )

 Non-governmental organizations (NGOs) – Five public comment submissions from NGOs (Californians for Pesticide Reform, People for the Ethical Treatment of Animals (PETA) and Physicians Committ ee for Responsible Medicine (PCRM),
The Natural Resources Defense Council (NRDC), Farmworker Association of Florida, The International Center fo r Technology Assessment (ICTA) and Center for Food Safety (CFS))

Citizens

Commenter 1: Clean Production Action (E PA-HQ-OPP-2012-0594-0014, Received 9/26/2013)

Comment 1.1: There needs to be greater scrutiny, oversight and transparency about hazards associated with [NSPW-L30SS] and EPA should be discriminating about specific uses. For example, uses that result in discha rge to water should be considered differently from uses that are unlikely to discharge to water.

Response 1.1: With respect to concerns about differe ntiating use sites, EPA considered all proposed uses of NSPW-L30SS (including uses that would result in discharges to water and uses that are unlikely to discharge to water) when preparing th e registration decision. As part of problem formulation, EPA groups use sites and assesses the higher exposure use sites to screen for risks, separating and refining such grouping as needed during the assessment phase to discriminate, for example, between uses or use sites which present no risk concern and therefore merit no further assessment or mitigation versus those which may present a risk concern and therefore may merit further assessment or potential mitigation such as label changes. Since the degree to which each specific use is assessed separately from all other uses depends on how refined an as sessment is needed, separate quantitative risks will not necessarily be calcu lated for each specific use site. As in this case, if a use with the highest possible exposure for a given pathway poses no unacceptable adverse effects, no additional refinement and resources are needed by the Agency to perform calculations for uses w ith lower exposure conditions.

Commenter 2: Joseph S. Hayes (EPA-HQ-OPP- 2012-0594-0016, Received 9/26/2013)

Comment 2.1: It is apparent from the Draft Decision Document th at “Nanosilva” is a trade name or trademark (which should not be used as a stand-alone noun) and a company name. It is not a known chemical name, but the word is also used freely throughout the document as a common noun to identify an (allegedly new) chemical substance. This usage is confusing and should be rectified.2 of 57 Response 2.1: The decision document has been revised to clarify referenc es to the product (NSPW-L30SS), company name (Nanosilva LLC ), and substance (nanosilver in NSPWL30SS).

Comment 2.2: The proposed label describes the activ e ingredient as “Covalently Bound Elemental Silver.” It is proposed that this is somehow new. However it would appear that [NSPW-L30SS] consists of metallic silver (PCC 072501) in the shape of nanosilver (PCC 072599), attached to silica by thiolate bonds and deriving antimicrobial activity by production of silver ions (P CC 072501) by oxidation at the surface. There are already existing products with similar or comparable structure and function and classified under each of the existing PC Codes mentioned. The need for designation of this as a “new” chemical, under yet another PC Code, is not apparent.

Response 2.2: The FIFRA Scientific Advisory Pane l (SAP) considered the issue of nanosilver toxicity in its November 2009 mee ting. In general, the SAP advised that the toxicity of nanosilver could differ from and might be higher than ot her forms of silver.
While additional research has been c onducted and published on intercellular and intracellular transport and toxi city of nanomaterials, including different nanosilvers since the 2009 SAP, the understanding of how physiochem ical properties, such as size, shape, surface area, surface chemistry, and reactivity affect behavior a nd toxicity of nanomaterials is still in its infancy. While the Agency has not reviewed all of the research published since 2009, the research that has been reviewed continues to support the same concerns identified in the 2009 SAP, that the hazards of nanosilvers cannot be fully characterized using data for the silver ion alone nor by us ing only data on other nanosilver products. Taking into consideration the SAP recommenda tion, the current understanding of behavior and toxicity of different manufactured nanosilvers, especial ly as it relates to ionic silver, and accumulation and toxicity, and in response to Nanosilva LLC’s request for registration of a new active ingredient, EPA determined that it would evaluate the manufactured
nanosilver in NSPW-L30SS in the same manner as a new active ingredient given (i) that
NSPW-L30SS could not be assessed as containing or releasing ionic silver alone and (ii)
that the nanosilver in NSPW-L30SS was not si milar to the manufactur ed nanosilver in any previously issued registration. Until ther e is sufficient research defining how the
characteristics of different na nosilvers affect behavior and toxicity, applications for a pesticide product containing a new nanosilver ma terial may need to be assessed as EPA would assess a new active ingredient. The Agen cy also determined it would be appropriate to establish a single PC Code to categorize and review all products containing nanosilver to recognize that toxicity a nd behavior of manufactured na nosilvers potentially differs
from that of metallic silver and silver salts.

Comment 2.3: Considerable importance is also gi ven to numerous statements along the
lines that "silver at concentra tions greater than the analytical detection limit were not found leaching from plastic coupons incorporating [NSPW-L30SS]” (p. v). Much weight is clearly placed on “were not f ound”; however the key phrase he re is “greater than the analytical detection limit.”

Response 2.3: EPA agrees with the commenter that the key phrase is “greater than the analytical detection limit” and acknowledges that silver at levels below the limit of detection (LOD) could have been released. For this reason, EPA calculated risks based on one-half the LOD, which as stated in the decision document was in accordance with the3 of 57 OPP Policy Document “Assigning Values to Non-Detected/Non-Quantified Pesticide Residues in Human Health Food Exposure Asse ssment” (U.S. EPA, 2000). This document
can be found at http://www.epa.gov/pesticid es/trac/science/trac3b012.pdf . If EPA believed that no silver had been released, EPA woul d have assumed zero exposure and would not
have calculated risks. The decision document has been updated to clarify those statements.

Comment 2.4: I have searched in vain (perhaps with insufficient diligence) for discussion in the document of antimicrobial efficacy, but presume that efficacy is a requirement for registration. (If not, may I re gister distilled water?)

Response 2.4: As explained in 40 CFR §158.2200, each registrant must ensure through testing that their product is efficacious when used in accordance with label directions and commonly accepted practices. Product performance data must be submitted with any application for registration or amended regi stration for each product that bears a public health claim, as described in §158.2204(a). Th e regulations also make clear that the Agency reserves the right to require, on a case-by-case basis, submission of product performance data for any pesticide product re gistered or proposed for registration or amendment, for example, to support a benefits assessment where there is some concern for risks from use of the pesticid e. Because the product does not bear public health claims and
because there is no risk concer n with use of the pesticide dur ing the four year period for generation of the data which would otherwise ne cessitate a closer look at the benefits from use of the pesticide, there is no requirement to submit, and no need to review, product performance data for this pesticide.

Comment 2.5: If, ...“All silver-based pesticide prod ucts act via the release of a low
concentration of silver ions that then inter act with bacteria,” and if this material is effective, then that effectiven ess in and of itself should cons titute evidence of detection;
and inhibited or killed bacteria could be exam ined for the presence of silver (for instance by centrifugation, digestion, and ICP-AES).

Response 2.5: As discussed in Response 2.3, although s ilver was not detected, the Agency
did not assume absence of silver in assessing the risk, and used a release rate based on onehalf the LOD in accordance with OPP policy. The commenter’s proposed method for detecting silver (i.e., measuring the presence of silver in the bacteria inhibited or killed), while an interesting surrogate approach, is not a standard or proven method for preconcentrating silver in an aqueous sample in preparation for anal ytical quantitation and would require substantial reso urces to develop and validate ( http://www.epa.gov/waste/hazard/te stmethods/sw846/online/index.htm ; OCSPP 850.6100 on the docket at EPA-HQ-OPPT- 2009-0154-0008). Moreover, there are potentially a number of conven tional or standard approaches that can be applied to the study design or sample preparation to improve the sample detection limit, if needed, that would not require such a surr ogate measurement method. For example, inclusion of an evaporation step during sample preparati on to concentrate the sample. Additionally, Nanosilva LLC could have conducted and submitted a method detection limit study to support the lower method detection limits give n in the plastics leaching study report that ranged from 0.8 to 2 μg/L for the non-oil trials over the LOD of 5 μg/L used by the EPA for evaluating risk. Comment 2.6 also discu sses study design changes to improve detection of silver. However, such issues or refinements need not be resolved for this registration at4 of 57 this time because using the higher assumed rel ease rates did not result in a calculation of potential human health or envi ronmental risks of concern.

Comment 2.6: The commenter suggested that the analyti cal technique used to detect silver should be improved and identified a section of the proposed decision document where the amount of silver leaching from treated articl es might be misconstrued. The commenter also recommended specific modifications to the anal ytical technique for plastic leaching tests. These modifications are based on the assumption that neither silver nor silver ions would be expected to migrate or diffuse signif icantly through well-molded LLDPE [Linear Low Density Poly Ethylene]. The silver nanopartic les are said to have mean diameters of between 6.9 and 10.6 nm, therefore only nanopart icles centered within a surface layer of 11 nm could be expected to leach silver i ons. Based on a coupon surface area and volume, the maximum amount that could be leached from the outer 10 nm layer would be 2 ng
which would be below the LOD for the 50 ml leaching volume that was used in the study.
The commenter recommended that a smaller amo unt of leaching fluid be used, that the coupons be made much thinner, that multiple coupons be placed in each pouch and that NSPW-L30SS loading be increased in order.

Response 2.6: EPA concurs that some of the modifications recommended by the
commenter could allow for the measurable dete ction of an amount of nanosilver or other forms of silver released, that when calculate d would likely have resu lted in lower assumed
leach rates than those used in the assessm ent and the risks calculated based on lower
measured leach rates would also have been lower. These issues will be considered when reviewing protocols for future studies. However, these issues need not be resolved for this registration at this time, given the very hi gh MOEs in comparison to the target MOEs calculated using the assumed release rate. Si milarly, the calculated ecological risks are
below levels of concern even with the assumed release rates. In sum, taking into account
the low release rates and resul ting levels of concern, such re finements to the leaching study are not necessary at this time.

Comment 2.7: If testing of disabled bacteria and improved leaching tests should still fail detect any leached silver it might be reasona ble to conclude that none appears, although even then data on hydrolysis for the agent alone should not be waived. In the (unexpected)
event that none of these te sts, including hydrolysis, show emission of any silver, then maybe the extensive discussion of silver and Na no silver in this Draft can be eliminated
from the final Decision Document and we can think instead about some other mechanism of antimicrobial efficacy -- perhaps Ei nstein’s “spooky action at a distance.”

Response 2.7: Please see Response 2.5. Also, as expl ained in Appendix A of the proposed decision document, EPA waived the need to conduct a hydrolysis test because metals, including nanosilver, do not unde rgo hydrolytic transformation.

Trade Associations

Commenter 3: Harold T. Michels, Copper Develo pment Association (EPA-HQ-OPP-2012- 0594-0017, Received 9/26/2013)

Comment 3.1: As with other silver-based “antimic robial” pesticide products already registered by EPA, CDA is concerned about the efficacy of and claims made for this product which is intended to be incorporated into “treated ar ticles.” There is a long history
– reflected in EPA enforcement actions and the numerous unaddresse d complaints filed by5 of 57 CDA and others with the agency – demonstra ting that “treated ar ticles” often are not
marketed in a manner consistent with th e clear requirements fo r “non-public health” products. Rather, these types of products are consistently ma rketed with implicit and, in some cases, explicit public health claims and with advertising and labeling language that
does not make clear to the consumer that the products do not afford public health protection. As a result of such marketing e fforts, there is a widespread belief among consumers and users that products containing silver-based “materia ls preservatives” provide “public health” bene fits. Regardless of the actual label language for [NSPWL30SS] or other silver-based antimicrobial addi tives, the fact is that there is a general association in the mind of the public that a pr oduct containing a silve r-based additive can protect the user against bacteria or other microorganisms that endanger public health. Accordingly, CDA urges EPA to require submi ssion of efficacy data, comparable to that required for “public health” antimicrobial pr oducts, prior to finaliz ing the [NSPW-L30SS] registration. Such data are necessary before EP A can conclude, as it states in the Draft Decision Document (at 67), “t hat use of [NSPW-L30SS] offers the potential for
conservation of the environment and consumer benefits which contribute to the public
interest.”

Response 3.1: 40 CFR 152.25(a) exempts from regulati on articles or substances treated with, or containing, a registered pesticide to protect the articl e or substance. Examples of this exemption are textiles treated with silv er and wood products treated with copper. As explained in PR Notice 2000-1, this exemption does not apply to articles or substances “bearing implied or explicit public health claims against human pathogens.” Thus, any article treated or containing a registered pesticide but b earing implied or explicit public health claims must be separately registered. If it is not, distributi on of such product is a
violation under the Federal In secticide, Fungicide, and Rode nticide Act (FIFRA) section 12(a)(1)(A), subject to corre ctive action and penalties under FIFRA section 13 and 14, respectively. In addition, unde r sections 12(a)(1)(E) and 2(q)(1)(A), and 40 CFR 156.10(b)(2) and 40 CFR 156.10(a)(5), pesticide products with brand names that, in a false or misleading manner, state or imply safet y, efficacy or comparative claims, or are otherwise false or misleading in any particul ar, are considered to be misbranded and may not be sold or distributed. With respect to the comment that efficacy data/product performance data are necessary to conclude that use of the pesticide is in the public interest, in this case, EPA disagrees. As explained in Response 2.4, product performance data that might provide more de tailed analysis of the efficacy of the product is not required to be submitted here because no public health claims are made as part of the proposed registration of this product and because ther e are no risk concerns with granting this registration. However, EPA belie ves it is appropriate to rely on the following information in determining that granting use of the proposed product is in the public interest: (i) clear
evidence of low release rates of nanosilver and silver when using the proposed product; and (ii) lower application rates for the propos ed product as compared to higher application rates for other silver-based products on the market (see Table 1). Collectively, this information supports the conclusion that there wi ll be less exposure to humans and aquatic and terrestrial systems to the silver (in the fo rm of nanosilver) in this product as compared to exposures from use of traditional silver-based products. Significantly lower releases and exposures, where there is no evid ence of significantly higher toxi city, is inherently in the public interest.6 of 57 Table 1 – Application Rates for Conventi onal Silver Products Used on Textiles

Product Name EPA Registration

Number Max. Application Rate (ppm)

IRGAGUARD B5000 40810-18 132

BACTEKILLER AZ 82415-2 525

ZEOMIC TYPE AV SILVER ZEOLITE A 71227-6 600

ALPHASAN RC 5000 11631-2 760

NOVARON AG 300 74079-1 760

ZEOMIC TYPE AW SILVER ZEOLITE A 71227-5 1180

ZEOMIC TYPE AJ SILVER ZEOLITE A 71227-1 1250

ZEOMIC TYPE AC SILVER CU ZEOLITE A 71227-7 1750

NOVARON AGZ330 74079-2 2000

ALPHASAN RC 2000 11631-3 2000

ALPHASAN RC 7000 11631-4 2000

ZEOMIC TYPE AK SILVER ZEOLITE A 71227-4 2500

APACIDER - AW 68317-2 4060

SILVA DUR 707-313 5000

AGION SILVER ANTIMICROBIAL TYPE AL 88165-2 5000

AGION SILVER ANTIMICROBIAL TYPE AD 88165-1 11000

Comment 3.2: Concerns of equity and fairness de mand that, instead of allowing silverbased antimicrobial products, including [NSPW-L30SS], to be marketed under the guise of the “treated article” exempti on, EPA insist that the efficacy of silver-based products be supported by meaningful, real world, GLP efficacy data.

CDA urges EPA to undertake a rigorous revi ew of the label claims and marketing materials for all silver-based products, incl uding [NSPW-L30SS] a nd other “nano-silver” products, to address the consumer confusi on these products engender by, at minimum, implying protection of users from ba cteria and other microorganisms.

Response 3.2: Please refer to Responses 2.4 and 3.1, above. A review of other existing registrations is not applicable to the registration in question, and is not addressed in this response-to-comments document.

Comment 3.3: CDA provided the Agency with informa tion (including a j ournal article) on a materials preservative test protocol, Japanese Industr ial Standard (“JIS”) Z 2801.

Response 3.3: The Agency thanks CDA for the information regarding JIS Z 2801. As explained in Response 2.4, product performance data that might provi de more detailed analysis of the efficacy of the product is no t required to be submitted here because no public health claims are made as part of the proposed registration of this product and
because no benefits assessment is necessary for this registration.

Commenter 4: Roslyn Volpe, Silver Nanotechnolog y Working Group (EPA-HQ-OPP-2012- 0594-0015, Received 9/19/2013)

Comment 4.1: The Silver Nanotechnology Working Gr oup (SNWG) is extending support of the Agency decision to register a s econd nanosilver-containi ng product named [NSPWL30SS]. The SNWG feels this is a bold move that gives credibility to efficient, sustainable, cost-effective nanotechnology pr oducts and encourages furthe r opportunities to prove their benefits to society. The SNWG and its membership appreciate the careful risk analysis that7 of 57 the EPA has done on all possible health and e xposure endpoints of concern using the most current data available and appl ying conservative estimates of possible risk and responding to concerns that have emerged since the last conditional Nanosilver Registration was approved.

The SNWG recognizes the vulnerability of such pioneering efforts. We trust that each of these emerging products will be able to withst and the inevitable scrutiny that will occur until the ongoing EPA requested research studies are complete. We are confident that the research results will provide support and confirmation of EPA's conservative risk assessments on these nanosilver products, and will mitigate concerns about the safety of Nanosilver products to the public health and the environment.

The SNWG looks forward to the allowance of the Conditional Registration for [NSPWL30SS], and to all future conditional regist rations for safe and effective Nanosilver products.

Commenter 5: Erin M. Tesch, Silver Task Force North America (STFNA) (EPA-HQ-OPP2012-0594-0021, Received 9/26/2013)

Comment 5.1: The draft decision docu ment acknowledges that the biologically active moiety for silver

‐ based active ingredients is the silver ion. This is the position of the STFNA and it is supported by the preponderance of scientific literature. On a practical level this acknowledgement will facilitate the Agen cy’s review of silver

‐ based actives during the current DCI and eliminate the duplicat ion of studies that would result from the Agency treating each silver

‐ based active individually.

The Agency refers to [NSPW-L30SS] as cont aining nanosilver as a new active ingredient. The STFNA has previously expressed the position that the ac tive component of toxicological interest for all silver

‐ based antimicrobials is the s ilver ion, and therefore all
silver

‐ based antimicrobials should be categorized and reviewed as a group. The Agency’s decision to categorize [NSPW-L30SS] as cont aining a new active is confusing and is a departure from the Agency’s longstanding de finition of ‘new active ingredient’. Specifically, the Pesticide Registration Manual: Chapter 5

‐ Registration Fees defines a “New Active Ingredient” as “An active ingredie nt that is not currently contained as an active ingredient in any registered pesticide product.” This longstanding definition of “new active ingredient” is not left to the registrant’s discreti on, nor is it dependent upon inert ingredients included in the pr oduct, but rather is evidence

‐ based with “new” being derived from a comparison to currently registered pe sticides. In other wo rds, the Agency has historically determined if an active ingredie nt is new by comparing the chemical structure of the active ingredient to the chemical st ructures of active ingredients of currently registered products. Because [NSPW-L30SS]’s active ingredient is silver (and its antimicrobial activity is derived from silv er ions) STFNA believes that [NSPW-L30SS] should be categorized with other metallic silver compounds for the purposes of risk
assessment. This would be consistent with the conclusion that th e active component of toxicological interest and the biologically active moiety is th e silver ion. This would also allow the Agency, the registrant , and other current s ilver registrants to benefit from the efficiency derived from joint review and data generation.

Response 5.1: As stated in the decision document, the active ingredient addressed by much of this assessment is the nanosilver in NSPW-L30SS. The Agency does not agree8 of 57 that the silver ion is the only component of toxicological interest for NSPW-L30SS and nanosilver. The Agency is aware that the ST FNA suggests that the health and safety properties of NSPW-L30SS and nanosilver can be fully characterized using data for the silver ion. However, the FIFRA Scientific A dvisory Panel (SAP) considered the issue of nanosilver toxicity in its November 2009 mee ting. In general, the SAP advised that the toxicity of nanosilver could differ from and might be higher than ot her forms of silver including the silver ion. The Ag ency is aware of, and commenters provide, no new data to suggest that the SAP review and recommendati on is misplaced or that the hazard for the
nanosilver in or released from use of a pesticide product can be fully characterized using only silver ion hazard data. Thus, EPA continue s to agree with the SAP concerns discussed in 2009. As a result, while silver ions are pres ent and EPA relies in part on the silver ion assessment to grant this conditional registra tion, the nanosilver moiety is present and requires review to grant the registration. With respect to the commenter’s concern regarding EPA’s determination that the nanosilver in NSPW-L30SS is a new active ingredient, EPA’s decision to accept the applic ation for this product and to evaluate the
nanosilver in NSPW-L30SS in the same manner as any new active ingredient is based on the fact that (i) NSPW-L30SS could not be asse ssed as ionic silver alone and (ii) EPA had
no information to otherwise demonstrate that the nanosilver in NS PW-L30SS was similar to an ingredient in any previously issued re gistration. Contrary to commenter’s claim, this approach is not a significan t departure from the advice provided to registrants in the Pesticide Registration Manual; consistent with the description for “new active ingredient,”
EPA considered whether the nanosilver in NSPW-L30SS was found in any previously issued registration. While past approaches for determining whether an ingredient is a new active ingredient may not have focused on the size, size range or other physiochemical properties of the ingredient, the definitions of “active ingredient” and “new active ingredient” are not drafted to pr escriptively address issues of th is specific nature, and thus leave with the Agency the necessary discreti on to use its scientific judgment on how best to classify an ingredient. With respect to Commenter’s suggestion that EPA is referencing inert ingredients or properties to justify the “new active” cl assification, EPA is making the
determination based on the nanosilver in the product (the nanosilver in NSPW-L30SS has a different size range than the nanosilver in other products regist ered as containing nanosilver).

Comment 5.2: The data requirements also seem to be inconsistent with those requirements of the most recent registrations and associat ed DCIs. The STFNA believes that the Agency has the responsibility to normalize data requi rements across all silver compounds not only as a matter of fairness, but also to perm it efficient review and data generation.

Response 5.2: The nanosilver data requirements iden tified as terms and conditions on the registration of the current product are based on the data requirements specified in 40 CFR Part 158, adapted to address nanos cale silver. To the extent silver is also present or released from the current product, the data re quirements identified as a term and condition on the current product can be cited to satisfy the relevant data required by the recent silver DCIs, available at regulations.gov (Docket ID: EPA-HQ-OPP-2009-0334).

Comment 5.3: On a specific technical level, the ST FNA is critical of the leaching study
reviewed in the document. Due to the small size of the test sample s and the corresponding small amount of leachable silver present near the surface of the sample, it is questionable if there was sufficient silver present to be detected in the leachate.9 of 57 Response 5.3: Leaching studies are used to reveal the release rate of the proposed pesticide based on the maximum legal rate of application. The release rate is one factor influencing the estimate of potential exposure from use of the proposed pesticide. Per the proposed label, the application method fo r NSPW-L30SS is incorporation, and although the leaching study identified no measurable dete ction of the proposed pesticide from test fabric incorporating the pesticide, EPA estimat ed a release rate based on one-half the LOD in accordance with OPP policy (see Response 2.3). While this approach admittedly may exaggerate the release rate and therefore the exposure to the pe sticide, given the calculated MOEs were significantly greater than target MOEs and environmental risks were below levels of concern, EPA does not believe it is n ecessary to consider th e types of refinements recommended by the commenter. These issues will, however, be considered in future applications and with future assessments, as appropriate.

Comment 5.4: Per EPA guidance, as a federal govern mental agency, neither the EPA nor its programs can endorse any products of serv ices. However, the Draft Decision Document clearly states that, “EPA believes that us e of [NSPW-L30SS] offers the potential for
conservation of the environment and consumer benefits which contribute to the public interest.” The STFNA understands that the Agen cy must articulate a benefit to the public interest in order to conditionally regist er a new active ingredient. The STFNA has no
information to assess the relative effectiveness of this product compared to other products, but in general the STFNA believes that the Agency should refrain from these types of apparent endorsements as it can create an unequal competitive landscape based on no empirical evidence.

Response 5.4: Please see Response 3.1 for a discussion of the public interest finding in this case. Concluding that gran ting the registration is in the public interest is not an endorsement of the product. Under its authority set forth in FIFRA section 3(c)(7)(C), the Agency is making only a public interest findi ng, which is provided for purposes of this finding only and is not to be inferred as any endorsement of a pesticide product. EPA and its employees do not endorse any particular produc t, service or enterpri se. If any registrant were to include "any statement di rectly or indirectly implying th at the pesticide or device is recommended or endorsed by any agency of the Federal Government", then such statement, pursuant to 40 CFR 156.10(a)(5 )(v), would be false or misleading.

Comment 5.5: There is no evidence to suggest, as the Agency states, that nanosilver particles will retain efficacy for longer peri ods of time than conventi onal silver particles, nor can the Agency make the claim that nanosilver as an active ingredient is more effective
than conventional silver at ta rgeting pests. Furthermore, EP A does not require, nor has it evaluated, efficacy data for all silver based non

‐ public health materials preservative products. Therefore, the entire discussion of the consumer benefits of the [NSPW-L30SS] product are completely unsubstantiated given the fact the Agency has not reviewed efficacy data to be able to compare the be nefits of the [NSPW-L30SS] product to other silver based materials preservative products.

Response 5.5: The Agency acknowledges the co mment concerning the lack of comparative efficacy data between conventiona l silver particles a nd nanosilver particles
and has revised the decision document to remove language concerning comparative efficacy data. With respect to the comment relating to submission and review of efficacy/product performance data, please see Responses 2.4 and 3.1.10 of 57 Non-governmental organizations (NGOs)

Commenter 6: Patricia L. Bishop, People for the Ethical Treatment of Animals (PETA) and Kristie Sullivan, Physicians Committee for Responsible Medicine (PCRM) (EPA-HQ-OPP2012-0594-0020, Received 9/26/2013)

Comment 6.1: EPA’s State of the Science report on Nanosilver indicates that tests that have already been conducted on nanosilver us ing animals display a c onsiderable lack of reproducibility in experimental re sults. Variations can be traced to the vast differences in morphological shape of nanosilver (from rods, to spheres, particles, cubes, truncated triangles, wires, and films) and even, more importantly, to the differing animal species used in experiments. As the available data also demonstrate, nanos ilver properties change depending on the exact size/surface area of th e nanosilver particles, the carrier used, any coatings, and whether the nanosilver has surf ace modifications, which in turn can have effects on its biological activity. These variable properties also can contribute to nanosilver behaving differently from bulk silver.

The bioavailability, fate and transport of na nosilver are dependent upon numerous factors. These include particle size, ease of aggreg ation, surface characteris tics, and colloidal stability, which in turn is a function of the capping agent, pH, ionic strength, and presence of ligands, to name a few. Nanosilver toxici ty has been shown to vary with route of exposure, oxidation state, and most importan tly, physicochemical charac teristics. The State of the Science report declares “The physicochemical featur es of the nanoparticles must be characterized under the experimental setting so that definitive associ ations between these parameters and any biological re sponses observed may be identifie d.” It is also noted in the State of the Science report that “...a good disper sion of the silver nanoparticles is required for effective toxicological and/or antibact erial activities, and might influence its subsequent toxicity. Toxicity determination of nanosilver particles may be dependent on the size distribution of the particles.” Thus, for an animal test to have any validity, characteristics such as the concentration, di ameter and chemical composition of nanosilver in the exposure scenario must be identified and mimicked in the experimental setting. Yet, the report goes on to say that there are diffi culties in accurately measuring and delivering doses as well as monitoring nanomaterial behavior, particularly in solution (and in vivo ). With a potential biological response dependent on numerous factor s – and many of these factors lacking reliable means of measurement – it is impossible to generate meaningful information by conducting the above-mentione d animal tests. For example, it will undoubtedly prove technically cha llenging to deliver representa tive and appropriate doses
of nanosilver to rats in the inhalation toxicity test being proposed for this antimicrobial pesticide registration review. Th erefore, due to the high potentia l for generating the type of equivocal results seen in many ot her animal studies with nanosilver, it is likely that these tests may need to be repeated and so would be a waste of animal lives and resources.

Response 6.1: Variability between nanosized and conventional-sized chemicals and among nanosilver chemicals was addressed in the SAP 2009 Report and is recognized by the Agency as an important part of charac terizing nanomaterials. With regards to the
differences between nanosilver and silver ions, please see Responses 2.2 and 5.1. With regard to the differences among nanosilver chemicals, because a nanosilver ingredient may have different hazards or different degree of hazards as compared to another nanosilver ingredient, each nanosilver ingred ient may need to receive an assessment that is equivalent11 of 57 in many cases to that provided for new active ingredients. Any poten tial differences in toxicity due to physiochemical differences be tween the nanosilver in these studies and the nanosilver in NPSW-L30SS is covered by an additional 10X database uncertainty factor. Please see Response 6.2 for information on the inhalation requirements. These positions were summarized in the proposed decision document. Thus, while there may be some variations in the toxicity pr ofile of nanosilvers, EPA found th at using studies that offered
the best available data and an additional 10X database uncertainty factor to cover any
variations between the nanosilvers resulted in calculated MOEs well above the LOC. With respect to concerns that data on nanosilver ingredients are not reproducible for the reasons noted in the comments, registrants will be requi red to submit protocols for review to ensure that the studies required as a term and c ondition on the registration will be conducted in a fashion to provide meaningful information and so that repetition of a study would not be

necessary.

Comment 6.2: In addition to the considerable uncerta inty in toxic potential associated with the physicochemical variability of nanomaterials, there are many documented uncertainties in extrapolating from laborat ory animal studies to the human situation including: differences in meaningful dosages, variations in responses to chemicals and in target organs and tissue effects with different species and stra ins of animals, as well as different toxic thresholds between species including humans. Importantly, biological relevance is unlikely with the currently-used rat tests – issues rela ting to breathing mode, physiology, relative sizes of nerve bulbs and the different rate of particle clearance of rats compared to humans all point to important anatomical and physiological differences that preclude clear data extrapolation between specie s. Certainly, some of these differences will make interpretation of the proposed inhalati on study results challenging and given the likely unrealistic oral dosages and exposure ti mes involved, it seems impossible that the rat reproductive/developmental toxicity test bei ng called for in this pesticide registration review could provide meaningful data.

Risk of longer-term exposure to [NSPW-L30SS] would seem to be grea test at the factory where workers handle, mix, and load the produc t. Yet, EPA has issued strict mitigation measures to ensure very low exposure potential . These include: 1) closed system loading of [NSPW-L30SS] suspensions ; 2) NIOSH certified full-face respirators immediately available for use in emergency; 3) use of gloves that are chemically resistant to all components of [NSPW-L30SS] liquid suspension ; 4) use of long-sleeve shirts, long pants, and shoes plus socks. It would appear extr emely unlikely that any exposures under these conditions would result in long-te rm reproductive and developmental effects in workers, so that results of rat reproduc tive/developmental screening unde r relatively high dosages are unlikely to provide any useful , human-relevant information.

Response 6.2: As is common in most risk analyses, EPA used a 10X uncertainty factor in identifying the target LOC to account for variability between animals and humans (interspecies) and another 10X uncertainty factor to account for variability between humans (intraspecies). An additional 10X uncer tainty factor is used here to account for uncertainties in the data base generally, and an additional 3X uncertainty factor was used to assess risks for intermediate exposures to account for the absence of a NOAEL in the study used for identifying the intermediate P OD. The 10X database uncertainty addresses potential variations among nanos ilver ingredients in the substance tested in the studies
cited and the nanosilver in NSPW-L30SS. Fo r example, the 10x database uncertainty12 of 57 covers in part how the different physiochemi cal properties of the nanosilver used in Song et al. (2012) and nanosilver in NSPW-L30SS affect inhalation al toxicity, and takes into consideration (i) the sensitive effects of decreases in physiological measures of lung
function combined with chronic alveolar inflammation and macrophage accumulation in the lungs, and (ii) that the i nhalation POD from the Song et al. (2012) study results in a MOE that is near the LOC when exposure is assessed with a closed system. In EPA’s judgment, while the use of the POD from the Song et al. (2012) st udy and the 10x database uncertainty ensures that the a ssessment is protective of potential inhalation effects, the uncertainty regarding the difference between physiochemical properties for purposes of assessing inhalation toxicity, and taking into consider the effects observed in the public literature inhalation study, is best addressed by the 90-day Inhalation Study required as a term and condition on the registration. Additi onally, the Agency has developed protocols and programs such as Regional Dose Deposite d Ratio (RDDR) which specifically accounts
for differences in human and rat inhalati on mechanisms. The addition of a functional observation battery and detailed neuropathology will also help address the uncertainties noted above with this route of exposure.

There are uncertainties based on the st udy results relating to reproductive and developmental effects via any route of expos ure. Specifically, ther e were dose-dependent
increases in the concentration of silver in the te stes of rats after oral ingestion (Kim et al, 2008), inhalation (Song et al, 2012 ) and injection (Lee et al. 2012) of nanosilver and, in another study, nanosilver was distributed to major maternal organs and extra-embryonic tissues although no adverse morphological effects on the developing embryos were observed (Austin et al, 2011). However, a pape r by Yu et al. (Yu et al, 2013) shows that there were no maternal or developmental effects up to 1000 mg/kg bw using a nanosilver 7.5 nm in size. Thus, although “EPA belie ves that the inhalation NOAEL of 49 μg/m 3 based on the Song et al. (2012) study is expected to be protective of developmental and reproductive effects of nanosilver”, and the Yu et al, 2013 study supports this conclusion, in EPA’s judgment, the uncertainty with resp ect to reproductive and development effects and with respect to potential variations among nanosilver ingred ients is best refined by the reproductive/developmental screening study vi a the inhalation route, and will help determine whether a POD for reproductive/deve lopmental toxicity should be used in assessing NSPW-L30SS.

Comment 6.3: Furthermore, there is no clear rati onale given in the Draft Decision Document for Conditional Registration of [NSPW-L30SS] for conducting a 90-day inhalation study. In 2012, EPA was reviewing a similar silica-nanosilver composite product, HeiQ AGS-20, which contains nanosil ver particle sizes in the 1-10 nm range, similar to [NSPW-L30SS]. At that time, EPA required a 90-day inhalation study in rats be conducted to confirm findings of cited non-guideline studies submitted for HeiQ AGS-20. These same studies (i.e., Sung et al. 2008, 2009) were cited for [NSPW-L30SS] as well as a newer inhalation study (Song et al. 2012). Sung et al. (2009) conducted a 90-day inhalation study using nanosilver particles that EPA notes were of similar size to the pesticide product under review, and a NOAEL of 133 ug/m 3 was determined. Song et al. (2012) followed up with a lung-recovery st udy that indicated lung pathology findings similar to Sung et al. (2009) and showed gr adual clearing in fema les, but persistent inflammation in high-dose males. A NOAEL of 49 ug/m 3 was derived from this study. In addition, two 28-day inhalation studies are avai lable. EPA states in the above document13 of 57 that the Song et al. (2012) study is the most appropriate st udy for inhalation exposure and is using the lower NOAEL of that study as th e point of departure (POD) for short- and intermediate-term inhalation exposures to th e nanosilver in [NSPW-L30SS]. EPA goes on to state that the inhalation NOAEL of 49 ug/m 3 is expected to be protective of developmental and reproductive effects of nanos ilver, as well as neurotoxic effects.

However, a supplemental DER was issued on 8/1/2013 for the 90-day inhalation toxicity test for nanosilver, and indicated that while the Song et al. (2012) study was acceptable and
both a NOAEL and a LOAEL could be determ ined, the study still did not satisfy the guideline requirements for OCSPP 870.3465. EPA should provide further details on what necessary information is lacki ng and how this information, if gathered, would be used to modify labeling and further mitigate the already stringent [NSPW-L30SS] handling procedures. EPA should also provide evidence that the two products ([NSPW-L30SS] and HeiQ AGS-20) are substantially different in toxicologically-relevant ways that justify performing two separate 90-day inhalation studi es. Otherwise, the re sults of the pending HeiQ AGS-20 study should be obtained befo re requiring inhalation studies on [NSPWL30SS].

Similarly, requiring a reproduction/developmenta l toxicity screen for both materials may be duplicative. EPA should wait for the resu lts of the testing on HeiQ AGS-20 before requiring that hundreds more animals be killed.

Response 6.3: Please see Response 6.2 for the reason for requiring the inhalation studies. The reason that inhalation and reproductive/ developmental (via the inhalation route) studies are required for both na nosilver pesticides is to re duce the separate database uncertainty used in the risk assessment for eac h, as each nanosilver is considered a new, separate active ingredient, th eir databases are also consider ed separately. It is unclear whether newly generated data will require any modification of the label or further mitigation of the registration. Once the data are submitted, however, EPA will determine whether any PODs should change, and thus wh ether the risks are adequately mitigated. Finally, as a general matter, EPA does not condition a registration on submission by another registrant of data nor may it unila terally delay a respons e on the application pending submission by another entity of what may be relevant data. However, Nanosilva LLC and HeiQ may work together to submit data that may be relevant to both products and to both registrations. If Nanosilva LLC and HeiQ choose to jointly pursue generation of the required data, EPA recommends that they consult EPA in the process.

Comment 6.4: Further, when considering the h azard assessment of nanosilver, its potential ubiquity in the environment cannot be ignored. Of the more than 250 consumer products claiming to contain nanosilver, only a relatively few are being registered as pesticide products. Nanosilver is found in food packaging materials, textiles, electronics, cosmetics, medical devices, water disinfectants , and room sprays. However, there are very little data quantifying its pres ence or characterizing its forms in the environment or describing the amounts to which humans are cumulatively exposed. There are many questions regarding the degree to which nanos ilver leaches from products, and what forms it may take, whether it remains as nanopartic les or aggregates, whether it dissolves or converts to ionic silver, and under what condi tions these transformations may take place. Lacking information on the characterization and presence of nanosilver in the environment, data on amounts and forms being released from all types of products, and a clear14 of 57 understanding of the possible inte ractions with the surrounding environment, it is difficult
to see how a realistic hazard assessment and e xposure scenario can be determined for the product subject to this pes ticide registration review.

Response 6.4: Assessing aggregate exposure and cumulative risk is only explicitly
addressed in the FFDCA and FIFRA for f ood use pesticides, and are not similarly addressed for nonfood use pesticides. See, 21 U.S.C. § 346a(b)(2)(A)(ii) and 7 U.S.C. § 136(bb). The Agency has reviewed leaching stud ies (plastics and text iles) that determine
the amount and form of silver that consumer s may be exposed to when in contact with plastic and textiles incorporating NSPW-L30SS. These leaching studies were incorporated into exposure estimates for the dermal and incidental oral rout es of exposure. The Agency’s risk assessment also evaluate d and is protective for children who may simultaneously be exposed to nanosilver via th e incidental oral and dermal routes of exposure while mouthing toys, contacting floor ing, and mouthing textiles incorporating NSPW-L30SS. Inhalation exposure to chil dren during laundry drying of textiles incorporating NSPW-L30SS is not anticipated and was not considered as part of the aggregate exposure. Aggregate assessments may also include other sources of exposure to NSPW-L30SS such as in food and drinking wate r, and exposure to other nanosilvers in the market place that are identic al to the nanosilver in NSPW -L30SS. However, there is no
food use for NSPW-L30SS and neither NSPW-L 30SS nor the nanosilver that might break away from NSPW-L30SS is anticipated to en ter drinking water becau se any particulates
released to surface water woul d be removed by gravitational sedimentation and adsorption.

The only other pesticide product registered as containing nanosilver is HeiQ AGS-20. The nanosilver in HeiQ AGS-20 has different size range and surface coatings than the nanosilver in NSPW-L30SS, and EPA has not determined that AGS-20 and NSPW-L30SS contain the same active ingredient or pres ent exposures that sh ould necessarily be aggregated.

Finally, even if the Agency had concluded that the nanosilver in NSPW-L30SS and the nanosilver in HeiQ AGS-20 were the same and exposures to each were to occur concurrently (i.e., the markets for each pestic ide are separate and th erefore exposures to each pesticide could be additive), they would not result in MOEs that would be of concern (i.e., the Margin of Exposure is large). Therefore the Agency has evaluated the form and
amount of nanosilver released from NSPW-L30 SS treated articles and has determined that for the most sensitive subpopulati on (children) there are no risk s of concern and the margin of safety is large.

With respect to other products (i.e., products th at are not registered as pesticides containing nanosilver) in the marketplace that are advertis ed or believed to contain nanosilver the Agency has no reliable information to determ ine whether these products in fact contain nanosilver or, if containing nanosilver, whether the nanosilver in thes e products have the same physiochemical properties or toxicity as the nanosilver in NSPW-L30SS. Thus, the
commenter is correct that EP A does not have reliable information that might allow an aggregated exposure assessment with respect to all non-pesticidal products marketed or
believed to contain nanosilver.

Nonetheless, the following discussion may be helpful in addressing some of the inherent concerns raised by the commenter with re spect to products marketed as containing nanosilver. First, if a regist ered pesticide is advertised or marketed as containing15 of 57 nanosilver but has not been registered as c ontaining nanosilver, as part of registration review, additional data will be required to addr ess whether any currently registered silverbased pesticides contain nanosilv er and have similar physiochem ical properties or toxicity, and such data will be used to assess any na nosilver component of a pesticide product. In contrast, if a product is not regi stered but makes pesticidal claims relating to nanosilver as a component of the product, such product ma y be an unregistered pesticide subject to
enforcement if offered for sale or distribut ion in the United States. While other products advertised or marketed as containing nanosilv er may be subject to regulation or control under other authorities or by ot her federal agencies, EPA not es that even the Nanotech project consumer products inve ntory (PEN, 2014) indicates that few of the advertising or marketing claims for products on the market as containing nanosilver are verified or manufacturer supported while the remainde r are unsupported. Additional information regarding unregistered nanosilv er pesticides is included in the EPA Response to the International Center for Technology A ssessment (ICTA) Petition for Rulemaking Requesting EPA to Regulate Nano-Silver Pr oducts as Pesticides. The petition and the response may be found at www.regulati ons.gov in Docket ID # EPA-HQ-OPP-0650.

With respect to the suggestion that EPA s hould consider the cumulative and aggregate impact of all the various sources of silver ions loading to the environment. EPA has
conducted cumulative risk assessments to addres s human health risks for several pesticide groups that share a common mechanism of toxicity, but most human health risk assessments for pesticides are typically c onducted for single chemicals. Currently, for ecological risk assessments, the analytical methodologies and tools are unavailable to analyze the ecological risks of multiple sources of a si ngle chemical, mixtures of chemicals, and non-chemical stressors. However, at this time, it is not possible for the EPA to conduct aggregated or cumula tive ecological risk assessments.

As discussed in Response 2.3, although silver wa s not detected, the Agency did not assume absence of silver in assessing th e risk, and used a release rate based on one-half the LOD in accordance with OPP policy. While the specific form released from plastics or textiles below the LOD is unknown, the Agency has found that use of NSPW-L30SS will not
cause unreasonable adverse effect s to human health or the en vironment, whether resulting
in releases of ionic silver or nanosilver.

Comment 6.5: Due to the physicochemical complexity of nanosilver in the environment, EPA must approach its assessment in a co mprehensive manner, rather than requiring animal tests on individual produc ts. We urge the EPA to firs t gain an understanding of nanosilver’s forms, fate and transport in the environment, characterize the scenarios under which it is most bio-active, and determine the variables that in fluence its toxicity. Much of the preliminary toxicity ev aluation could be done using in vitro or other non-animal methods. There are already a number of promising nanomaterial-specific in vitro techniques available and in development that are likely to provide high-throughput and
reliable data on the cellular t oxicity of nanosilver. These tech niques will also be of use when looking at mechanisms and interactions of nanosilver within human systems, which will allow for better predictivity as well as allow assessment of cumulative exposures. Once this knowledge is gained, a screening model and other in silico methods could be developed to predict toxicity based on characte ristics of the particular nanosilver product, its use and length of exposure. At that point , specific nanosilver pr oducts that show the highest potential for toxicity could be iden tified for further testing. Using such an16 of 57 integrated evaluation and testing approach is more strategic, and more efficient in the long run, than testing on animals on a product-by-pr oduct basis. Not only will the latter approach kill thousands of animals, but the resu lts will be difficult to in terpret, particularly when so many more non-pesticide-regulat ed products containing nanosilver go uncharacterized and may repres ent a greater threat. We unders tand that not all of these products are under the Office of Pesticide Pr ograms regulatory purview; even so, a more holistic, cooperative appr oach is essential.

The EPA’s Nanomaterial Research Strategy focuses on a tiered approach based on in vitro toxicity testing methods and r ecognizes the critical differenc es in assessing nanomaterials
and bulk chemicals. We recommend that in stead of applying unproven and unvalidated animal-based methods used to test bulk chemicals, EPA consider nanosilver as a
nanomaterial first and foremost and allow for the safety testin g of nanosilver using available non-animal testing methods.

Because nanomaterials differ from traditional chemicals and have proven difficult to test using some of the animal-based methods used for traditional chemicals, it makes more sense to apply an Integrated Testing Stra tegy (ITS) that takes into account the data available for the nanomaterial of interest (i n this case, for nanosilver) and provides a rational testing strategy to satisfy regulato ry needs while minimizing animal testing. Methods that have proven most efficient and sensitive to nanomaterials include in vitro methods using bacterial, fungal, and algal toxicity tests as well as human cell- and tissuebased toxicity tests to assess human safety for these nanoparticles. Moreover, many of EPA’s newer testing designs could be modified slightly to accommodate the robust testing
of nanomaterials.

Another promising approach is described in a report focused on elucidating the impact of ingesting silver nanoparticles using a novel in vitro digestion model that has been accepted to the journal of Nanotoxicol ogy (publication date is to be determined). This study assessed nanoparticle effect after coming into contact with artificial saliva, gastric, and intestinal solutions. Because of the model’s sp ecificity to nanosilver and its ability to assess the nanoparticles as they traverse th e digestive system, we request that EPA
consider this method for further us e in risk assessment as well.

In order to most efficiently regulate nanomaterial-containing pesticides, EPA must require manufacturers to further develop and use in vitro and in silico human and environmentallyrelevant methods that are high throughput, efficient and flexible enough to handle the
infinite variations that ar e possible with a nanomaterial -based product. If the agency decides to require additional registration and testing of produc ts containing true nanosilver according to antimicrobial pesticide regulations , then manufacturers should be encouragedto assess these risks using a human-relevant intelligent testing scheme that relies on highthroughput, reliable, non-animal methods rath er than resorting to the problematic, expensive and time-consuming animal-based me thods used for tradi tional pesticides.

It makes little sense to require animal te sting on a product-by-product basis. EPA should delay decisions on toxicity testing requ irements until nanosilver products can be characterized and compared for similarities and differences, and until realistic exposure levels can be determined. We disagree with Scientific Advisory Panel recommendations that bridging opportunities may be limited am ong nanosilver products and request that a full examination of the physicochemical prop erties be completed before requiring any17 of 57 animal tests. A recent review of the applic ability of QSARs to nanotoxicology highlights the promise of computational toxicology met hods in evaluating nanomaterials, although the article does point out that some major gaps in research required to accelerate the use of QSAR methods for regulator y purposes do exist.

We urge EPA to support human-relevant toxi city test methods fo r assessing nanosilver. In

vivo methods are not validated for testing na nomaterials and given the myriad of conflicting data from animal studies w ith nanomaterials, testing nanomaterials in vivo is not only subject to the same pr oblems and constraints that pla gue all animal-based testing, but is further confounded by even more prac tical difficulties than experienced with traditional chemicals and pharmaceuticals.

EPA must employ a more robust and reliable syst em to assess nanomaterial safety and we urge EPA to facilitate the development, im plementation, and use of relevant and reliable
non-animal- based methods.

Response 6.5: EPA is committed to conducting further research on the form, fate and transport of nanomaterials and is constantly examining the scientific literature for new information on this topic. See Responses 6.1, 6.2, 7.4, and 7.19 for further discussion on
the risk assessment and the basis for uncertain ty factors and data requirements. While the Agency is moving towards encouraging regi strants to use more cell-based and other in

vitro systems, these technologies are largely still in the preliminary stage with the exception of certain systems designed for acute toxicity endpoints. The Agency continues to use those studies which it thinks will be most effective in determining the hazard and risk posed by a given chemical. In regard to QSAR, the Agency has and will continue to consider accepting SAR/QSAR to fulfill data requirements on a case-by-case basis, based on the quality and completeness of info rmation and supporting rationale provided. Registrants are encouraged to submit av ailable information to support SAR/QSAR analyses and then work with EPA to provi de any additional information needed. With regards to a new digestion model, the Agency examines all relevant research and thanks the commenter for sharing this paper with the Agency for further review.

Commenter 7: Jaydee Hanson, The International Cent er for Technology Assessment (ICTA) and Zack Marker, Center for Food Safe ty (CFS) (EPA-HQ-OPP-2012-0594-0019, Received 9/26/2013)

Comment 7.1: We are concerned that crystallin e silica is quartz, a highly toxic carcinogen. While we doubt that EPA would everapprove quartz, we suggest that [NSPWL30SS] may in fact be attach ed to synthetic amorphous silica. We wish to flag for EPA that the staff reviewing the data on [NSPW- L30SS] have not ade quately described the nanosilver material in [NSPW- L30SS], whether for lack of the necessary expertise in material chemistry or otherwise.

EPA failed to provide an adequate characte rization of the chemistry of [NSPW-L30SS], making it impossible for the public, and likel y even for EPA staff, to “guesstimate”
whether or not it would behave like other de scribed nanosilver mate rials. EPA describes [NSPW-L30SS] as, “a liquid suspension contai ning silica-sulfur-nanos ilver particulates where the nanosilver active ingredient is attached to crystalline silica via a thiolate bond.” First, the description of the silica as crystalline is likely in error; it is likely that the form of silica is synthetic amorphous sili ca. If this is not the case, and it is actually crystalline, then18 of 57 given crystalline silica’s known cancer effects, EPA’s determination of no cancer risk is certainly in error.

Response 7.1: EPA concurs that NSPW-L30SS contai ns amorphous silica rather than crystalline silica. In describing the stru cture and composition of NSPW-L30SS for the purposes of conditional registrati on, EPA relied heavily on the studi es by Lee et al. as cited in the proposed decision document. As outlined in Appendix B, Table 1B of the proposed decision document, EPA is requiri ng Product Chemistry and NSPW-L30SS
characterization data to confirm the composition and structure of NSPW-L30SS.

Comment 7.2: Presuming the error is in the descripti on of the material, this error raises red flags about whether or not EPA staff that reviewed [NSPW-L30SS] included material chemists, who would have the necessary expe rtise to characterize the material. [NSPWL30SS] appears to be a single silica pa rticle surrounded by multiple nanoscale PVPcoated-silver particles connected together through weak thiol linkages. However, EPA fails to define the thiol linkages adequately and raises significant questions. What is the thiol linkage to? Is it to the PVP coati ng, or to the silver atoms, or to a silver ion that is separate
from the surface? Research has demonstrated th e PVP-coated-nanosilver particles, such as those used in the [NSPW-L30SS] product, ma y be more toxic than uncoated particles.

Response 7.2: The information EPA is requiring as outlined in Appendix B, Table 1B of the proposed decision document, should aid in further characterizing the product. The potential difference in toxicity due to variations between na nosilver ingredients (e.g., due to coatings) has been accounted for in the da tabase uncertainty factor. See Response 6.2 for further discussion on the uncertainty factors.

Comment 7.3: Nanotechnology is a powerful new set of platform technologies for observing, taking apart, and recons tructing nature at the atomic and molecular level. While the public generally thinks of nanotechnology in the future tense, consumer products containing manufactured nanom aterials have already arri ved on market shelves, and comprise a product wave spanning many technologi es. Nanosilver is th e largest sector of these products, with hundreds of nanosilver products commercially available, although total numbers are unknown, since no labeling is required. These nanosilver products are properly defined and should be regulated as pesticides by EPA, since their only intended
use is as an anti-bacter ial, anti-microbial agen t, i.e., to kill pests.

Response 7.3: EPA does not agree with the comment that consumer products containing nanosilver are necessarily pesticides. The scope of EPA’s authority to regulate products as pesticides is more limited than noted by commenters. For example, EPA’s statutory authority extends only to those products that meet the definition of “pesticide” as that term is defined under FIFRA and applied in EPA re gulations. “Pesticide” is defined, in part, to expressly exclude a number of substances, su ch as liquid chemical sterilants. Thus, statutorily excluded substances cannot be cla ssified as a pesticide (FIFRA 2(u)). In addition, the statutory definition of “pest” in FIFRA section 2(t) explicitly excludes “viruses, bacteria, and other microorganisms on or in living man.” Similarly, if the “pest” targeted by the nanosilver is a “fungus” as defined under FIFRA section 2(k), the nanosilver is not a pestic ide if the targeted fungus is “on or in living man or other animals” or “on or in processed food, beverages, or pharmaceuticals.” Unde r EPA regulations, 40 CFR 152.5(d), EPA has also extended this statut ory exclusion to any fungus “on or in ... cosmetics (as defined in FFDCA section 201( i)).” In addition, EPA has, by regulation,19 of 57 identified a set of substances (e.g., deodor izers and cleaning agen ts), that are not considered to be pesticides unless a pesticidal claim is made on the label or in connection
with the substance’s sale or distribution (40 CFR 152.10). As a result, products that are intended solely for uses that fall within th e statutory or regulato ry exclusions are not pesticides and are not subject to the requirements for regi stration. Please see 40 CFR 152.6
for a discussion of these and other statut ory exclusions, and 40 CFR 152.5 for EPA’s regulations on what is a “pest” and 40 CFR 152.8 for a list of products that are deemed not for use against a “pest.”

Further, EPA’s authority to regu late a product as a pe sticide extends only to substances or mixtures intended for a pesticidal purpos e. As commenters note, EPA’s implementing regulations at 40 CFR 152.15 state:

(a) The person who distributes or sells the substance claims, states, or implies (by labeling or otherwise):

i. That the substance (either by itself or in combination with any other substance) can or should be used as a pesticide; or

ii. That the substance consists of or co ntains an active ingredient and that it can be used to manufacture a pesticide; or

(b) The substance consists of or contains one or more active ingredients and has no significant commercially valuable use as distributed or sold other than (1) use for pesticide purpose (by itself or in comb ination with any other substance), (2) use for manufacture of a pesticide; or

(c) The person who distributes or sells the substance has actual or constructive knowledge that the substance will be us ed, or is intended to be used, for a pesticidal purpose.” (40 CFR 152.15)

Only paragraph (b) allows EPA to concl ude that a substance has “no significant commercially valuable use other than use for pesticide purpose” and that it thus may be presumed to have a pesticidal purpose (40 CFR 152.15(b)). As noted in the preamble to the final rule adopting these regul ations, “EPA acknowledges that a certain degree of judgment must be exercised in deciding whether a subs tance meets this definition. On the other hand, the Agency believes that a large percentage , if not the majority, of pesticide active ingredients are clearly identifiable either as pesticides or as multi-purpose substances, and that the Agency will rarely be compelled to use this criterion alone to judge whether a substance is a pesticide” (53 FR 15952, at 15954 - May 4, 1988). This position holds true
in this case as well.

While EPA agrees with the commenter that silv er and nanosilver ingredients have inherent bactericidal properties, that a substance has anti-bacterial pr operties does not alone address the issue; there must be no other significant commercially valuable use. In this case, silver and nanosilver have other properties that may instead be the purpose for a substance’s use in a product. For example, public literature indicates that s ilver has many other properties that allow uses for other purposes, such as in analytical instrumentation, cloud seeding, electroplating, mirrors, photography, and catalysts (Etris, S.F. and Cappel, C.R., Silver Compounds. Kirk-Othmer Encyclopedia of Chemical Technology. 16 May 2003). As a result, the information before EPA at this time does not allow a general conclusion that20 of 57 nanosilver has no other significan t commercially valuable use and that such ingredients should therefore be presumed on that basis to be used for a pesticidal purpose.

In sum, EPA disagrees with commenter that all nanosilver products ca n be classified as pesticides or that any nanosilver product can be classified as a pest icide solely on grounds that nanosilver is generally understood to have anti-bacterial properties. EPA does, however, agree that it may conc lude, on a case-by-case basis, that a particular product is, or that certain types of products containi ng nanosilver are, intended for a pesticidal purpose. Additional information can be found in the EPA Response to "Petition for Rulemaking Requesting EPA Regul ate Nano-Silver Products as Pesticides", available at regulations.gov (Docket ID: EPA-HQ-OPP-2008-0650).

Comment 7.4: The same new properties that so excite industry—tiny size, vastly increased surface area to volume ratio, high re activity—can result in new risks to human health and the environment. Swiss insurance gi ant Swiss Re noted: “Never before have the risks and opportunities of a new technology b een as closely linked as they are in nanotechnology. It is precisely those characteristics which ma ke nanoparticles so valuable that give rise to concern regarding hazards to human beings and the environment alike.” These risks essentially take two forms: in creased potential toxicity and unprecedented mobility for a manufactured material.

First, nanoparticles’ exceptionally large re lative surface area crea tes increased surface reactivity and enhanced toxici ty potential, which cannot be accurately predicted from larger material cousins. As the European Commission’s (EC) Scientific Committee on Emerging and Newly Identified Hea lth Risks (SCENIHR) explained:

“[e]xperts are of unanimous opinion that the adverse effects of nanoparticles cannot be predicted (or derived) from the known toxicity of material of macroscopic size, which obey th e laws of classical physics.”

It is accepted, therefore, that it is not possible to infer the sa fety of nanomaterials by using information derived from the bulk parent material.”

Response 7.4: ICTA’s summary matches the EPA’s statements in the decision and supporting documents regarding the hazard char acterization of nanosilver. EPA established points of departure (POD) using whole-animal studies performed using OECD guideline studies on nanosilver ingredients, not on the bu lk silver parent material. As the final decision document states, “As the size of s ilver particles decreases...the potential for releasing silver ions increases, due to the increasing unit of surface area...” However, the
other factor to consider is release rate . NSPW-L30SS contains nanosilver that is complexed to a larger particle that is then embedded into a polymer. The submitted leaching studies show that nanosilver is unlik ely to be released in quantities above the detection limit from this polymer. Absent release from the polymer, the mobility of nanosilver in NSPW-L30SS is greatly reduce d. As EPA explained in the proposed and final decision documents, the available data s how release of nanosilver below the level of detection. Taking into considera tion these low releases, the ava ilable toxicity data, use of multiple risk uncertainty factors (UFs) and required risk mitigation measures on the product label, the calculated margins of e xposure (MOEs) and risk quotients (RQs) were well above the Agency levels of concern (L OCs). On these grounds, EPA determined that
there is substantial evidence in the record to conclude th at the proposed use of NSPW-21 of 57 L30SS during the conditional registration pe riod will not cause unreasonable adverse
effects on human health or the environment.

Comment 7.5: Scientists have yet to determine even what physicochemical properties will be most important in determining ecological an d toxicological propertie s of nanomaterials. Standard toxicological analysis correlates heal th risks with the mass to which an individual is exposed, resulting in an accumulated mass as an internal dose or exposure. However, the biological activity of nanopart icles is likely to depend on physicochemical characteristics that are not routinely considered in toxicity -screening studies. There are many more factors affecting the toxicological pot ential of nanoscale materials, at least sixteen in fact, including: size, surface area, surface charge , solubility, shape or physical dimensions, surface coatings, chemical composition, and a ggregation potential—a “far cry from the two or three usually measured.” Nanotoxico logy is an emerging field in its own right, requiring new paradigms of predictive toxico logy, which are only now being delineated. Yet EPA relied solely on mass as its risk me tric for [NSPW-L30SS], despite being “aware” that “metrics other than mass (such as part icle number or surface area) may be more suitable for assessing nanoparticle risks.”

Response 7.5: The Agency is aware of the ongoing deba te within the scientific community that metrics other than mass (such as particle number or surface area) may be more suitable for assessing nanosilver risks and therefore acknowledges the potential for limitations of mass-based risk estimates. EPA will be collecting data on such factors during the period when newly required data are being develope d as outline in appendix B of the decision document. However, as EPA explained in th e proposed and final decision documents, the
available data show release of nanosilver below the level of detection. Taking into consideration these low releases, the availa ble toxicity data, us e of multiple risk uncertainty factors (UFs) and required risk mitigation measures on the product label, the calculated margins of exposure (MOEs) and risk quotients (RQs) were well above the Agency levels of concern (LOCs). On thes e grounds, EPA determined that there is
substantial evidence in the r ecord to conclude that th e proposed use of NSPW-L30SS during the conditional registration period will not cause unreasonable adverse effects on
human health or the environment.

Comment 7.6: [D]ue to their tiny size, nanomaterials have unprecedented mobility for a manufactured material. They are more eas ily taken up by the human body and can cross biological membranes, cells, tissues, and organs more efficiently than larger particles. Once in the blood stream, nanomaterials can circulate throughout the body and can be taken up by the organs and tissu es including the brain, liver, h eart, kidneys, spleen, bone marrow, and nervous system. In addition, un like larger particles, nanoparticles are transported within cells and ta ken up by cell mitochondria and the cell nucleus, where they can interfere with cell signaling, induce ma jor structural damage, and result in DNA mutation. EPA has, in fact, voiced its concerns regarding nanomaterials’ ability to be absorbed into the body and cross the blood-brain barrier, as well as the high durability and reactivity of some nanomaterials.

Response 7.6: The EPA relied on the same toxicity studies to which ICTA referred, and
concluded that use of NSPW-L30SS will not cause unreasonable adverse effects to human health or the environment. Furthermore, NSPW-L30SS contains nanosilver that is complexed to a larger particle that is then in corporated into plastics and synthetic textiles22 of 57 and the leaching studies show th at nanosilver is unlikely to be released from plastics and
textiles at levels above detection limit.

Comment 7.7: As little as is known about nanomateria ls’ health impacts, even less is known about their environmental impacts. While EPA acknowledged that no fate or ecotoxicity studies are ava ilable for [NSPW-L30SS], EPA nonetheless proposes granting conditional registrati on of [NSPW-L30SS].

Response 7.7: EPA disagrees that the state of knowledge about NSPW-L30SS is insufficient to make a conditional registrati on finding. Data show the nanosilver in NSPWL30SS leaches out of plastics and textiles belo w the LOD. While the specific form released from plastics or textiles below the LOD is unknown, the Agency has found that use of
NSPW-L30SS will not cause unreasonable adverse effects to human health or the environment, whether resulting in releases of ionic or nano-silver, pending generation of the requisite data as a term and condition on the registration. For a ny portion released as ionic silver, this finding is based on the data and analysis in the Reregistration Eligibility Decision for silver for these material preserva tive use patterns. For any portion released as nanosilver, this finding is based on the data and analysis discu ssed in the decision document, and further explanations in the current document. More specifically, on the exposure analysis, while the specific knowledge of which form is released is desirable and is necessary to confirm the identified margin of safety determined in the risk assessment (and thus is required as a term and conditi on on the registration pe r Appendix B of the decision document), the Agency knows identifying which form of silver is released would decrease, not increase, the nanosilver exposure estimates provided in the decision document, as the risk assessment conservati vely assumed all silver was released as
nanosilver.

With respect to assessing the acute and inte rmediate health impacts, see Responses 6.1, 6.2, 7.4, and 7.19. With respect to assessing the ch ronic health impacts, although children’s short- and intermediate-term exposure durations to plastic toys and textiles treated with NSPW-L30SS are expected, children are not anticipated to play with NSPW-L30SStreated toys or contact NSPW-L30SS-treated tex tiles every day for a period of greater than six months, thus long-term exposures are unl ikely. Because of the potential for NSPWL30SS to be used in flooring, long-term dermal and incidental oral exposures to children contacting flooring are possible. However, EP A does not believe that children will have continuous and daily exposure to flooring for a period of greater than 6 months. Even if these unlikely long-term exposures were to o ccur, the calculated MOEs for children’s dermal and incidental oral exposure to plas tics and textiles inco rporating NSPW-L30SS are greater than 100,000 indicating th at daily exposure to plastics and textiles incorporating NSPW-L30SS for greater than 6 months are no t of concern. Therefore, the EPA believes this chemical does not meet the requirements for triggering the conditional requirement of
either a chronic or carc inogenicity study as indi cated in Part 158W.

On the ecotoxicity issues, there are sufficien t ecotoxicity data on nanosilver to make the requisite finding pending generation of data for NSPW-L30SS. First, ecotoxicity data on other nanosilver materials provide inform ation on the expected effect range (e.g., milligram versus microgram versus nanogram range) for such materials. Second, the ecotoxicity data in the decision document use nanoscale particles coated with PVP, similar to NSPW-L30SS, and the most sensitive freshwater invertebrate Daphnia magna . Together23 of 57 these data show that the ecot oxicity effect range obtained from the different nanosilver particles and coatings considered in the d ecision are protective, taking into account the
estimated release rates and environmental exposures. Supporting this conclusion is the comparison between data on nanosilvers and da ta on other forms of silver. Specifically, even assuming the chronic toxicity of NSPW-L 30SS may be more toxic than silver salts, the toxicity of silver nanoparticles is not e xpected to be orders of magnitude more toxic than acute values for the more acutely sensit ive species and life stages, based on general silver nanomaterial toxicity data and the acute-to-chronic ratios (ACRs) seen for silver salts. For example, one silver nanomaterial study with a sensitive life stage was identified and discussed in the proposed decision document. The 96-hour EC 50 Danio rerio embryo
test results for three differe nt silver nanomaterials (b are, polyvinylpyrrolidone-coated (PVP-coated), and bare monodispersed na noparticles with a dispersant) are not significantly different or are less toxic than comp anion silver nitrate results on a total silver basis (Wang et al. 2012b; Tables 17 and 18 of the proposed decision document). Blinova et al. (2013) conducted acute and chro nic 21-day reproduction tests with D. magna using a
PVP-coated nanosilver and colla rgol-coated nanosilver in tw o natural waters. This study was not included in the proposed decision docu ment and while there are several issues which limit use of the data qua ntitatively in a risk asse ssment, the study does provide
evidence that the ACRs for silver nanomaterials for D. magna on a total silver basis potentially are around or less than 2, which is si milar to silver salts. In the case of silver salts, acute toxicity values for the most sensitive freshwater species D. magna (unfed during duration of acute study pe r guideline standards) are lo wer than chronic values on a total recoverable silver basis (USEPA Ambi ent Water Quality Criteria for Copper 1980, 1987). When daphnids are fed during the silver salt acute tests, acute toxicity has been observed to be reduced (2.9 to 40 times less t oxic), with resulting ACRs of at least 2 for D.

magna (USEPA 1980). Similar decreases in acute toxicity have been observed for other sensitive cladoceran species ( Ceriodaphnia reticulata, Daphnia pulex ) when fed (USEPA 1987). While the Agency has not reviewed more current public literat ure on acute toxicity for silver salts for acceptability for use in a risk assessment, open literature reviews of available silver toxicity data based on total recoverable silver demonstrate this pattern has
also been observed in later studies with D. magna . (Ratte 1999). This difference has been attributed to the presence of food providing a mitigating e ffect (i.e., food binds silver, rendering it less bioavailabl e). There have been limited chronic tests with D. magna where
the soluble or dissolved concentrations of silver have been measured along with companion acute data, but in these cases, the ACR is less than 2. This means if there are no
acute risks based on the D. magna, unfed, acute value there are definitely no chronic risks for this species. Similar effects on acute to xicity of silver nano materials have been observed. Blinova et al. (2013) discuss how the mortality in chronic tests was lower than that observed in acute tests (unfed). One excep tion to a low silver nitrate ACR for sensitive
cladocerans is based on acute a nd chronic results from Bielmyer et al. (2002), cited in the EMERGANO review. Bielmyer et al. (2002) conducted acute and ch ronic testing with
silver nitrate for the cladoceran Ceriodapnia dubia which results in an ACR of 550 but this value is greater than a factor of 10 of all ot her silver ACRs for cladocerans and is based on
nominal rather than measured total silver a nd a dose-space factor of 10 for the chronic study. Dose-spacing <3 is standard guidance fo r acceptable chronic tests with dose-spacing of 10 only suitable for range-finding. Bielmyer et al. (2002) reported for C. dubia a 21-d NOEC and LOEC of 0.001 and 0.1 ppb, respecti vely, and an acute value of 0.55 ppb for24 of 57 total silver–these results are based on nominal, unmeasured values (note quantitative measurements in the study were made only in exposure concentrations >2 ppb—detection limit).

In sum, the general knowledge of the ecotoxic ity effect range obtained from the different nanosilver particles and coatings considered in the decision provides adequate data to determine that, pending generation of newly re quired data, the proposed uses in this case will not cause unreasonable adverse effects, es pecially given the large difference between the LOC and RQs and how much more toxic the nanosilver in NSPW-L30SS would need to be to exceed the LOC (see Responses 7.10, 7.14 and 7.15). Tiered fa te and ecotoxicity data are required as a term and conditi on on the conditional regi stration allowing the Agency to have additional data points to confirm the margin of safety.

This analysis is also relevant to the redu ced environmental loading basis for the public interest finding. Specifically, EPA has register ed a number of silve r-based antimicrobial products for use as materials preservatives in textiles. Most of these antimicrobial silverbased pesticide products cu rrently contain a silver salt (e.g., AgCl or AgNO 3 ). Compared to the amount of silver in Nanosilva LLC’s produc t, most currently registered silver-based materials preservative registrati ons allow far larger application rates than allowed for the proposed registration. Therefore, the overall potential environmental loading of silver resulting from the lower-volume use of the Nanosilva LLC product should be smaller than from a comparable use of currently re gistered silver-based pesticides.

Relevant assumptions used by the Agency include the following:

 Assumed all treated plastic (non-textile) was linear low-density polyethylene (LLDPE) which is amongst the most porous of plastics and thus the possibility of leaching is higher compared to other available plastics.

 Assumed all treated in-service plastic lumber would be exposed to water daily, and thus leach nanosilver to the environment daily.

 Assumed 100% of nanosilver in the in-s ervice plastic lumber would leach out annually (i.e. 0.274% leaches out daily) even though an estimated <0.042% would leach out in 10 days (or <0.0042% daily) based on the LLDPE coupon leaching data. The assumption also requires nanosilver to migrate at the same or higher rate daily from the interior to the exterior of the plastic product to replenish nanosilver for leaching availability the next day.

 Assumed no removal of nanosilver in run-o ff from plastic lumber due to adsorption to soil (i.e., all released silver goes directly to a stream).

 Assumed everyone in the U.S. population has a NSPW-L30SS treated t-shirt, and washes it weekly.

 Assumed the nanosilver in the NSPW-L30SS is stable (i.e., does not dissociate into ionic silver in the environment) and fo r aquatic water column organisms none of the nanosilver discharged from a WWTP is removed from the water column.

 For assessing acute risks to aquatic species, total silver results from an acute test where daphnids were not fed during testi ng were used. When food is present in

acute tests with D. magna, reduction of acute toxicity in terms of total silver by

about a factor of 10 has been observed.25 of 57 Comment 7.8: EPA cannot show that [NSPW-L30 SS] will not cause “unreasonable
adverse effects on the environment” as re quired by FIFRA for conditional registration.

Before granting a pesticide registration, EPA must determine that the pesticide will not cause any “unreasonable adverse effect on the environment.” The term “unreasonable
adverse effects on the environment” mean s “any unreasonable risk to man or the environment, taking into account the econom ic, social, and environmental costs and benefits of the use of any pesticide.”

EPA’s conditional registration of [NSPW-L30SS] is unlawful because nanosilver poses
unreasonable risks to man and the environmen t. The unreasonableness of the risks posed by nanosilver pesticides are furt her underscored by the dearth of health and safety data in
the record.

Response 7.8: Please refer to Response 6.1, 7.7, 7.14, 7.15, 7.27, and 7.28

Comment 7.9: EPA applies the wrong standard in making its determination to conditionally register [NSPW-L30S S]. EPA states that it “has determined that there is a low probability of adverse risk to human h ealth and the environment from plastics and textiles incorporating [NSPW-L 30SS].” Applying this “low pr obability of adverse risk” standard in granting [NSPW-L30SS] conditi onal registration not only puts human health and the environment at risk, but is also indi cative that EPA failed to consider the proper factors, and thus is arbitrary and capri cious agency action on behalf of EPA.

Response 7.9: ICTA ignores the sentence that follows:

“...there is a low probability of adverse risk to human health and the environment from plastics and textiles incorpor ating NSPW-L30SS. Thus, the Ag ency concludes that use of NSPW-L30SS will not cause unreasonable adverse effects on the environment during the period when newly required data are being developed.” The calcu lated MOEs are well above the target MOEs, and thus EPA conclude d the proposed use of the pesticide will not
cause unreasonable adverse effects on human health. Similar findings were made for ecotoxicity risks.

Thus, EPA made the statutorily required fi nding and used the correct legal standard.

Comment 7.10: EPA lacks adequate data to make its decision. As with nanomaterials more generally, there is a lack of research on the human health and environmental safety of nanosilver, and especially with a composite product like [N SPW-L30SS] that the company plans to use more extensivel y than any existing nanosilver products. Indeed, it plans more
extensive use than even a ny existing bulk silver products . Among other things, proposed incorporation of [NSPW-L30SS] includes textiles , plastic films, sheets, slabs, and molded parts, as well as consumer products such as footwear, sportswear, uniforms, and auto parts, floor coverings, outdoor furniture, decking, and house siding. To our knowledge, no other silver pesticide product registra tions cover floor coverings, plastic films, slabs, and molded parts, such as those that would be found in outdoor furn iture, decking and house siding.

SAP specifically acknowledged that “data ga ps about potential e xposures and hazards related to nanosilver are broad,” noting that “there is very little information about
nanosilver in the environment related to fate, transport, and transformation.” Further,
EPA’s Draft Decision Document admits that there are “no fate or ecotoxicity studies26 of 57 available for [NSPW-L30SS],” which required EPA to estimate the fate and ecotoxicity using existing studies in the scientific literature.

EPA acknowledged the existence of many gaps in scientific knowledge with regard to
nanosilver’s effects on health and the environment. These gaps include:

 no intermediate- or long-term human or environmental toxicity studies available for [NSPW-L30SS] or for th e nano-sliver released from products incorporating [NSPW-L30SS]

 no studies on environmen tal fate and transport

 no studies in the scientific literature that investigate mutagenicity or carcinogenicity of nanosilver

 no subchronic or chronic oral or dermal toxicity studies available for [NSPWL30SS] or on the nanosilver that might break away from products incorporating [NSPW-L30SS]

 no acceptable studies on the reproductive and developmental toxicity for
nanosilver

 inadequate information to assess muta genic and carcinogenic potential of
nanosilver due to differences in results between in vitro studies and in vivo studies, and limitations of the only available in vivo study

 insufficient information on aggregate expos ures to other nanosilvers currently in the market place.

Yet the absence of data cannot replace the ag ency’s burden to show, based on substantial evidence, that there will be no unr easonable impacts on the environment.

Response 7.10: The Agency disagrees that it lacks adequate data to determine that the proposed uses, during generation of required data, will not cause unreasonable adverse
effects on the environment. While data on the nanosilver in NPSW-L30SS or on NPSWL30SS specifically do not exist for the listed pa thways/toxicities there is adequate data on
nanosilvers sufficient to determine that the proposed uses in this case will not cause unreasonable adverse effects, especially give n the large difference between the LOC and MOE for most routes of exposure. For thos e routes where the difference is smaller (inhalation) or there are areas of additional interest (e.g., re production/fertility), data are being required (90 day inhalation study with a functional observ ation battery, motor activity and detailed neuropathology, modified reproduction/developmental toxicity via the inhalation route and a Tier 2 non-guideline pe ri- and post natal deve lopmental study) to reduce the 10X database uncertainty factor applied and to determine whether any other
POD should be used in the risk assessment. Fo r similar reasons, tiered fate and ecotoxicity data are being called in for the duration of the conditional registration at which point the Agency will have additional data points to confirm the margin of safety. In regard to the comment that no other silver-based registrati ons cover the range of the uses that are covered by the NSPW-L30SS application, the commenter is incorrect. The Agency has registered silver-based products for use in plas tics including such uses as floor coverings, plastic films, slabs, molded parts, sidings, fu rniture, etc. In regards to mutagenicity, as noted in the decision document, available in vitro studies suggest th at nanosilver is equivocal to mutagenic potential. However, th e lack of mutagenicity in several wellconducted in vivo studies, showing cytotoxicity a nd evidence that the nanoparticles reached the target tissue, suggests that the in vitro mutagenic potential ob served in some of27 of 57 the in vitro studies may be intrinsic to nanoparticles, but is not expressed in whole animals. There is evidence that silver nanoparticle s are genotoxic, expressing DNA damage in cultured human lung cells and in the lungs and liver of intact animals (comet assay) via intracellular generation of ROS. These fi ndings are supported by the inflammatory processes observed in the lungs. However, since initiation of RO S-induced oxidative DNA damage can be blocked by ROS scavengers, th ere is not a concern for mutagenicity or genotoxicity. Furthermore, EPA believes that the short-term oral NOAEL and
intermediate-term oral LOAEL of 30 mg/kg/day and i nhalation NOAEL of 49 μ g/m 3 are expected to be protective of mutagenicity. In regards to chroni c toxicity, including carcinogenicity, the potential exposure to NSPW-L 30SS is not likely to result in significant human exposure over a considerab le portion of the human life sp an which is significant in terms of frequency, time, duration, and/or magn itude of exposure. The release rate based on the leaching study from the use of NSPW-L30 SS is so small and the resulting MOEs so high that the EPA has determined that the ch ronic/carcinogenicity toxi city studies are not triggered as conditionally required as part of 158W. For more information on environmental fate, transport and toxicit y, see Response 7.7. For more information on reproductive and developmental toxicity, see Response 7.28. For more information on subchronic toxicity, see Response 6.2. For more information on aggregate exposure, see Response 6.4.

Comment 7.11: Nanoscale particles including nanosilver have been shown to be capable of penetrating biological barri ers such as cell membranes and can enter into the cells themselves. Nanoparticles are able to attach to cell membranes, producing changes in membrane permeability, redox cycling in the cy tosol, intracellular radical accumulation, and dissipation of the proton motive force for ATP synthesis. Each of these has been reported as a possible mechanism for nanopa rticle toxicity. Ev idence from scanning transmission electron microscopy also shows th at smaller particles (< 10 nm) may enter the cell directly to inhibit microbial growth.

Response 7.11: While the studies have shown the above effects, these studies are in vitro
studies. These studies have not b een characterized to represent in vivo effects as they do not account for the complexities of biological systems, including things as varied as first pass effects and blood protein bindi ng. Furthermore, the other fact or to consider is release
rate. NSPW-L30SS contains nanosilver that is co mplexed to a larger particle that is then embedded into a polymer. The submitted leaching studies show that nanosilver is unlikely to be released in quantities above the dete ction limit from this polymer. Absent release from the polymer, the mobility of nanosilver in NSPW-L30SS is greatly reduced. As EPA explained in the proposed and final decision doc uments, the available data show release of nanosilver below the level of detection. Taking into consideration these low releases, the available toxicity data, use of multiple risk uncertainty f actors (UFs) and required risk mitigation measures on the product label, the calculated margins of exposure (MOEs) and risk quotients (RQs) were well above the Agen cy levels of concern (LOCs). On these grounds, EPA determined that there is substantia l evidence in the record to conclude that the proposed use of NSPW-L30SS during the c onditional registration period will not cause
unreasonable adverse effects on human health or the environment.

Comment 7.12: Among documented potential harms to hum an health, in vi tro (test tube)
studies demonstrate that nanosilver is toxic to mammalian liver cells, stem cells and even brain cells. One 2009 study discovered that abso rption of nanosilver ma y interfere with the28 of 57 replication of DNA molecules, potentially creating geneti c mutations. Two other studies have demonstrated that exposure to nanos ilver can reduce mitochondrial function. The
number of diseases associated with mito chondrial malfunction is increasing and includes Parkinson’s, Alzheimer’s, a nd Huntington’s disease.

Response 7.12: Again, the studies listed above are in vitro studies. These studies have not been characterized to represent in vivo effects as they do not account for the complexities of biological systems, such as first pass effects and blood protei n binding. The Agency recognizes the potential risks associated w ith nanosilver products. However, as EPA explained in the proposed and final decision doc uments, the available data show release of
nanosilver below the level of detection. Taki ng into consideration these low releases, the available toxicity data, use of multiple risk uncertainty f actors (UFs) and required risk mitigation measures on the product label, the calculated margins of exposure (MOEs) and risk quotients (RQs) were well above the Agen cy levels of concern (LOCs). On these grounds, EPA determined that there is substantia l evidence in the record to conclude that the proposed use of NSPW-L30SS during the c onditional registration period will not cause
unreasonable adverse effects on human health or the environment. For further information
on how the current risk assessment addresses neurotoxicity, and on why certain studies are required, please refer to Responses 6.1 and 6.2.

Comment 7.13: Beyond the issue of toxicity, nanosilver may also create a public health burden by producing antimicrobial resistance. The Centers for Disease Control and Prevention (CDC) recently acknowledged antimicr obial resistance as one of the world’s most serious health threats, in part becau se of the use and overuse of antibiotics in medicine and food production. As with antibioti cs, the use and overuse of nanosilver may promote resistance to important antimicrobials, which must be addressed before it is too
late.

Response 7.13: As explained in the decision document, while development of antibacterial
resistance due to the use of nanosilver in NSPW-L30SS is possible, the Agency concluded
that the likelihood is low that the levels used in NSPW-L30SS treated articles will lead to the development of silver resistant microbes which will spread throughout the environment resulting in widespread bacterial resistan ce to silver. For example, in terms of environmental impact, a recent study involve d releasing 1 mg/L of nanosilver into microcosms containing estuary water overlying estuarine sedime nt cores (Bradford et al., 2009). The study found no impact to the microbi al community over a 30 day monitoring period. Evidence for antibacterial resistance wa s also evaluated dur ing this study and no
increase in antibiotic resistance to the b acterial population in the sediment was found (Mühling et al. 2010). Wigginton et al. (2010) suggested that the lack of antimicrobial effect in the microcosm was expected given that bacterial proteins efficiently bind to
nanosilver. The commenter does no t specifically respond to th is detail in our proposed decision document. Nor does the commenter provide any additional detail to better
understand the comment or to allow the EPA to engage on the substantive issue.

Comment 7.14: Nanosilver is also toxic to a variety of aquatic and terr estrial organisms. EPA acknowledges that, even in its bulk form, s ilver is extremely toxic to fish and other aquatic species. EPA ignores that, at the na no-scale, nanosilver can be many times more toxic. Swiss researchers recently modeled th e environmental concentrations of several29 of 57 commercially available nanomaterials and predic ted that nanosilver emissions may already pose risks to aquatic organisms.

Response 7.14: EPA agrees that there is evidence in th e literature that nano-scale silver can potentially be more toxic th an ionic silver alone, but not sufficiently more toxic to raise risk concerns when taking into account leaching rates for the proposed uses. For the plastic screening scenario, the scale of the incr ease in toxicity over ionic silver, or other nano-scale ecotoxicity data used in this asse ssment would need to be on the order of 5 to 53 times more toxic to raise any potential concer n with respect to nanosilver ecotoxicity or causing any potential for refini ng the risk assessment. Moreove r, given that at a minimum exposure due to leaching is highly likely to be overestimated (e.g., 0.00042 fraction leached / 10 days x 365 days/year = 0.015 fraction leach ed/year or 1.5% leached/year not 100%/year; for a surface water c oncentration of 0.00021 ppb for the 10 th percentile 1Q10 stream flow) the order of sensitivity of aqua tic organisms to this particular nanosilver would need to be 360 to 3600 times greater. Fo r the textile scenari o, the scale of the increase in toxicity over ionic s ilver, or other nano-scale silver ecotoxicity data used in this
assessment would need to be on the order of 19 to 190 times more toxic, which, while a narrower margin, is still not likely. The or der for both textiles and plastics would additionally increase by about a factor of 10 (i.e., 3600 to 36,000 and 190 to 1,900 times, respectively), if taking into acc ount that in the presence of food the acute value on a total silver basis is expected to be at leas t a factor of 10 higher (see Response 7.7).

Comment 7.15: Further, the same property that make s these nanoparticles attractive to manufacturers—their highly enhanced antimic robial properties—can be highly destructive to ecosystems, by threatening the bacteria-d ependent processes th at underpin natural systems. Microorganisms are the foundati on of all ecosystems and provide key environmental services ranging from primar y productivity to nutrient cycling and waste decomposition. Early studies show that nanos ilver can reduce the activities of microbes employed in treating wastewater. Widespread use of household products that release nanosilver into the sewage system could adve rsely affect waterway s, exacerbated by the inability of public utilities a nd water treatment plants to pr operly treat the substance.

Response 7.15: While there are reports suggesting the potential for nanosilver to impact wastewater treatment operations, the Agency does not anticipate that proposed use of
NSPW-L30SS will cause unreasonable adverse effects to the environment during the period for generation of the data. Estimated c oncentration in influent from the decision document would be on the order of 0.03 ppb (e.g., from Table 19 of the decision document – 0.004 ppb effluent ÷ (1-0.85 fracti on removed) = 0.03 ppb). Based on general nano-scale silver toxicity data as discussed in the decision document, toxicity of nano-scale silver to wastewater microorganisms is on the order of 500 to 1,000 ppb or higher. The
nanosilver in NSPW-L30SS would need to be >18,000 times more toxic than ionic silver or the general nano-scale silver data in Section 6.1.3 of the decision document for there to be a concern with impacts to wastewater treatment operations.

Comment 7.16: In 2009, as a result of these and ot her potential adverse impacts on the environment, EMERGNANO, the first global revi ew of environmental, health, and safety studies examining the risks of nanotechnology exposure, found that there is “sufficient evidence to suggest that silver nanoparticl es may be harmful to the environment and therefore the use of the precautionary principl e should be considered in this case.”30 of 57 Response 7.16: Commenters do not explain how use of the precautionary principle here would change the Agency’s assessment or decision. However, EMERGNANO states that the reason to apply the precautionary principle in the case of silver nanoparticles is that “[t]he RO [research re ports] present indicativ e evidence of the harm of silver nanoparticles at low concentrations on aquatic invertebra tes, which suggest that the environmental release of silver nanoparticle s should consider taking the ne cessary steps to reduce or eliminate the potential exposure of the e nvironment to these nanoparticles.” In the Executive Summary, the report also states that in the case of silver “I n these specific cases further investigation as to the need to invoke the precautionary principle is required, taking into consideration all available data.” Thus, the report does not necessarily call for application of the preca utionary principle. Moreover, to the extent that comments are calling for a delay in a regi stration decision pending receip t of additional data, EPA disagrees. For the reasons discussed throughout the decision document and this responseto-comments document, it is appropriate to gran t the registration in this case because the requisite statutory findings can be made. Finally, while silver nanoparticles may be toxic at low concentrations on aquatic invertebrates, some evidence of toxicity alone does not define the appropriate steps the Agency may take. In this case, the low release rates contribute significantly to a de termination that, notwithstandi ng data showing some aquatic toxicity, use of the active ingredient will not cause unreasonable adverse effects on the
environment. This is similar to the case of other antimicrobial pesticides, like silver salts, and other conventional pesticides that are toxic to aquatic invertebrates, also at low
concentrations. Like these othe r active ingredients, the Agency considered all available information in the decision and compared exposure levels to toxicity le vels to evaluate the potential risk for registra tion of the proposed uses.

Comment 7.17: Given the improper standard that EPA applies to its decision, the acknowledged data gaps about potential exposures and hazards, significant red flags raised by existing data, and new broad uses propos ed for [NSPW-L30SS], EPA has failed to show that conditional registration of [NSPW-L30SS] will not cause unreasonable adverse
effects on the environment.

Response 7.17: Please refer to Responses 6.1, 6.2, 7.7, 7.14, 7.15, 7.23, 7.27, and 7.28.

Comment 7.18: Nanosilva [LLC] has had sufficient time to generate and submit required
data.

FIFRA allows EPA to grant conditional registra tions of active ingredie nts not contained in any currently registered pesticides to allo w registrants to genera te and submit required data. However, only when a data requirement is “first imposed” so recently that a registrant is unable to generate the data in time for the registration application may EPA grant a conditional registration.

For example, EPA may require additional inform ation from a registrant because those data specified in the regulations ar e insufficient for EPA to properly evaluate the product. Upon such a request, the registrant should be given sufficient time to generate that data, and a conditional registration may be applicable. However, that is not the case here.

Nanosilva LLC applied in August 2009 to register this product. EPA concluded that because it had not yet reached a final decision as to which types of data would be required for [NSPW-L30SS], in part to apply the advi ce provided by SAP, that insufficient time had31 of 57 elapsed from the point at which EPA determin ed and informed Nanosilva LLC of the data requirements needed to assess Nanosilva LLC ’s application for Nanosilva LLC to have generated the data. Nearly four years have passed since SAP convened in November 2009
and identified what would be needed to ma ke a decision on [NSPW-L30SS]’s application. EPA now proposes to grant another three year s to develop the newly required studies. More than sufficient time has elapsed for the company to perform adequate toxicological testing of its product.

Response 7.18: While it has been several years sin ce the SAP convened in 2009, the SAP did not make specific recommendations on th e data needed to assess a nanosilver ingredient or how to adapt existing data requi rements and guidelines to assess nanosilver. Rather it is the Agency that needed to take th e steps to address these and other issues in the
course of its consideration of applications it had alrea dy received. In response to and
consistent with the SAP advice and after a revi ew of the data available at that time, the Agency first determined that it cannot rely on data for macrosilver alone when assessing the risks from products contai ning nanosilver and that it need ed to cautiously approach general use of nanosilver data to evaluate sp ecific nanosilver ingredie nts given the stated concerns from the SAP that the toxicity of different nanosilver ingr edients could differ. Then, the Agency took steps to assess the risks from use of nanosilver in the subject product based on a review the existing data av ailable on nanosilver. Fr om that assessment, the Agency considered what data would still be needed to more fully assess use of the current product, and whether or how to adap t the existing data requirements and guidelines to address any additional data needs or concerns. Generall y, EPA determined that the existing data requirements would be a good st arting point, but that those requirements
needed to be refined or new data would be needed to more specifically address the unique nanosilver issues or concerns. Thus, in some cases, for example, EPA determined a study not currently required by the regulations woul d be needed (e.g., additional leaching data). In other cases, for example, EPA determined that adapting the regulat ory data requirements and/or guideline references through combining elements of existing data requirements and other guideline references (e.g., developmental/re productive) or tiering da ta (i.e., all Tier II data) would be needed to assess the produc t and to avoid doing additional/unnecessary studies. These specific data requirements and ad aptations of existing requirements are not captured by the existing regulatory data tables , and had not previously been communicated to or required of the applicant. Taking into consideration the uniquene ss of this registration and the notice and comment process, the deci sion about what data would be required for this nanosilver product was not made final unt il after EPA heard from commenters on the proposed decision, considered the comments and prepared the final decision. However, the decision made on this product will inform how to approach future applications for pesticide products containing nanosilver, and thus EPA expects the time for generation of data post-application or post re gistration will narrow over time . Thus, for the reasons noted above, EPA disagrees with the commenter that Nanosilva LLC had a reasonable period of time within which to generate and submit require d data to the Agency. With respect to this registration action, EPA notes th at the required studies must be completed within four years after issuing the registration. This time period was chosen to allow time for protocol reviews prior to initiation of the studies, co mpletion of the studies, and Agency review of the study results. The Agency will evaluate th ese data as they are submitted to confirm elements of the risk assessment supporting th e Agency’s determination that the use of
NSPW-L30SS will not cause unreasonable adverse effects to human health and the32 of 57 environment. If Nanosilva LLC fails to take appropriate steps to initiate the required studies, or if Nanosilva LLC fails to submit th e protocols or data, EPA will issue a notice of intent to cancel NSPW-L30SS’s registra tion under FIFRA section 6(e). In addition, the conditional registration for NSPW-L30SS will auto matically expire four years after being issued. Nanosilva LLC should request an amen dment to remove the expiration date oncethey have submitted the required data if they wish to continue to sell and distribute NSPWL30SS in the United States.

Comment 7.19: To grant a conditional registration, EP A must determine that the use of the pesticide is in the public interest. EPA believes that the registration of this product benefits the public based on th e following points: 1) conservation of the environment, 2) consumer benefits, and 3) innovation.

For the first claim, EPA notes that a number of silver-based pesticide products are registered for use as materials preservatives , and that the use of [NSPW-L30SS] could result in less environmental loading of silver than from currently registered silver-based pesticides. However, because nanosilver is a mo re potent pesticide than traditional silverbased pesticides – that is, less nanosilver k ills more microbes – even if [NSPW-L30SS]
results in a reduction in the overall mass of s ilver released into the environment, the potential for environmental damage and non-targ et impacts may still be greater than that resulting from currently register ed silver-based pesticides. In fact, SAP noted that the rate
and concentration of silver i ons released from nanosilver wi ll likely affect the acute or chronic toxicity of nanosilv er compared with silver.

EPA ignores the fact that there is no silver pesticide product on the market right now that is used as a material preservative in plastic fo r products like decking and plastic lumber, which have not previously relied on silver-bas ed pesticides. Thus [NSPW-L30SS] will be in addition to, rather than in place of othe r silver-embedded products in the environment. Therefore, conditional registration of [NSPW-L3 0SS] will necessarily increase, not reduce,
the amount of silver ions that will be released into the environment

SAP noted that nanosilver, but not silver, ca n penetrate cell membra nes and deliver toxic ions directly inside of cells; the toxicity of silver nanoparticles appear to be much higher than that of silver nitrate; and that because of these differences in chemical properties, there are likely differences in exposure and environmental fate of nanosilver that should be considered. Thus, in the case of [NSPW-L30SS] replacing si lver-based pesticides in commerce, any reduction in environmental load ing of silver is not likely to result in
conservation of the environment.

Response 7.19: With respect to the public interest finding, please refer to Response 3.1. For more detailed information on why reduced environmental loading is in the public interest, even assuming nanosilv er is more toxic than silv er, please refer to Response 7.7. With respect to existing uses of silver ba sed products in plastics, see Response 7.10. As EPA explained in the proposed and final de cision documents, the available data show
release of nanosilver below the level of det ection. Taking into consideration these low releases, the available toxicity data, use of multiple risk uncertainty factors (UFs) and required risk mitigation measures on the product label, the calculated margins of exposure (MOEs) and risk quotients (RQs) were well a bove the Agency levels of concern (LOCs). On these grounds, EPA determined that there is substantial evidence in the record to33 of 57 conclude that the proposed use of NSPW-L 30SS during the conditional registration period
will not cause unreasonable adverse effects on human health or the environment.

Comment 7.20: In its second claim, EPA asserts that conditional registration of [NSPWL30SS] will lead to consumer benefits, such that “plastics or textiles incorporating nanosilver may have longer-term ability to reduce the number of odor and stain causing bacteria as compared to othe r similar products on the market that contain conventional silvers.” However, EPA has failed to explain wh y consumers need antimicrobial plastics or
textiles in the first case.

Response 7.20: EPA agrees that the potential for cons umer benefits does not address the need for the pesticide. See Response 3.1 for further discussion of the public interest finding.

Comment 7.21: EPA claims that it sees the emer gence of nanotechnology as offering benefits for society includi ng pest control products, and s eeks to encourage innovative work to realize those benefits. However, EPA does not provide any supporting data that suggests how or why it believes that nanotechnology “may allow for more effective targeting of pests and use of smaller quantities of pesticide.” Moreover EPA fails to assert how conditional registration of [NSPW-L30SS] will encourage such innovative work, or in the alternative, how requiring sufficient da ta and studies of [NSPW-L30SS] would discourage such innovative work.

Response 7.21: Based on the review as detailed in the decision document, EPA believes the registration of NSPW-L30SS has the poten tial to reduce envir onmental loading of silver. EPA has registered a number of silv er-based antimicrobial products for use as materials preservatives in textiles. Most an timicrobial silver-based pesticide products currently contain a silver salt (e.g., AgCl or AgNO3). Compared to the amount of silver in Nanosilva LLC’s product, most currently regist ered silver-based ma terials preservative registrations allow far larger application rates than allowed for the conditional registration of NSPW-L30SS. Therefore, the overall potential environmental loading of silver resulting
from the lower-volume use of the Nanosilva LLC product should be smaller than from a comparable use of currently registered silver-based pesticides.

The White House has specifically identif ied nanotechnology as an emerging field ( http://www.whitehouse.gov/sites/ default/files/omb/inforeg/ for-agencies/nanotechnologyregulation-and-oversight-principles.pdf and http://www.whitehouse.gov/assets/docum ents/SEPT_20__Innovation_Whitepaper_FINAL .pdf - Released September 21, 2009). EPA supports innovation when its review shows the product developed under innovative technologies meets the statutory standards. Granting the registration of NSPW-L30SS provides i ndustry with a second example of EPA’s assessment of a nanosilver pesticide while al so providing increased certainty for data needs, which contributes to a more efficien t registration process and thus encourages innovation in pesticides.

See Response 7.14 for a discussion of how most cu rrently registered s ilver-based materials preservative registrations allow for larg er application rates than NSPW-L30SS.

Comment 7.22: Given the potential harm to human health and the environment, significant scientific unknowns, and lack ofsupport for alleged benefits of [NSPWL30SS], the conditional registration of [NSP W-L30SS] is not in the public interest.34 of 57 Response 7.22: Please refer to Responses 3.1, 6.1, 7.4, 7.7, 7.14, and 7.15.

Comment 7.23: CFS/ICTA is opposed to conditional regi stration generally and to that of [NSPW-L30SS] specifically. Condi tional registrations of pestic ides have been overused by EPA and the management of EPA’s conditional registration program raises significant red flags about its ability to prot ect the American public while allowing products with known
risks to remain on the market while undergoing further study.

Section 3(c)(7) of FIFRA provides EPA the au thority to grant a “c onditional registration” for a pesticide product under certain circumstan ces, even though some necessary data have not been provided by the registrant in the a pplication. By doing so, EPA allows pesticides into the marketplace without complete data, such as toxicity te sts and studies that demonstrate the pesticides’ impact on th e environment. EPA’s Office of Pesticide Programs (OPP) has overused conditional registra tions, not in keeping with their original intent – to be used only in limited circumst ances where a public need was established.

In March 2011, an internal review conducted by OPP dete rmined that of 16,156 active pesticide registrations, 11,205 ( 69 percent) were conditionally registered. Of those, over 3,200 pesticides had been in conditional stat us since 1995, and 2,100 pesticides had been
in conditional status since 1990. OPP officials alle ge that these numbers are inaccurate as a
result of misclassifications and that th e basis for many registration decisions was
mischaracterized as conditional.

The high numbers of products registrations that remain conditionally registered after so many years raises several concerns.

At best, EPA has poorly overseen its registra tion program to the point that its tracking system cannot even identify the status of conditio nally registered pesticides to ensure that registrants submitted, and EPA reviewed, the required additional data upon which registration is conditioned, in a timely manne r. As currently cons trued, the conditional registration program calls into question EPA’s a ssertion that it will evaluate the additional required data “to confirm the Agency’s risk assessment.”

More importantly, OPP may be failing to m eet its requirements under FIFRA to review each chemical every 15 years, allowing products to stay on the market despite lacking the data required by law.

The Government Accountability Office (GAO) a ddressed these issues, amongst others, in a 2013 report entitled, “PESTICIDES: EPA Should Ta ke Steps to Improve Its Oversight of Conditional Registrations.” GAO made severa l conclusions regarding EPA’s improper handling of conditional registration, including:

EPA lacks a reliable system to track key info rmation related to conditional registrations, including whether companies have submitted the additional data re quired by conditional registration within the require d time frames. Thus, EPA lacks an important registration management tool and cannot ensure that co mpanies submit the required data, which may allow pesticides to remain on the market fo r years without EPA’s receipt and review of
these data.

GAO has well documented OPP’s problems with data management, with studies dating back to 1980, 1986, 1991, and 1992 noting problems with OPP data systems used to track the status of pest icide registrations.35 of 57 GAO was unable to verify OPP offi cials’ assertion that all ac tions mistakenly categorized as conditional registrations were legitimate program actions which were lawful under other
sections of FIFRA. EPA needs to correct mi sclassifications to ensure the accuracy and integrity of its data and make clear the statutory basis for these actions.

OPP’s use of conditional registrations for actions other than those that meet the criteria outlined in FIFRA Section 3(c)(7) has created confusion for its staff. OPP lacks written guidance or a consistent me thodology for maintaining its pe sticide registration files, resulting in difficulty developing summary in formation about the status of pesticide registrations, and managing the pe sticide registration program.

Given the mishandling of EPA’s conditional registration program, its usage here is troublesome. Specifically, because EPA cannot adequately track conditional registrations and assure that the requested data is timel y submitted, the public cannot be assured what will happen upon the expiration of the four y ears which EPA has granted Nanosilva [LLC] to supply the required data. EPA provides no clue as to what will happen upon expiration of this four year time period, such as [N SPW-L30SS] products being removed from the market, or prosecution for continued production of [NSPW-L30SS] incorporated products.

Thus, even if [NSPW-L30SS]’s conditional regi stration expires in four years there is no guarantee that EPA will take proper action to pr otect environmental safety and ensure that [NSPW-L30SS] products are removed from th e market or prevented from entering the
market.

EPA has overused conditional registrations ge nerally, failed to adequately oversee its conditional registration program allowing pesticide products to remain on the market without adequate and required studies, and shou ld curtail its use of conditional registration to adhere to its original intent. Specifi cally, EPA’s proposed conditional registration for [NSPW-L30SS] is not supported by necessa ry elements as required by FIFRA.

Response 7.23: The Agency’s Conditional Registration web page (http://www.epa.gov/pesticides/r egulating/conditional-registra tion.html) addresses many of these issues in great detail.

EPA project managers are assigned with revi ewing and monitoring the progress registrants make in meeting the required deadlines for submission of protocols and studies for conditional registrations including this regi stration. The Conditional Registration Status table (available at: http:// www2.epa.gov/pesticide-registra tion/conditional-registrationstatus-2000-2014), also provides information regarding pesticide active ingredients initially registered under th e conditional registration author ity in FIFRA sec. 3(c)(7)(C) from FY2000 to the present.

The expiration date on a conditionally register ed product is an eff ective tool because it makes sales or distribution of such product afte r the expiration date a violation and subject to corrective action and penalt ies under FIFRA. The expirati on date requires that the registration be amended to auth orize continued sale and distri bution of the pesticide by the end of the expiration period, or th at a new registration be issue d. In either case, whether the data have been timely submitted and reviewed and what submitted data show will be taken into consideration in determining whethe r an amended or new registration may be
authorized and under what conditions. If Nanosil va LLC fails to take appropriate steps to initiate the required studies, or if Nanosilva LLC fails to submit the protocols or data, EPA36 of 57 will issue a notice of intent to cancel the registration of NSPW-L30SS under FIFRA section 6(e) even before the e xpiration of the registration. If the registration is allowed to expire, EPA will issue an order under section 6( a) to address existing stocks requirements.

Through the registration review program, the EP A is reevaluating all registered pesticides to ensure that they continue to satisfy stat utory standard for regist ration – that is, these pesticide registrations are base d on current scientific and ot her knowledge and can still be
used without unreasonable a dverse effects on human health and the environment. Nanosilver is currently under going registration review by th e EPA’s Office of Pesticide Programs. The Preliminary Registration Review Work Plan for nanosilver, available at regulations.gov (Docket ID: EPA-HQ-OPP- 2011-0370), explains the next steps the Agency is proposing in the review process. More information about the Registration Review Process is available at: http:// www2.epa.gov/pesticide-reev aluation/registrationreview-process#program status.

Comment 7.24: Proceeding with a conditional registra tion based on the rationale provided
in the Draft Decision Document would be an arbitrary and caprici ous action by EPA, and contrary to law. Agency action must be set as ide if it is arbitrary and capricious, an abuse of discretion, otherwise not in accordance w ith law, or without observance of procedure required by law. Agency action is arbitrary a nd capricious if the agency relied on factors Congress has not intended it to consider, entirely failed to consider an important aspect of the problem, offered an explanation for its deci sion that runs counter to the evidence before the agency, or is so implausible that it could not be ascribed to a difference in view or the product of agency expertise. EPA’s Draft Decision Document overlooked important gaps in scientific data, applied faulty scien ce to determine possible risks to conditional registration of [NSPW-L30SS], and if approved would be arb itrary and capricious agency
action.

Response 7.24: FIFRA authorizes EPA to issue regi strations under Section 3(c)(5) or “conditional” registrations under Section 3(c )(7). 7 U.S.C. §§ 136a(c)(5), (c)(7). To support either type of regist ration, applicants must submit studies intended to identify potential effects on human health and the envi ronment. 7 U.S.C. § 136a(c); 40 C.F.R. Parts 158, 161. While a conditional regist ration provides a registrant with the same rights as a registration under Section 3(c)(5), EPA is authorized to issue a conditional registration even where it has not yet received certain required data concerning the risks associated with a pesticide, so long as EPA has sufficien t information to determ ine that use of the pesticide “will not cause any unreasonable adverse effect on the environment” while the required data are being generated, that ther e has been insufficient time to submit the required data since the Administ rator first imposed the data re quirement, and that the “use of the pesticide is in the public in terest.” 7 U.S.C. § 136a(c)(7)(C).

Commenters suggest that in the absence of all required data, EPA cannot make the determination that the proposed use of the pesticide “wil l not cause any unreasonable
adverse effect on the environment” while th e newly required data are being generated. Such an argument reduces the authority in FI FRA section 3(c)(7)(C) to a nullity. Congress contemplated that there would be an absence of required data when it authorized issuance of conditional registrations. In this case, there are data still needed to assess the nanosilver in NSPW-L30SS. The data are required as a condition of the registration and are a combination of (i) data not yet required by the regulatory data requirements (e.g., leaching37 of 57 studies), (ii) data that ar e nanosilver-specific adaptations of the regulatory data requirements for antimicrobials (e.g., 90-day inhalation toxicity study, reproduction/developmental toxicity screening te st) and (iii) regulatory data requirements determined by EPA to be unnecessary unless Tier 1 data results trigger the need for the data. These data are required for this product because the Agency determined that it cannot rely on data for macrosilver alone when assessing the risks from products containing nanosilver and yet determined that the existi ng regulatory data requirements and guidelines generally needed to be adapted to address th e needs specific to revi ew of nanosilver. In some cases, for example, this means re quiring a study not currently required by the regulations. In other cases, for example, this means adapting the regulatory data requirements for this case to avoid requiring unnecessary data or to focus the study on a narrow need, known only after assessing the pestic ide. With respect to concerns that the absence of these data means the Agency’s decision is arbitrary and capricious, as EPA explained in the proposed and final decision documents and throughout this document, the
available data show release of nanosilver below the level of detection. Taking into consideration these low releases, available toxicity data, multiple risk uncertainty factors (UFs) into the risk assessment, which incl uded an additional 10x to account for missing data that will be submitted in response to the condition on the regi stration, and required risk mitigation measures on the product label, the calculated margins of exposure (MOEs) and risk quotients (RQs) were well above the Ag ency levels of concern (LOCs). On these grounds, EPA determined that there is substantia l evidence in the record to conclude that the proposed use of NSPW-L30SS during the c onditional registration period will not cause
unreasonable adverse effects on human health or the environment, even absent some of the data that EPA is requiring as a condition on the registration. Thus, this case is a clear example of circumstances that support findi ng that use of the pesticide will not cause unreasonable adverse effects, notwithstanding the need for additional data.

Comment 7.25: EPA’s cursory look at aggregate eff ects is insufficient and fails to
consider the other nano-scal e antimicrobials which are on the market without having undergone a full chemical risk asse ssment on the nano-scale material.

EPA’s proposed conditional registration of [N SPW-L30SS] while turn ing a blind eye to other nanosilver pesticides currently on the ma rket is contrary to its obligations under FIFRA. The agency is legally obligated to adopt a consistent policy with regard to nanosilver products, because nanosilver is a pe sticide requiring registration. These other nanosilver products, like [NSPW-L3 0SS], are properly classified as “pesticides” since the only purpose of the infused nanosilver is to fi ght bacteria, i.e., prev ent pests. Nanosilver thus meets the definition of a pesticide.

EPA argues that, because Congress specifica lly required consideration of aggregate exposures for registration unde r FIFRA for food-use pestic ides, but not for non food-use pesticides, that such studies are not required to determine whether registration of [NSPWL30SS] will cause any unreasonable adverse effects on the environment.

Thus, for the sake of “transparency,” the ex tent of EPA’s consid eration of aggregate exposures involved [NSPW-L30SS] and HeiQ AGS-20, “the only other pesticide which was knowingly registered as containing nanosilv er.” In so doing, EPA concluded that if exposures to the two active nanosilver ingredients in [N SPW-L30SS] and HeiQ AGS-20, were to occur concurrently, they would not resu lt in margins of exposure that “would be of38 of 57 concern.” However, this fails to account for aggregate human and environmental exposures from other sources of nanosilver, which ar e many. Given that EPA’s rationale for approving a conditional registrati on for this product is the pur ported environmental benefit
to the environment from the release of silver ions, EPA must consider the cumulative and aggregate impact of all the various sources of silver ions in the environment.

According to the Woodrow Wilson Internationa l Center for Scholars, Project on Emerging Nanotechnologies (PEN), which maintains a regi stry of self-labeled products containing nanomaterials, there are over 300 nanosilver pr oducts already on the market. Since no labeling or government registration is curren tly required, these self-labeled products are likely only the tip of the iceberg. PEN estimates that there are three to four new nanotech products hitting the market every week.

EPA has acknowledged that it suspects it alr eady approved the registrations of some likesituated products on the market that contain nanosilver as the active ingredient without knowledge that these products may contain na nosilver and without assessing any potential risks that might be associated with nanosilver . Though EPA intends to seek more data from those products, such an admission s hould call for more caution, not less.

Response 7.25: With respect to comments stating th at all products containing nanosilver
or advertised to contain nanosilver can be cl assified as a pesticide, please see Response 7.3. With respect to comments that EPA is obligated to consider all exposures to nanosilver in products on the market, please see Response 6.4.

Comment 7.26: EPA acknowledged that it lacks the n ecessary information required to conduct an adequate aggregate risk assessment as to exposure to other nanosilver products in the market place. Not only does EPA not have sufficient information to conduct an aggregate risk assessment, EPA asserts th at it lacks adequate information on the composition of the nanosilver or potential nanos ilver in other silver based pesticides to
determine if all nanosilver s hould be treated as a single chem ical. Yet, EPA claims it had
sufficient information to determine that [NSPW-L30SS] would not pose unreasonable
adverse effects on the environment. Without including such increased aggregate exposure and cumulative risk, the agency’s determinati on failed to ensure that the registration will not cause any “unreasonable adverse effects” on the environment or health, and is plainly contrary to the public interest.

Response 7.26: Please refer to Responses 6.4 and 7.25.

Comment 7.27: EPA’s reliance on available studies on the effect of nanosilver is misplaced because [NSPW-L30SS] is unique as a nanosilver and nanosilicon based combination nano-particle, a combination for which there is no public data.

[NSPW-L30SS] is a silica-sulfur-nanosilv er complex where the nanosilver activeingredient is attached to crys talline silica via a thiolate bond. This configuration presents a more than substantial alteration to existing nanosilver combinations. Minimal public data exists on the unique combination of nanosilver and nanosilicon, such that any reliance on available studies on the effect of nanosilver by EPA is misplaced and inadequate in evaluating the risk to human health and the environment.

EPA acknowledged that SAP “cautioned about extrapolating from one nanosilver formulation to another when assessing hazards because differences in particle formulation (e.g., coating and inert ingredient s) are likely to affect bi ological activity, among other39 of 57 things.” Yet, EPA has done exactly that. For example, because no repeated-dose subchronic or chronic toxicity studies exist for [NSPW-L3 0SS] or the nanosilver in [NSPW-L30SS], the Agency relied on studies in the scientific literature on nanosilver toxicity based on the belief that they would be sufficient for assessing the risks of the unique [NSPW-L30SS] complex.

Response 7.27: Please refer to Responses 6.1, 6.2, 7.7, 7.10, 7.14, 7.15, and 7.28. While the Agency acknowledges the poin ts addressed by the SAP, it feels the cited existing data are sufficient for assessing the risks in th is case because, in addition to those data addressing the significant routes of exposur es and identifying hazards, EPA accounts for any variation between the nanosilvers th rough use of the additional 10X database uncertainty factor and the resulting MOEs are well above any risk concern. For further information on why specific studies are requir ed, please refer to Responses 6.1 and 6.2. As EPA explained in the proposed and final de cision documents, the available data show
release of nanosilver below the level of det ection. Taking into consideration these low releases, the available toxicity data, use of multiple risk uncertainty factors (UFs) and required risk mitigation measures on the product label, the calculated margins of exposure (MOEs) and risk quotients (RQs) were well a bove the Agency levels of concern (LOCs). On these grounds, EPA determined that there is substantial evidence in the record to conclude that the proposed use of NSPW-L 30SS during the conditional registration period
will not cause unreasonable adverse effects on human health or the environment.

Comment 7.28: Until EPA has data which shows that [NSPW-L30SS] is not a reproductive or development toxicant, a carcinoge n, an endocrine disrupter, and that it is not toxic to the aquatic environment, EPA ca nnot allow this product to enter the market. Without these data, EPA cannot show that ther e are no unreasonable a dverse effects to the
environment and human health associated wi th the use of [NSPW-L30SS], and as such, cannot conditionally register this pesticide product.

Response 7.28: The Agency disagrees with commenters’ premise that data showing no toxicity is required to grant the pesticide registration request. FIFRA section 3(c)(7)(C) requires EPA to find that use of the pesticide will not cause unreasonable adverse effects, and that finding takes into account both toxi city and exposure information. In this case, there is sufficient information on the endpoints noted above and to make this finding. With respect to data on reproductive or developm ental toxicity, as explained in both the proposed and final decision documents, the Agen cy disagrees that there is no information sufficient to make the requisite statut ory finding. Please see Responses 6.1 and 6.2.

There is a paper by Yu et al . (Yu et al, 2013) supporting th ese conclusions which shows that there were no maternal or developm ental effects up to 1000 mg/kg bw using a
nanosilver 7.5 nm in size. These levels at which no effects were observed support the Agency’s conclusion that PODs chosen to a ssess the risks from the use of NSPW-L30SS are protective of any potential developmental or reproductive e ffect. Finally, as noted in the Proposed Decision Document, the Agency is also requiring the regist rant to complete a modified reproductive/developmental assay. The additional 10X database uncertainty factor is sufficient and health protective until these additional data are submitted to the Agency and incorporated in the assessment.

In regards to carcinogenicity, a cancer st udy is conditionally required for “all other nonfood uses” under 158W. Additionally, test note 21i states the cancer study is required if40 of 57 “the use of the pesticide is likely to result in signif icant human exposure over a considerable portion of the human lifespan which is significant in term s of frequency, time, duration, and/or magnitude of exposure.” Alt hough children’s short- and intermediate-term exposure durations to plastic toys and text iles treated with NSPW -L30SS are expected, children are not anticipated to play with NSPW-L30SS-treated toys or contact NSPWL30SS-treated textiles every day for a period of greater than six months, thus chronic exposures are unlikely. The EPA also does not be lieve that children will have continuous and daily exposure to NSPW-L30SS treated floo ring for a period greater than 6 months. Based on the lack of chronic exposure, a carc inogenicity study is not required for NSPWL30SS. Furthermore, the in vitro mutagenicity data are e quivocal and the available in vivo micronucleus rat assay of oral administration of nanosilver at concen trations of up to 1,000 mg/kg/day (Kim, et al, 2008) is neither clast ogenic nor aneugenic. Therefore there is no concern for mutagenic ity or genotoxicity.

In regards to endocrine disruption, the EPA has developed the EDSP to determine whether certain substances (including pesticide active an d other ingredients) ma y have an effect in humans or wildlife similar to an effect pr oduced by a “naturally occurring estrogen, or
other such endocrine effects as the Admini strator may designate.” The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next st age of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-re lated effects caused by the substance, and establish a dose-response relationship between th e dose and the E, A, or T effect. In the case of NSPW-L30SS, the Tier 2 test for mammals (Extended One-Generation Reproduction Study with modi fications) is required upon registration. This route appropriate study will provide endocrine rela ted endpoints and will be used by the Agency
to determine if further endocri ne testing is warranted. Rega rdless, the current points of departure and total uncertainty factors are health protec tive for endocrine effects.

Comment 7.29: EPA’s reliance on available studies on th e effect of silver is misplaced because it is not possible to infer the safety of nanomaterials by using information derived from the bulk parent material.

In its Draft Decision Document, EPA acknow ledged the conclusions of SAP that:

“existing information on conventional silv er could be useful but would not necessarily be sufficient in assess ing potential nanosilver risks. SAP recommended that the Agency trea t nanosilver differently from its conventional silver counterpart in evaluating proposed nanosilver product applications (in terms of both data requirements and the conduct of risk assessments). Moreover, the Panel reco mmended that EPA require additional data on the physical chemistry, exposure pot ential, and the pote ntial hazard to
human health and the environment.”

Yet, EPA’s conclusion that human health or ecological risk from expos ure to silver ions derived from products incor porating [NSPW-L30SS] are not of concern, “relied on the existing reregistration decision for silver.” Similarly, despite known risks of silver’s41 of 57 toxicity to aquatic life, Nanosilva [LLC] did not submit any tests with aquatic organisms. However, after mentioning the concentrations of silver in surface waters, EPA summarily concluded that it does not expect any unreas onable adverse effects to the environment by citing a twenty year old assessment of c onventional silver, from 1993, with no further explanation. Such reliance is misplaced and fails to adequately a ssess the risk exposure from granting [NSPW-L30SS] conditional registration.

Response 7.29: The Agency did not infer the safety of nanosilver by using information on
bulk silver. For more detailed discussion of the assessment, including on both nanosilver and silver ions, please refer to Re sponses 6.1, 6.2, 7.7, 7.14, 7.15, 7.27, and 7.28. With respect to reliance on the 1993 RED for assess ment of silver ions, comments do not provide enough detail for the Agency to understand why it should not be relying on the 1993 Silver RED for the portion of the NSPW-L 30SS risk assessment relating to silver
ions.

Comment 7.30: EPA’s proposed conditional registrati on of [NSPW-L30SS] would be an arbitrary and capricious agency action contrary to law and in violation of FIFRA. Given significant unknowns about nanotechnology gene rally, and [NSPW-L30SS] specifically, EPA’s proposed conditional registration woul d expose the environment to unreasonable adverse effects. These significant known a nd unknown risks provide all the more reason that EPA should require more testing before allowing [NSPW-L30SS] on the market. EPA has overused and misused its authority under FI FRA in its use of conditional registrations, allowing untested products on the market wh ile relying on improper science and ignoring significant data gaps about their effects. EP A must withdraw its pr oposal to conditionally register [NSPW-L30SS] so as to act in acco rdance with its duties under FIFRA and to protect human health and the environment.

Response 7.30: Please refer to Response 7.25.

Commenter 8: Mae Wu and Jennifer Sass, The Natural Resources Defense Council (NRDC) (EPA-HQ-OPP-2012-0594-0022, Received 9/26/2013)

Comment 8.1: We are concerned that crystalline sili ca is quartz, which is highly toxic carcinogen. We doubt that EPA would ever ap prove quartz, and suggest that [NSPWL30SS] is in fact attached to synthetic am orphous silica. We will address the issue of the poorly defined material later in these comments, but here wish to flag for EPA that the staff reviewing the data on [N SPW-L30SS] seem not to have the necessary expertise in material chemistry required to adequately describe the Nanosilver material. This is not the training of toxicologists.

Response 8.1: Please refer to Response 7.1.

Comment 8.2: The FIFRA Scientific Advisory Pa nel (“SAP”) reported in 2010 that several major differences between silver and na nosilver were likely to result in a distinct hazard profile for nanosilver. However, the SAP noted that there are no studies that are definitive regarding a comparison of silver and nanosilver toxicity, and more research is required. These findings showcase the problem with EPA’s proposal to put nanosilver on the market essentially untested, with an inad equate hazard database, while knowing that it is likely to be more hazardous than silver.

Response 8.2: Please refer to Responses 6.1, 6.2, 7.7, 7.14, 7.15, 7.27, and 7.28.42 of 57 Comment 8.3: At this time, EPA has so many unsolved problems with conditional registrations that it should not grant any conditional registration of a new pesticide active ingredient. EPA is inappropriately using the conditional registration process and should not do so until it can fix the problems and ensure that it is protecting the environment and public health from dangerous pesticides.

In March, 2013, NRDC released its report “Superficial Safegu ards: Most Pesticides are approved by a flawed EPA process.” The report indicates that the majority of pesticides registered by EPA were condi tionally registered. In fact, NRDC’s review of the EPA database showed that 65 percent of all regi stered pesticides were done so through the conditional registration process. In addition to the misuse of conditional registrations,
NRDC also found that EPA’s database to track these conditional registrations was a mess. EPA was unable to tell whether requested data had been submitted in a timely manner, whether the data had been reviewed by the ag ency, or whether any review of the data resulted in changes to the pesticides regi stration designation. NRDC further highlighted two specific examples of pesticides that were improperly registered conditionally, including AGS-20, which is also a nanosilver pesticide product that EPA conditionally registered in 2011. In response to news artic les about this report, EPA stated “We will continue to work on improving record-keeping a nd have developed a plan to update the IT (information technology) system s to address that need.”

On September 9, 2013, the U.S. Government Accountability Office (“GAO”) released its report, “PESTICIDES: EPA Should Take Step s to Improve Its Oversight of Conditional Registrations” (hereinafter referred to as the “GAO Report.”) Similar to NRDC’s report,
the GAO found that EPA had inaccurate data on the total number of conditional registrations that have been granted du e to “insufficient guidance and training, management oversight, and data management.”

The GAO found that EPA does not have a wa y to track the status of conditional registrations. Although EPA officials believed that routine program operations would provide a suitable quality control check, the GAO found that “they fall short of what is needed because they are neither comprehensiv e nor do they ensure the timely submission
of these data.”

For example, EPA believed that “good faith submissions” by registrants would satisfy the data requirement, despite the fact that EPA had found cases where “required data were not
submitted or were submitted late.” EPA al so relied on individual product managers to develop their own tracking sy stems, including “electroni c spreadsheets or reminder notices, handwritten notes, and memory,” wh ich opens up to many problems especially when managers retire, resign, or take extended absences.

The GAO further explained th at “without a reliable track ing system, [EPA] may miss conditional pesticides where, had the addi tional required data been submitted and reviewed, [EPA] might have altered the terms of a registration.” “[W]ithout the ability to systematically track conditional registrations , [EPA] is not well-positioned to produce summary data to enable it to easily identify situations for priority follow-up; enforce FIFRA and its implementing regulations; and report to Congress and others on program

status.”43 of 57 GAO recommended three major changes that EPA should undertake to improve this program. The most important of the three was the first: “Complete plans to automate data related to conditional registrations to more read ily track the status of these registrations and related registrant and agency actions and identify potential problems requiring management attention....”

While EPA responds that it is taking some steps to achieve this goal, it hedges its bets by saying “it plans to develop a more comprehensive system for tracking conditional registrations; however, the agency ’s ability to do so depends on the availability of funding and the complexity of incorpora ting changes in the databases.”

In the Draft Decision Document, EPA states that [NSPW-L30SS]’s registration will automatically expire after four years and that Nanosilva [LLC] will have to submit another application to obtain an uncondi tional registration. If this is EPA’s weak attempt to circumvent the systemic problems with its conditional registration program, it is not enough. There is no indication that [NSPW- L30SS] products will automatically be removed from the market at expiration of th e four year time period. While EPA may argue that any [NSPW-L30SS] products still on the market after four years would be there illegally, this argument is not comforting. As EPA acknowledged in conditionally registering AGS-20, there are many nanosilver products illegally on the market. Hei-Q was merely the first company to take steps to legally register its pr oduct. To our knowledge, EPA has never prosecuted or taken any other actions to ensure th at illegal nanosilver products are removed from the market. Therefor e, even if the [NSPW-L30SS] registration were to expire in four years, there is no guarantee that EPA would take any action to ensure that all [NSPW-L30SS] products are actually remove d from the market.

Response 8.3: With respect to general concerns with issuing conditional registrations, please refer to Response 7.23. With respect to claims that there ar e illegal nanosilver products, nanosilver products that have been id entified as unregistered pesticides are being addressed through various administrative and enforcement actions. Additional information can be found in the EPA Response to "Petit ion for Rulemaking Requesting EPA Regulate Nano-Silver Products as Pesticides", avai lable at regulations. gov (Docket ID: EPA-HQOPP-2008-0650).

Comment 8.4: Early in the Draft Decision Docume nt, EPA explains its decision to conditionally register [NSPW-L30S S]. It states “EPA has dete rmined that there is a low probability of adverse risk to human health a nd the environment from plastics and textiles incorporating [NSPW-L30SS]...” This is the wrong standard. FIFRA allows a pesticide to be conditionally registered onl y if the Administrator has de termined that “use of the pesticide will not cause any unreasonable a dverse effect on the environment...” 7 U.S.C. §136a(c)(7)(C). The standard is not “low probability” of adverse risk – it is no unreasonable adverse effect. EPA’s finding of “l ow probability of adverse risk” weakens the statutory standard and is impermissible.

Response 8.4: Please refer to Response 7.9.

Comment 8.5: In August 2009, Nanosilva [LLC] applie d to register [NSPW-L30SS] as a new active ingredient. EPA may only conditionally register a new active ingredient for a period of time to allow the registrant to generate required data because “a period reasonably sufficient for generation of the data has not elapsed since th e Administrator first44 of 57 imposed the data requirement....” 7 U.S.C. §136a( c)(7)(C). EPA relies on the fact that it
had to consult with its SAP to determine the data requirements needed to assess Nanosilva [LLC]’s application. The SAP convened in November, 2009 meaning that almost four years have passed since EPA would have iden tified the data requirements that would be needed to make a decision on Nanosilva [ LLC]’s application. EPA is now granting Nanosilva [LLC] another three years to deve lop the requisite health effects studies including the health effects toxicity test s, the ecological effects tests, and the
environmental fate studies. The time that ha s transpired between the SAP meeting when EPA developed the list of te sts that are necessary and now does provide a reasonably sufficient period of time for generation of the data, and argues against granting a conditional registration.

Response 8.5: Please refer to Response 7.18.

Comment 8.6: The conditional registration of [NSPW-L 30SS] is not in th e public interest. It provides no measurable medical or health be nefits to consumers, but puts them in harm’s way. There seems to be little doubt that consum ers will come in direct contact with the pesticide while wearing treated clothing, a nd that children have a high likelihood of ingesting the pesticide while mouthing the clothi ng in addition to direct dermal contact. It is also possible that nanosilver that break s away from the [NSPW-L30SS] product will be another source of exposure – potentially from floor coverings, outdoor furniture, or other uses. Because the proposed application is to tr eat textiles and plastics that consumers will come into direct contact with, exposure will be unavoidable. The potential harm from such contact is poorly understood and untested, wh ich is a direct violation of FIFRA’s requirement for a safety finding.

Response 8.6: EPA agrees that NSPW-L30SS is not proposed to have any medical or health benefits. However, EPA disagrees that NSPW-L30SS puts the public in harm’s way and that exposures in this case are poorly understood or untested. EPA’s exposure analysis was thorough. The analysis of use of NS PW-L30SS to treat textiles takes into consideration exposure scenario s, such as dermal exposures while wearing clothing and potential ingestion by children from mouthing textiles. EPA’s exposure analysis also takes into consideration the potentia l exposures from use of NSPW-L30SS to treat plastics. This analysis is driven by the low release rates fr om NSPW-L30SS treated textiles and plastics that yield low exposures, which, when compared to effects seen in toxicological studies, support the finding that the proposed use w ill not cause unreasonable adverse effects. Thus, EPA disagrees with the commenter’s conclusions. For additional information on EPA’s public interest findi ng, please see Response 3.1.

Comment 8.7: To grant a conditional registration for a new active ingredient, EPA must show that use of the pesticid e is in the public interest. The legislative history of the conditional registration process is clear that the “public in terest” encompasses a narrow, not broad, range of interests, such as when there “is a significant pest control problem which cannot satisfactorily be handled by use of products which have been fully registered.” As explained by the then-EPA Administrator, the c onditional registration would be important when “there may be a real need for use of the pe sticide to avoid pest outbreaks.” Furthermore, he not ed that “[a]lthough we think that the exercise of this conditional registration authority for new chemicals would be rare , we feel that it should be available in appropriate cases.45 of 57 To ensure that conditional registration for new chemicals only occurred in the limited situations when the public interest was at stake, the House of Representatives agreed during conference to adopt a vers ion of the amendment similar to the Senate’s that would require the Administrator to “determine as a condition to granting the registration that use of the pesticide is in the public interest.”

In the GAO report on EPA’s use of conditional registrations, EPA also acknowledges that the conditional registration is to be used sp aringly. EPA explains that in creating the conditional registration process, “Congress also recognized that it would be appropriate to give EPA discretionary authorit y, in very narrow circumstances, to approve the registration of a product containing a new active ingredient for which EPA requires additional data.”

Despite the requirements that the conditiona l registration not be overused, EPA is proposing to conditionally regist er this pesticide product usin g an improperly generic and broad definition of public interest. Furthermor e, some of the conclusions that EPA makes
about the benefits associated with [NSPW-L30SS] are wrong.

Response 8.7: Please see Response 3.1 for a discussion of the public interest finding in this case. The Agency disagr ees that conditional registrati ons for new active ingredients are only authorized in such narrow cases as wh en there is a need to avoid pest outbreaks. Although the “public interest” may clearly be se rved in granting a registration request to address such a situation, EP A does not believe that Congr ess intended such a narrow interpretation of the “public in terest” finding. This is evident from the fact that the early Senate bill referring to the pest outbreak ex ample permitted a conditional registration for a new active ingredient only when “required in the public inte rest.” See, S. Report No. 95- 334, at 21 (1977). However, while the House companion had no such public interest requirement, the Conference Committee adopte d a public interest finding, but without reference to “required.” This compromise be tween the position of the House and Senate indicates an intent to allow public interest findings for new active conditional registrations even when the pesticide use is not needed or required, but when th e pesticide use would nonetheless be in the public interest. As di scussed in EPA’s 1986 statement on the public interest finding considerations other than “need” are important in determining whether use of a pesticide is in the pu blic interest. 51 Fed. Reg. at 7632 (“... EPA will consider a variety of factors pertaining to the need for the chemical, its comparative benefits, risks, and costs.”) Although this narrow circumstan ce is one that extends beyond the public interest finding typically offe red in past conditional registration actions because here, for example, there is no comparative risk analysis that reviews each of the alternative silverbased pesticides, it is nonethel ess consistent with the purposes of FIFRA. This is because, in this case, the already-registered silver-bas ed pesticides with similar textile and plastic use patterns allow greater amounts of silver to be used, thus allowing greater amounts of
silver to be released to the environment. Taking this information into consideration and
based on the available data reviewed in the cont ext of this registration request, there is a strong basis to believe that releas es through use of this product wi ll result in a lesser risk to the environment than might result from similar silver-based registra tions. Because of the very low release rates, the nanosilver in NSPW-L30SS would need to be orders of magnitude more toxic than the comparable si lver pesticide products on the market for the risks as between NSPW-L30SS and silver-based pesticides to be comparable, and, as noted in Response 7.7, that is simply not exp ected in light of the available data.46 of 57 Comment 8.8: EPA contends that one of the public in terest benefits of [NSPW-L30SS] is “Conservation of the Environment.” However, EPA’s explanation actually points to a greater adverse impact on the enviro nment from [NSPW-L30SS], not lower.

EPA states that because a smaller mass of silv er is used in [NSPW-L30SS] than in other products, “the overall potential environmental lo ading of silver from the lower-volume use of [NSPW-L30SS] “should be smaller than from a comparable use of currently registered silver-based pesticides.” Howeve r, EPA ignores the fact is that there is no silver pesticide product on the market right now that is used as a material preserva tive in plastic for products like decking and plastic lumber. The [NSPW-L30SS] will be incorporated into wholly new products, not taking the place of ot her silver-embedded products. Therefore, the introduction of [NSPW-L30SS] into commerce – no matter the amount – will necessarily increase, not reduce, the amount of silver ions th at will be released into the
environment.

More problematically, EPA acknowledges that mo re silver ions will be released because the nanosilver particles are smaller and theref ore have higher surface ar ea per unit mass of silver. Since nanosilver is much more potent (e ffective) than conventio nal sized silver, less nanosilver kills more microbes. While [NSPW-L 30SS] may possibly lead to a reduction in
the overall mass of silver released into the en vironment, its killing potential is greater and therefore the potential for environmental damage and non-target impacts is greater. In fact,
the SAP noted that the rate and concentrati on of deadly silver ions released from nanosilver is different and will likely affect the acute or chronic toxicity of nanosilver compared with silver. The data referenced by SAP show that nanosilver , but not silver, can penetrate cell membranes and deli ver toxic ions directly inside of cells and that this may be its mechanism for killing microbes so eff ectively. The SAP also noted that “when compared as a function the Ag+ concentration, to xicity of silver nanopa rticles appeared to be much higher than that of silver nitrate. ” Moreover, the SAP noted that because of these differences in chemical properties, there ar e likely to be differences in exposure and
environmental fate of nanosilver that should be considered.

Silver is highly toxic to aqua tic organisms. Increasing the amount of silver ions that will enter rivers and streams through our wastewater system or fr om run-off during rainstorms will only harm the environment. It does not conserve the environment.

Response 8.8: Please refer to Response 6.1, 6.2, 7.7, 7.10, 7.14, 7.15, 7.27, and 7.28. Regarding the concern expressed for higher rel ease rates of ionic silver, the commenter is incorrect in their interpreta tion of the proposed decision do cument. The Agency did not state that nanosilver particles result in a greate r release of silver ions because the particles
are smaller than conventional silver salt activ e ingredients. Rather, the discussion in the decision document referenced by commenters co mpares the release rate between different sizes of particles composed of the same active ingredient.

Comment 8.9: EPA contends that benefits inur ed to consumers by [NSPW-L30SS] contribute to the public interest enough to wa rrant a conditional registration of a product missing critical toxicity data. Part of this argument is grounded in EPA’s assumption that [NSPW-L30SS] products “are repor ted to retain the ability to reduce the number of odor and stain causing bacteria.” EPA also assume s that [NSPW-L30SS] “should be able to maintain its ability to reduce” bacteria longe r than other silver active ingredients. EPA47 of 57 assumes that products using nanosilver “may have longer-term ab ility” to reduce the bacteria compared to conven tional silver embedded products.

EPA’s contention that nanosilver provides a consumer benefit is grounded in assuming nanosilver’s efficacy. EPA provides no eviden ce and does not indi cate that any data regarding [NSPW-L30SS]’s efficacy exist. Without such evidence, EPA’s claim that consumers benefit from the presence of [NSPW- L30SS] on the market is mere conjecture and is an inappropriate basis for making a regulatory determination.

Response 8.9: Please see Response 2.4 relating to e fficacy data, and Response 3.1 relating to presumed efficacy and other aspects of the Agency’s public interest finding. EPA disagrees that efficacy data is necessary to make a determination that consumers benefit from the presence of a product on the market.

Comment 8.10: EPA wishes to encourage innovati on in nanotechnology, but allowing untested pesticides into products to be used in ways that are potentially harmful is not the appropriate way to do so. EPA’ s mission is to ensure that products that are brought to market will be used in ways that will not harm the environment or public health. But in this case, EPA is turning a blind eye to all th e possible environmental and health hazards associated with [NSPW-L30SS] in an e ffort to encourage broadly the field of nanotechnology. EPA has many other opportuni ties to actually encourage innovation through supporting research a nd through its existing programs to ease market access for pesticide products that are adequately tested and shown to be reduced risk. EPA has even established criteria for determining that pesticides are reduced risk, which include compatibility with Integrated Pest Manageme nt (IPM) strategies. Ironically, the pivotal principle of IPM is to avoid using pesticides if they are not necessary – an approach undermined by this prophylactic integration of nanosilver into consumer products. By EPA allowing an untested product like [NSPW-L30SS] on the market where consumers learn after-the-fact that it might cause unreasonable health or environmental effects will only stifle real innovation, undermine desirable IPM strategies, pose unknown environmental risks, and undermine consumer confidence.

Response 8.10: Please refer to Response 3.1, 6.1, 7.4, 7.7, 7.14, 7.15, 7.21, 7.27, and 7.28.

Comment 8.11: To conditionally register a new active ingredient, EPA must determine that that use of the pestic ide during the period of the conditions will not cause any
unreasonable adverse effect on the environment. 7 U.S.C. §136a(7)(C). In the case of nanosilver (and specifically [NSPW-L30SS]), the flaws in the studies relied on by EPA and the critical data gaps especially on reproductive toxicit y, carcinogenicity, and endocrine disruption (among many others) mean that, scientifically, EPA cannot make that
determination.

Response 8.11: Please refer to Response 6.1, 7.4, 7.7, 7.14, 7.15, 7.27, and 7.28.

Comment 8.12: EPA failed to provide an adequate ch aracterization of the chemistry of [NSPW-L30SS], making it impo ssible for the public, and likely even for EPA staff, to “guesstimate” whether or not it would behave like other (equally poorly) described
nanosilver materials. EPA de scribes [NSPW-L30SS] as “a liquid suspension containing silica-sulfur-nanosilver particulates where the nanosilver active ingredient is attached to crystalline silica via a thiolate bond.”48 of 57 First, the description of the silica as crystalline is likely in error; it is likely that the form of silica is synthetic amorphous sili ca. If EPA did not make an error, and the silica is actually crystalline, then given crysta lline silica’s known cancer effect s, EPA’s determination of no
cancer risk is in error. If EPA did make an error in describing the material, then it raises red flags about whether or not EPA staff that reviewed [NSPW-L30SS] included material chemists, who would have the necessary expertise to characterize the material.

Response 8.12: Please see Response 7.1.

Comment 8.13: Furthermore, [NSPW-L30SS] appears to be a single silica particle surrounded by multiple nanoscale PVP-coated-s ilver particles connected through weak thiol linkages. The thiol linkages have not been defined in the sense of “linkage to what?” Is it to the PVP coating or to the silver atoms or to a silver ion that is separate from the surface? In a product, these may be in some sort of equilibrium relationship, but in a realistic environmental exposure scenario, one is likely to dominate. This would mean that the chemistry – and therefore the toxicol ogy – depends on the route of exposure.

Response 8.13: Please refer to Response 7.2.

Comment 8.14: Moreover, Lee et al. (2006) (refe renced by EPA) describes [NSPWL30SS] as a material with 4% PVP, only 0.1% silica, and even less thiol. This means that there is a much greater chance of nanosilver reacting with PVP than silica particles. It is arguably much more likely that the PVP outnumbers the number of thiol groups on the silica surface. EPA’s description of a nanosil ver active ingredient coated with PVP and sulfur is wholly unsupported, un likely, unscientific, and inadequa te to predict the behavior
of the material under real-world conditi ons relevant to a hazard assessment.

Response 8.14: Please refer to Response 7.2.

Comment 8.15: There is no scientific ev idence to support statemen t that “the resulting liquid suspension contains 1% nanosilver by wei ght where the nanosilver surface is coated with sulfur and PVP, and is attached to sili ca.” First, for that to be true, the sulfur
connected to a thiol connected to a silica particle w ould need to surround the silver particles (instead of silver particles surrounding the silicon di oxide particle). Second, that would mean the sulfur has disengaged from th e thiol, meaning disengaged from the silicon dioxide. It is unknown if the above complex w ould survive the temperature and chemical
conditions of a master batch. If disengaged (broken at the poin t of contact with the silicon dioxide or chemically attacked and “corroded” through at a n eck point) then the silver and silicon dioxide may migrate to sepa rate locations within the fiber.

Response 8.15: Please refer to Response 7.2. Additionally, Nanosilva product has been characterized by the registrants through the use of techniques like TEM as: “sulfur is bonded to the nanosilica particle s. Nanosilver cluster (consisting of ten atoms of nAg) is covalently bonded to sulfur.” Thus sulfur acts as a tie for nanosilver particles. Nanosilver particles are then capped with PVC. The release of nanosilver to the surface is restricted. Thiol (SH) was used to generate a silica/sulfur /nanosilver bond.

Comment 8.16: In short, the [NSPW-L30SS] is not characterized well enough to
determine with confidence that data on other na nosilver materials can be used to predict the toxicology of [NSPW-L30SS] . Scientific support for extr apolating from one nanosilver to another is lacking. EPA should use scien ce, not speculation, to evaluate pesticide
hazards.49 of 57 Response 8.16: Please refer to Response 6.1, 7.4, 7.7, 7.14, 7.15, 7.27, and 7.28.

Comment 8.17: It is unreasonable to rely on data on nanosilver particles that are not [NSPW-L30SS].

In August 2009, EPA turned to its SAP regardin g some open questions about the hazard of and exposure to nanosilver. The SAP “cautioned about extrapolating from one nanosilver formulation to another when assessing hazards because differences in particle formulation (e.g., coating and inert ingredient s) are likely to affect bi ological activity, among other things.” Despite the warnings from the SAP, EPA appears to rely on studies of different
nanosilver formulations to make the determ ination that [NSPW-L30SS] could be used without any adverse effects on the environment or on human health.

The SAP also noted that “not enough literature is available to draw any firm conclusions regarding human (occupational or consumer) and environmental exposures to nanosilver
under realistic use scenarios.”

Response 8.17: Please refer to Responses 6.1, 6.2, 7.4, 7.7, 7.14, 7.15, 7.27, and 7.28.

Comment 8.18: EPA identifies five studies in the scie ntific literature that investigate the oral toxicity of nanosilver in rodents. Three of the most robust studies are not complete enough to determine regulatory limits. The ot her two are even less well described, and
therefore less useful for s upporting regulatory decisions. As such, EPA does not have a reliable study that addresses the oral toxicity of [NSPW-L30SS].

In December 2011, EPA conditionally registered HeiQ AGS-20 containing nanosilver as a materials preservative in textiles. As part of its final de cision to register the product, EPA relied on Park et al. (2010) for the poin t of departure (“POD”) of 0.5 mg/kg-day to
calculate the oral and dermal POD for the nanosilver in HeiQ AGS-20.

In this proposed conditional re gistration of [NSPW-L30SS], EP A has determined that Park et al. (2010) is no longer reliable for calculating a POD. EPA stat es that in its recent review of the study for this assessmen t of [NSPW-L30SS], EPA revers ed its reliance on the study, and now finds that it lacks enough analysis of the cellular changes to draw conclusions with confidence. EPA says, “In the absence of histopathological findings, the clinical chemistry changes observed [in Park et al. 2010 ] are insufficient evidence of an adverse
effect.”

Response 8.18: EPA disagrees with the comment that there is no reliable study to address oral toxicity of [NSPW-L 30SS]. The Agency has determined that the combined toxicological database of the Kim 2008 and Kim 2010 studies (both of which are rated by the Agency as Acceptable/Non-guideline) are sufficient for fulfilling the requirement for a 90 day subchronic oral study. As explained in the decision document, these studies “identified histopathological patt erns in the liver that were indicative of distinct adverse effects.” A 3X uncertainty factor was a dded to the Kim 2010 study to account for the LOAEL to NOAEL conversion, as is typically done in the absence of a NOAEL in a study.
Since the Kim 2008 and Kim 2010 were conducte d by OECD guidelines, they present a more robust understanding of the toxicity of nanosilver. With re spect to Park et al. (2010), it was previously used to assess the na nosilver in another product, HeiQ AGS-20. However, it has since been determined by the Agency that the Kim et al studies were a more robust series of studies, including hist opathology of a larger number of organs in addition to a longer dosing regimen, and t hus are more approp riate for a baseline50 of 57 assessment of nanosilver generally. Finally, the Hadrup (2012) study did not determine a LOAEL and thus was not acceptable for deri ving a quantitative POD, though information is used in a WOE approach toward risk assessment.

Comment 8.19: EPA calculated a POD from Park et al. (2010) of 0.5 mg/kg/day for oral and dermal toxicity, based on effects observed in mice that ingested nanosilver for 28 days. After discarding that study for this current assessment of [NSPW-L30SS], EPA calculated a POD of 30 mg/kg/day, based on the 28-day oral toxicity st udy by Kim et al. (2008). This
result weakened oral and derm al exposure limits by 60-fold.

The scientific community has id entified Kim et al. (2008) as not useful for derivation of a POD. The study provides no information on the form or shape of the silver nanoparticles in
the solution that was used to dose the animal s. Further, the study misstated that it was performed in accordance with OECD 407 st udy guidelines. In fact, no neurotoxicity endpoints were investigated, and the histopat hology (observation of cellular damage) failed examine the spinal cord, peripheral nerve, bone marrow, lymph nodes, stomach or small or large intestines.

EPA moved away from the more protective POD from Park et al. (2010) claiming that the histopathology analysis was t oo weak, and unjustifiably proposes to rely on this lessprotective study by Kim et al. (2008) that lacks any histopa thology analysis on so many critical organs and tissues.

Importantly, Kim et al. (2008) reported a dose-de pendent accumulation of silver content in a broad range of tissues incl uding blood, liver, lungs, kidneys , stomach, testes and brain. Cellular damage in the liver of male and fe male rats included dos e-dependent bile-duct hyperplasia, dilation of the central veins, and inflammation. However, the authors failed to specify which dose groups had these effects. S ilver concentrations were dose-dependent in blood and all examined tissues, with the kidne y concentrations in females being 2-fold higher than males.

That ingested nanosilver is accumulating in ma ny critical organs, where its antimicrobial activity may lead to significant cellular dama ge that has not been adequately studied, is
evidence that EPA cannot determine that there are no unreasonable adverse effects associated with the use of [NSPW-L30SS].

Response 8.19: With respect to comments on the reev aluation of the Park study and the use of the Kim studies (both 2008 and 2010) in determining the POD for NSPW-L30SS, see Response 8.18

. With respect to accumulation of na nosilver in critical organs, the presence of silver in the varied organs is not considered adverse in the absence of histopathology indicating an e ffect. Thus in the absence of histopathology indicating an effect, the presence of silver was not used to identify a NOAEL or LOAEL. As explained throughout the decision document and this re sponse-to-comments document, the PODs chosen are protective at the leve ls at which effects are observed in the studies available. In any case, given the low release rate, the ca lculated MOEs are protective, 310,000 for the
subchronic oral route for the most sens itive population (with an aggregate MOE for incidental oral of 110,000 for the most sens itive population) and take into account the differences between the chemical composition of the studied chemical and NSPW-L30SS and database gaps through use of an additi onal 10X uncertainty factor. Finally, although Kim et al. (2008) did not investigate neur otoxicity endpoints, EPA believes there is51 of 57 adequate data on neurotoxicity to find that use of [NSPW-L30SS] will not cause
unreasonable adverse effects on human healt h, pending generation of the required 90-day inhalation study. As noted in the proposed deci sion document, the “curre ntly available oral toxicity studies indicate that nanosilver causes liver and ki dney toxicity in laboratory animals where silver is distributed to all orga ns and tissues with accumulation of silver in
the brain and male animal testes. ... There were potential neurotoxic e ffects identified with
increases in neurotransmitter concentrations and loss of sp atial cognition; however, these
same effects were not observed in a fo llow-on study. As explained in the Proposed Decision Document, EPA believes that these neur otoxicity studies are inadequate in their
assessment of behavioral effects and do not us e optimal methods to evaluate the potential toxicity to the nervous tissue structure and function.” EPA also stated that it believes “the
short-term oral NOAEL and intermediate-term L OAEL of 30 mg/kg/day are expected to be protective of neurotoxic eff ects” of [NSPW-L30SS] base d on the “study by Liu et al. (2013) [which] reported no effects on the spa tial cognition or hippocampal activity of mice after injecting nanosilver into the body cavity (i.e., intraperitoneal injection) at concentrations of up to 50 mg/kg.” “The effects on spatial cognition and hippocampal activity observed by Liu et al. (2012) after administering nasa l drops containing nanosilver
at concentrations of 3 and 30 mg/kg to rats suggest possible neurotoxic effects from the inhalation of nanosilver. However, EPA believe s that the doses used in the Liu et al. (2012) study were greater than the maximum dos e used in the inhala tion toxicity study by Song et al. (2012). Therefore, EPA be lieves that the inhalation NOAEL of 49 μ g/m 3 based on the Song et al. (2012) study is expected to be protective of neurotoxic effects of nanosilver. (Proposed Decision Document at 24). Commenters do not address EPA’s analysis on this issue. Further, the subchr onic inhalation study will include a functional observation battery, motor activity and detail ed neuropathology, as it is the route of greatest exposure and should confirm that the existing analysis is protective of neurotoxic
effects.

Comment 8.20: EPA identified Hadrup et al. (2012) as another study that investigates the oral toxicity of nanosilver in rats.

First, EPA itself determined that the study lacked histological s upport for determining a POD. Second, the nanoparticles studied by Hadr up et al. are silver nanoparticles stabilized with polyvinylpyrrolidone (PVP ), whereas the particles in [NSPW-L30SS] are very different, formed of a composite of silica-su lfur-nanosilver particles. The PVP-coated nanosilver particles are likely to disengage and transport separate ly from the silica. This is also significantly different from the He iQ product that EPA recently conditionally approved, which probably transports in the envi ronment more like a silica particle carrying along the silver. In short, th e scientific support for extrap olating from one nanosilver composite type to another is lacking. EPA s hould use science, not speculation, to evaluate pesticide hazards.

Response 8.20: While the Hadrup study is not being us ed to determine a POD due to the inability to establish a NOAEL/LOAEL, the toxicity data are being included in the proposed decision document because the results, while not sufficient to come to a risk conclusion on their own, contribute to the know ledge base on nanosilvers by increasing the understanding of distribution of nanosilver and the changes in hematology and clinical chemistry. This knowledge base forms the wei ght of evidence in the Agency’s approval process for this chemical.52 of 57 Comment 8.21: Critical data gaps for nanosilver prevent a finding of no unreasonable
adverse effects

EPA acknowledges that it is missing data on entire categories of hazards. These missing studies are essential to a complete assessmen t of the potential adverse effects associated with the proposed uses of [NSPW-L30SS]. Th erefore, because EPA lacked essential data, its determination that [NSPW-L30SS] will not have unreasonable adverse effects on the environment is unreasonable, unsuppor ted, and arbitrary and capricious.

Response 8.21: Please refer to Response 6.1, 6.2, 7.4, 7.7, 7.14, 7.15, 7.27, and 7.28.

Comment 8.22: EPA has no acceptable studies on re productive and developmental toxicity

Reproductive and developmental toxicity are es sential components of a full human health risk assessment, and without information abou t that hazard, EPA cannot determine whether a pesticide will have unreasonable adverse impacts on human health. (“Disorders of reproduction and hazards to reproductive hea lth have become prominent public health issues.” Developmental toxicity is manifest ed as “death, structural abnormality, altered growth, and functional deficit,” all critical to a complete human health risk assessment.)

Information about the hazard characterization is a crucial component to a complete risk assessment. “A statement of the potential for human risk and the consequences of exposure can come only from integrating the hazard ch aracterization and quantitative dose-response analysis with human exposure estimat es in the risk characterization.”

In proposing to conditionally register [NSPW-L3 0SS], EPA states that it has enough information to determine that [NSPW-L30SS] will not have any unreasonable adverse impacts on human health. However, EPA highlig hts the critical data gaps on reproductive and development toxicity in its assessme nt of nanosilver. Specifically, EPA states,

 There are studies showing significant , dose-dependent increases in the
concentration of silver in the testes of rats after or al ingestion, inhalation, and injection of nanosilver...; however there are few studies available on the reproductive and development toxicity of nanosilver.

To counter this data gap, EPA is requiring Nanosilva [LLC] to submit the results of a Modified Reproduction/ Devel opment Toxicity Screening Test 37 months after the conditional registration is issued. EPA’s ra tionale is that this test “will provide initial information on possible effects on reproduction and/or development.” To make a first determination whether [NSPW-L30SS] has any unreasonable adverse impacts on human health, EPA needs to be able to assess whether there are any reproductive or developmental toxicity concerns. Reproducti on and development are essential components of human health, and therefore, without even basic “initial” information about reproductiveand developmental toxicity, EPA cannot complete its safety determination of [NSPWL30SS].

Response 8.22: EPA agrees that the reference to ne eding “initial information” is not
accurate and the Final Decision Document has been edited to be more precise on this issue. Further the Agency disagrees that there is no information on the developmental/reproductive toxi city of nanosilvers sufficient to find that use of NSPW-53 of 57 L30SS will not cause unreasonable adverse effects pending generation of the required data. Please see Response 7.28.

Comment 8.23: For the mutagenicity of nanosilver, EP A states that “there are no studies in the scientific literature that investigate the potential of nanosilver to cause cancer....” After reviewing the in vitro studies that exist, EPA conclude s that “there is inadequate information to assess mutagenic (and hence carcinogenic) potential of nanosilver due to
differences in results between the in vitro studies and in vivo studies, and the limitations of the only available in vivo study.” Without a full suite of muta genicity tests on the material of interest, [NSPW-L30SS], EPA cannot determ ine with scientific confidence whether or not [NSPW-L30SS] may be mutagenic to DNA, and therefore pose a risk of cancer, intergenerational effects, diseas e, birth defects, or other se vere adverse health endpoints related to mutagenicity.

Response 8.23: Please see Response 7.10 for information on mutagenicity.

Comment 8.24: According to EPA, Nanosilva [LLC] “has not conducted any studies to characterize the environmental fate of [NSPW-L 30SS] or the other particles that could be released during leaching or di sposal of plastics and textile s incorporating [NSPW-L30SS]” and “has not conducted any studi es to characterize the ecotoxicity of [NSPW-L30SS] or other particles that could be released during leaching or disposal of plastics incorporating [NSPW-L30SS]” These are crit ical components of an environmental assessment to determine where the [NSPW-L30SS] goes into the environment and what harm it causes when it is there. As a result, EPA is left to rely on studies of conventional silver and nanosilver particles that are different from [NSPW-L30SS].

Furthermore, EPA acknowledges that silver “may become toxic to aquatic life at elevated concentrations.” However, after mentioning the concentrations of silv er in surface waters, EPA concludes that it does not expect any unreasonable adverse effects to the environment, citing a twenty year old asse ssment of conventional silver from 1993. That old assessment never contemplated the presence of nanoscale silver particles – nanotechnology had barely begun as a scientific endeavor at that point. Therefore, EPA’s reliance on the old assessment is wholly im proper, and EPA has failed to provide any explanation for its determination at the nanoscale.

Nanosilva [LLC] did not submit any tests with a quatic organisms, and EPA is left to assess the scientific literature addressing aquatic organisms and other nanosilver particles – despite the SAP’s admonition that the di fferences in particle sizes cannot be underestimated. After identifying six studies in th e scientific l iterature on aquatic animals,
EPA concludes that the data “do not characte rize the effects from longer-term exposure to nanosilver.” One study (Wu and Zhou, 2013) looked at long term effect s, and while it did not show lethal effects, the authors repor ted non-lethal effects at all nanosilver
concentrations tested. Non-lethal effects ca n also reflect an unreasonable impact on the environment and cannot be summarily dismi ssed. EPA fails to address this finding in discussing the environmental toxicity of [NSPW-L30SS].

Response 8.24: Please refer to Responses 7.4, 7.7, 7.14 and 7.15.

Comment 8.25: The GreenscreenTM for Safer Chemicals (GS) is a comparative chemical
hazard assessment framework. It builds on the EPA Design for the Environment (DfE) approach, along with the OECD Globally Harm onized System (GHS) and other accepted54 of 57 systems. It is being used by industry, gove rnment and non-governmental organizations (“NGOs”) to support product design and developm ent, materials procurement, and as part of alternatives assessment to meet regulatory requirements.

A GS assessment of a chemical looks at eigh teen hazard endpoints (including chronic and acute toxicity, ecotoxicity, and physical ch aracteristics such as flammability and reactivity), scores each endpoint according to the available data or lack thereof (i.e. a data gap), and assigns a Benchmark score (BM) from 1 to 4, with 1 being the most hazardous. Where there are no data for an endpoint, GS can use analogues, modeled data, or other
available reasonable substitutes to inform that endpoint. Confidence in the score is identified as high (bold), low (i talics), or very poor (“DG” for data gap). Chemicals that are carcinogens, mutagens, reproductive and/or developmental toxicants, endocrine disruptors, and PBTs (persistent, bioaccumulative, and toxic) are considered substances of high
concern and receive a BM of 1.

Nanosilver, silver, and the silver-silica com posite AGS-20 were put through the GS and those assessments compared. The three GS a ssessments were all conducted by independent
scientists at NSF Internationa l, which is an approved GS profiler. They found an extensive lack of data on critical endpoints for na nosilver, and by extensi on for [NSPW-L30SS].

The specific materials evaluated for the silver case study were nanoscale metallic silver, a silicasilver nanocomposite, and conventional low- solubility dispersed silver and silver
salts. Both silver and nanoscale silver scor ed a benchmark of 1(high concern), based on high aquatic toxicity, high persistence, and acute inhalation toxicit y. The identified data gaps for nanoscale silver include reactiv ity, flammability, carcinogenicity, reproductive toxicity, and endoc rine disruption.

The HeiQ AGS-20 silica-nanosilver composite received a BM of U (unspecified) due to the large number of data gaps. Unfortunate ly, EPA approved the AGS-20 for textiles in 2011, on the assumption that hazard data on silver nitrate and other so luble salts could be used as analogues to fill data ga ps. It was not scientifically ju stifiable for EPA to substitute data on other nanosilver particles in its AGS -20 assessment. The SAP noted that “when compared as a function of Ag+ [ion] concen tration, toxicity of silver nanoparticles appeared to be much higher th an that of silver nitrate.” Because of these differences in chemical properties, there are likely to be di fferences in exposure and environmental fate. For this reason, the GS assessment did not use silv er nitrate or other so luble silver salts as analogs to fill data gaps, because the screen sought to examine particle size-specific
hazards.

The results of these three GS assessments de monstrates that there are numerous critical areas of information that EPA lacks knowledge about regarding the potential health and safety impacts of [NSPW-L30SS] for people and the environment.

Altogether, these critical h ealth endpoints and environmen tal impacts are essential to making a determination about registering this pesticide. Until EPA has data specific to [NSPW-L30SS] on reproductive a nd developmental toxicity, carcinogenicity, endocrine disruption, and environmental t oxicity, EPA cannot allow this product to enter the market. In the absence of these data, EPA cannot s how that there are no unreasonable adverse impacts to the environment and human health associated with the use of [NSPW-L30SS], and as such, cannot register this pesticide product.55 of 57 Response 8.25: Please refer to Responses 6.1, 6.2, 7.4, 7.7, 7.14, 7.15, 7.27 and 7.28. While GS is a hazard screening analysis, the EPA performed a more robust analysis, considering more information, when conducting the risk assessment for the nanosilver in AGS-20. EPA approved AGS-20 for textiles based on bridging data from open literature studies on nanosilver materials, not only on assu mptions of hazard data from silver nitrate
and other silver salts.

For NSPW-L30SS, as EPA explained in the proposed and final decision documents, the
available data show release of nanosilver below the level of detection. Taking into consideration these low releases, the availa ble toxicity data, us e of multiple risk uncertainty factors (UFs) and required risk mitigation measures on the product label, the calculated margins of exposure (MOEs) and risk quotients (RQs) were well above the Agency levels of concern (LOCs). On thes e grounds, EPA determined that there is
substantial evidence in the r ecord to conclude that th e proposed use of NSPW-L30SS during the conditional registration period will not cause unreasonable adverse effects on
human health or the environment.

Comment 8.26: In the aquatic risk portio n of the risk assessment, EPA states that it “only
considers silver that could be released by [NSPW-L30SS] and does not include other
sources of silver which will contribute to the environmental loading of silver.” Given that part of EPA’s rationale for condi tionally registering this produc t is the purported benefit to
the environment from the release of silver ions, EPA should consider the cumulative and aggregate impact of all the various sources of silver ions loading to the environment.

Response 8.26: Please refer to Response 6.4.

Comment 8.27: EPA relies on Song et al. (2012) for the short- and intermediate-term
inhalation No Observable Adverse Effect Level (“NOAEL”). The study by Song et al. (2013) exposed six week old male and female Sprague Dawley rats with either no dose (control group) or one of three dose groups (49, 117, and 381 μ g/m 3 ; each group consisted of 17 male rats and 12 female rats) with silv er nanoparticles 14-15 nm in diameter in an inhalation chamber for 6 hours per day over 12 weeks.

The authors report a statistically significant decrease in various measurements of lung
function in the male rats – but not female s – in the middle and high dose groups throughout both the exposure period and the recovery pe riod. Moreover, the authors report that the female rats gradually recove red from lung inflammation, wh ereas the males in the high dose group showed persistent inflammation th roughout the 12 week recovery period. Sex
differences were also observed for the distribu tion of silver across organs, with five times more silver accumulated in the kidneys of females compared with males in the same treatment group. There was a stat istically significant dose-depe ndent increase in lung tissue
silver concentration in both males and fe males after the exposure period, which was not completely cleared by the end of the 12 week st udy. The authors also reported that signs of inflammation were present in the middle -dose group after 12 weeks of exposure. Statistically significant accumulation of silver compared to the contro l group was reported in the liver and spleen in male rats after 12 weeks of recovery, and the kidneys in female rats contained five times more accumulated silver than the male kidneys.

Maybe most important, the male rats in the high-dose group showed persistent inflammation throughout the 12 week study peri od. Because the males did not completely56 of 57 recover during the study period, and because gender differences remain unexplained by either the authors or EPA, this study seems to raise more questions than it answers, and lacks confidence in the ability to rely on it to determine a POD.

Importantly, the nanoparticles studied by Song et al. are uncoated silver nanoparticles, whereas the particles in [NSPW-L30SS] are very different, formed of a composite of silica-sulfur-nanosilver particles. It is not clear how the rate of ion release may differ between these two markedly different material s. The scientific s upport for extrapolating from a nanosilver composite to an uncoated na nosilver particle is lacking. EPA should use science, not speculation, to ev aluate pesticide hazards.

NRDC does not support using Song et al. to de termine a POD. However, if EPA is going to rely on Song et al. to determ ine a POD, an uncertainty factor must be applied to adjust
for the lack of a NOAEL. An uncertainty factor of at least 10X should be incorporated because EPA has neither pharmacokinetic nor pharmacodynamic information to warrant lowering the default 10x factor in ad justing for the lack of a NOAEL.

Response 8.27: The Agency notes that the Song et al. study did establish a NOAEL at the low dose. The effects were only observed at the mid and high doses. Therefore a LOAEL
to NOAEL factor of 10x is not warranted and 49 μ g/m 3 is an appropriate point of departure
for short- and intermediate-term inhalation ri sk assessment. The target MOE is 1,000 based on 10x intraspecies, 10x interspecies, and 10x database uncertain ty factors. For information on uncertainty fact ors and inhalation MO Es, please refer to Responses 6.1 and 6.2. For more information regarding release ra tes, please refer to Responses 2.3 and 2.5. For additional information with respect to concerns of utilizing data from more than one form of nanosilver, please refer to Responses 6.1, 6.2, 7.4, 7.7, 7.14, 7.15, 7.27, and 7.28.

Comment 8.28: Over the years, EPA has abused the conditional registration provision in FIFRA and allowed pesticides to market that are inadequately tested and have wreaked havoc on the environment. Imprelis reportedly caus ed billions of dollars of damage in dead trees. Clothianidin is part the family of neoni cotinoid pesticides that are partly implicated in the massive bee death crisis. Examples of other pesticides allowed to enter the market
based on flawed or insufficien t data continue to emerge.

Separate reports by NRDC and the GAO exposed the flaws in the EPA conditional registration to the public’s scrutiny for the firs t time. Pesticides littering the market have been fast-tracked through the conditional regi stration process and EP A has not developed a method for properly tracking them. Despite the outcry against this misuse of conditional registrations, EPA once again turns to this fast track system to let another pesticide to market where many consumers will become unkn owing guinea pigs for the benefit of one company whose only duty is to its financial bottomline.

Because EPA does not have an established program in place at this time, granting this conditional registration means that [NSPW-L30 SS] could become the next poster child for a conditional registration system gone se riously wrong. The only unknown at that point will be the extent of the damage that ensues . If EPA continues down this path, the public confidence in the safety of pe sticide products will erode furt her. EPA must fix its program before it can go forward with this – or any ot her – conditional registra tion. For this, and the other reasons stated above, NRDC strongl y opposes the conditional registration of [NSPW-L30SS].57 of 57 Response 8.28: Please refer to Responses 6.1, 6.2, 7.7, 7.14, 7.15, 7.23, 7.27, and 7.28.

Commenter 9: Jeannie Economos, Farmworker Asso ciation of Florida (EPA-HQ-OPP-2012- 0594-0018, Received 9/26/2013)

Comment 9.1: The Farmworker Association of Fl orida is opposed to the conditional registration of [NSPW-L30SS]. Our concern is both for the environmental and human health potential impact s of a product whose long term fate and short term implications are not yet fully understood nor tested. Farmworker s are one of the most vulnerable members of the population in the United States. In the cour se of their daily wor k, they are exposed to a multitude of various pesticides and fertil izer chemical compounds. In addition, a recent study indicated that families in low-income, ag ricultural areas were pr one to higher levels of body burden of flame retardents (sic). This does not include th eir exposure to other household, occupational and environmental chemi cals. Farmworkers are the least likely to
be educated about the risks of chemicals in the products that they use and are more likely to purchase the least expensive, and possibly more risky, consumer items. This puts them at increased risk for additive, cumulative a nd synergistic impacts of chemical exposures. While we are not scientists, we are a commun ity based organization which daily sees the human health impacts - both acute and chronic – of occupational exposure to pesticides on a community of people who are struggling to survive and raise healthy children and to provide them with an education. We, also, represent a community of people who were exposed generationally to organochlorine pestic ides at a time when they were deemed to be safe. We now know otherwise, and, yet, an entire group of people are suffering chronic health problems likely related to such exposur es. We do not need any more inadequately
understood or tested chemicals to add to the current impacts on our society.

We support the comments submitted earlier by the Natural Resources Defense Council and call upon the EPA to be true to its mission to pr otect the environment, and, in so doing, to be protective of human health.

Response 9.1: In regards to comments submitted by NRDC, please see Responses 8.1 –

8.28.

Commenter 10: Tracey Brieger and Sarah Aird, Californians for Pesticide Reform (EPA-HQOPP-2012-0594-0013, Received 9/26/2013)

Comment 10.1: Californians for Pesticide Reform is a statewide coalition with over 185 member organizations. On behalf of our memb ers, we are writing to support the comment letter submitted to this docket by the Natural Resources Defense Council (NRDC).

Response 10.1: In regards to comments submitted by NRDC, please see Responses 8.1 –

8.28.