Expert Commentary

EPA Review Process May Cloud Nanosilver's Future

Silver (Ag) is used in a variety of industrial and consumer products. For example, silver may be found in wound dressings, swimming pool chemicals, personal care products, wood finishing varnish, textiles, paper, paints, polymers, washing machines, and socks. The antimicrobial properties of silver are well known. For example, a number of drinking water filters use various forms of silver to inhibit the growth of bacteria within the filter, with an ultimate goal of removing objectionable taste, odor, and color.


Nanotechnology
November 2012

Marc A. Nascarella**
Gradient

Edited by William S. Rogers Jr.
Prince Lobel Tye LLP

When silver is used as an antimicrobial, the chemical is subject to registration and regulation as a pesticide by the U.S. Environmental Protection Agency (EPA) under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). Since 1996, the EPA has been obligated to periodically review registered pesticides to reconfirm, based on the current state of the science, that such products will not cause unreasonable risks to human health or the environment when used as directed on product labeling.

Before this year, nanosilver (products containing silver in any form having a dimension that measures between 1 and 100 nanometers) was not required to be separately identified and registered. In 2010, the EPA provided conditional registration of one nanosilver product, a fabric treatment, allowing the registrant 4 years to provide the required health and safety data. In January 2012, the Natural Resources Defense Counsel (NRDC) challenged the validity of that conditional registration in a case currently pending in the U.S. Ninth Circuit Court of Appeals, Natural Res. Def. Council, Inc. v. U.S. Envtl. Prot. Agency (Case No. 12–70268). On July 6, 2012, the EPA announced the opening of a registration review docket for nanosilver,1 separate and apart from silver (last reviewed in 2009).

The separate registration and review process for nanosilver is based on the EPA's determination that the information required to assess the safety of nanosilver is different from that of silver.2 Generally, if registration is denied for nanosilver products, future and continued use is prohibited. Moreover, because the nanosilver review process will include one of the first comprehensive reviews and assessments of current scientific knowledge regarding the human and environmental effect of products with nanoscale components by the EPA, its conclusions may have broader impact on other substances in the emerging area of nanotechnology. This article will detail the EPA's new nanosilver registration review process and its potential implications for risk managers in corporations that manufacture or use nanosilver in products and for their insurers.

The requirements of the new "Nanosilver Registration Review Docket" (Docket ID: EPA–Q–OPP–2011–0370) obligate the registrant to submit several "phases" of new data on product characteristics, health and ecological effects, and environmental fate. Over the next 5 years, the EPA will review all test data and determine if nanosilver poses an unreasonable risk to human health or the environment; the results of this review are expected by 2017. According to Nanosilver Summary Document (accessed on November 1, 2012), the review will draw on several recommendations made by a FIFRA Scientific Advisory Panel that the Agency "treat 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)." According to the announcement, this process has been initiated to address EPA's concerns over "gaps in knowledge in the data that is key to understanding the substances' health and environmental risks."

While the FIFRA Scientific Advisory Panel on Nanosilver advised the EPA that it should treat nanosilver differently from conventional silver in terms of data requirements and risk evaluations, some have argued that the existing health standards for silver are actually based on nanosilver.3 A recent historical perspective, "120 Years of Nanosilver History: Implications for Policy Makers" by Bernd Nowack, Harald F. Krug, and Murray Height in Environmental Science & Technology, describes how silver, used for more than 100 years in over-the-counter (OTC) "colloidal silver" preparations, is actually nanosilver. In fact, the articles explain how, as early as 1889, scientists were synthesizing citrate-stabilized silver particles called colloids. (A "colloid" is a general chemistry term, referring to the suspension of fine particles in a continuous medium, in which the particles do not settle in the solution.)

These particles, with an average diameter between 7 and 9 nm, are reported to be nearly identical in physiochemical structure to contemporary manufactured nanosilver particles using silver nitrate and citrate. The implication of this similarity is that much of the historical toxicological literature on the adverse effects of colloidal silver represents early examples of nanosilver research. While the U.S. Food and Drug Administration has opined that OTC colloidal silver is not a recognized treatment for any disease,4 there is a significant body of historical literature on the toxicology of these preparations (e.g., clinical reports following the use of proprietary colloidal silver products such a Collargol®, Argyrol®, or Protargol®).

The adverse effects from extended use of the colloidal silver products can be summarized as reports of grossly discolored fingernails, generalized argyria (i.e., a cosmetic condition where there is a bluish-gray discoloration of the skin), or local argyrosis (i.e., argyria of the eye). It has been estimated that the total dose required to induce generalized argyria (via ingestion) is in the range of 1–30 g for soluble silver salts.5 Given that the clinical presentation of argyria is relatively conspicuous and that numerous cases have been identified, a fairly robust database exists on which to establish a safe level of exposure.

In fact, a number of authoritative national and international agencies have recommended or enforced regulatory guidelines based on colloidal silver-induced effects as the health-related endpoint. For example, in the United States, the EPA derived a safe level of ingested silver based on the presentation of argyria. Both the EPA ambient water quality standard (0.1 mg/L) and the safe level of a lifetime of ingestion (RfDoral 0.005 mg/kg/day) are based on a report of argyria in individuals who were administered colloidal silver (silver arsphenamine) injections for a period of 2 to 10 years. The EPA assessment used the lowest adverse effect level (LOAEL) of a patient receiving a total dose of 4 g silver arsphenamine (1 g of metallic silver).6

International Guidelines

International guidelines for silver are also based on this study. For example, in 1939, the World Health Organization (WHO) set a threshold value of 0.9 g of silver (exposure over the whole lifetime) as a level above which argyria could be expected.7 This value is similar to the value used by the EPA IRIS evaluation in an analysis that used the lowest intravenous dose resulting in argyria in one patient, 1 g of metallic silver, as the minimal effect level. The WHO has stated that a cumulative lifetime oral intake of about 10 g is the human no adverse affect level (NOAEL) (on the basis of contemporary epidemiological and pharmacokinetic knowledge). For example, the WHO has stated that "levels of silver, up to 0.1 mg/litre (a concentration that gives a total dose over 70 years of half the human NOAEL of 10 g), could then be tolerated without risk to health." This level (0.1 mg/L) is the same as the EPA's national recommended water quality criteria for silver, for the protection of aquatic life and human health.

The proper toxicological and human health risk-based characterization of any material, including nanomaterials, must include a consideration of the intended use, exposure levels, and potential hazard (toxicity) of an ingredient or formulation. These considerations become especially challenging when the material under evaluation is nanosilver. For example, a routine toxicology study on a bulk-scale chemical may include an assessment of accuracy in the administered dose/concentration, chemical stability, and purity. These assessments are fairly routine, and the methods of accomplishing them have been standardized and internationally harmonized (i.e., European Union, Organisation for Economic Co-operation and Development, or EPA Standard Methods).

The unique properties of materials at the nanoscale require the evaluation of new physiochemical properties, such as:

  • average particle size;
  • particle size distribution;
  • agglomeration and aggregation states;
  • particle shape;
  • chemical composition and purity;
  • surface area;
  • surface chemistry (reactivity and hydrophobicity); and
  • stability in the media or product being evaluated.

For example, the nanosilver that is bound to a substrate and used as an antimicrobial on the surface of a water filter is likely to have vastly different chemical properties and ultimately biological effects when compared to a nanosilver preparation that is used as a liquid swimming pool chemical. Confounding this difference is a lack of clarity on which "dose-metric" is the appropriate predictor of the effect (e.g., concentration, charge, shape, surface area, inter alia).

While significant efforts have been made to standardize the methods for nanomaterial physiocharacterization, there remain no universally accepted standards, as the science of dose-metrics and the field of analytical chemistry are rapidly evolving to address nanoscale chemicals. These issues combine to underscore the uncertainty in using historical toxicology data on silver (i.e., colloidal silver studies) to address current concerns with nanosilver.

To address these uncertainties and the unique characteristics of nanosilver, the first phase of data submission to EPA for silver-containing pesticides under this Nanosilver Registration Review Docket requirement will be focused on "determining the characteristics of the silver present in these products." This will be followed by a requisite analysis of the form and concentration of silver released from the product. If nanosilver is determined to be released, a third and final phase is required to evaluate the "health effects, ecological effects, and environmental fate." To comply with these new data requirements, in the absence of universally accepted testing standards, EPA must now review all test protocols prior to execution. Results from any test submitted without pre-agency review run the potential risk of being considered unacceptable.

U.S. Guidelines

In the United States, the regulation of products based on their incorporation of engineered nanoscale components is in its infancy, and the EPA's commencement of a registration review docket for nanosilver represents both the most focused U.S. regulatory response to date and, potentially, a template for further regulation. The EPA's preliminary recognition that the unique attributes of nanosilver warrant nano-specific scientific inquiry to establish the acceptable safety of nanosilver products may become a model applied to other nanoscale products by the EPA and other agencies. Moreover, the logical explanations of the EPA regarding the need for a nanosilver review docket are likely to provide substantial ammunition for legal challenges to "conditional registration," such as that mounted by the NRDC regarding the conditional registration of nanosilver fabric treatments as to why registration should follow and not precede acceptable science.

Moreover, and potentially of greater consequence, is the impact of the EPA decision on tort litigation and insurance if the scientific results of the nanosilver review docket point to specific harms caused by the unique nature of such materials on people and/or the environment. The scientific revolution that has allowed nanotechnology to advance may well be employed in evaluating and potentially establishing a causal relationship between such materials and resulting harms. Since nanosilver and other nano-engineered substances have been in the chain of commerce for years already, and years will pass before the nanosilver review docket is complete, the extent of individual and environmental exposure to such substances is potentially substantial. Negative scientific findings attributable to nano-engineered products in general or nanosilver in particular could lead to major impacts on businesses currently marketing such products and their insurers.

The EPA's nanosilver registration review docket is likely to accelerate the pace of scientific inquiry into the safety of engineered nanomaterials. The results of these evaluations, as well as the development of standardized methods for conducting chemical and toxicological testing, are likely to be a model for other national and international agencies responsible for chemical testing, regulation, and registration. While the full impact of the scientific inquiry into nanosilver remains to be seen, given the ongoing and widespread commercial applications of engineered nanomaterials, risk managers would be wise to "stay tuned."


177 Fed. Reg. 40048–40051 (July 6, 2012).

2EPA–HQ–OPP–2011–0370, Case No. 5042 Nanosilver Summary Document, 6.

3"Nanosilver," Silver Nanotechnology Working Group (SNWG), September 2011, accessed October 20, 2012, 4p.

4"Over-the-counter drug products containing colloidal silver ingredients or silver salts," Federal Register, 1999, 21 CFR Part 310, Rules and Regulations, FR Doc. 99–21253, Department of Health and Human Services, Food and Drug Administration, 44653.

5"IRIS record for silver (CASRN 7440-22-4)," U.S. EPA, October 28, 2003, accessed April 06, 2011, 13p.

6The reported LOAEL is equal to 0.014 mg/kg/day, assuming a body weight of 70 kg and an oral retention factor of 0.04. The EPA then used a total uncertainty factor of 3, applied to the LOAEL of 0.014 mg/kg/day (i.e., 0.014/3) to yield the RfDoral of 0.005 mg/kg/day reported above.

7"Silver in Drinking-Water: Background Document for Development of WHO 'Guidelines for Drinking-Water Quality,'" World Health Organization (WHO), 2003, WHO/SDE/WSH/03.04/14, 9p.


*Joseph S. Sano is an equity partner in Prince Lobel's Insurance and Reinsurance, Nanotechnology, and Litigation  Practice Groups, where he provides strategic advice and representation in the litigation, arbitration, and resolution of specialized insurance and reinsurance coverage matters and insurance and reinsurance policy drafting and risk recognition. Mr. Sano founded and is the principal contributor to the firm's first law-related blog, Consider The Risks, addressing current issues in insurance law and risk management. He is a frequent author and speaker regarding insurance, reinsurance, risk management, and emerging risks, including nanotechnology. Mr. Sano can be reached at

**Dr. Marc A. Nascarella is a senior toxicologist at Gradient where he specializes in comprehensive chemical evaluations, dose-response modeling/assessment, and regulatory toxicology. He is active in Gradient's Nanotoxicology Practice where he serves as a coeditor of the quarterly EH&S Nano Newsletter and provides technical guidance to the legal, medical device, and consumer products industry on the potential human health risks of nanoscale materials. Dr. Nascarella is a board certified public health professional and serves as an adjunct professor at the University of Massachusetts School of Public Health and Health Sciences. He can be reached at .


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