The September 2008 submission of an application to register a pesticide product containing silver nanoparticles set off a chain of events and decisions at the Environmental Protection Agency (EPA) that will "set the bar" for future nanopesticide registrations. While EPA concluded that the pesticide containing nanosilver "differed from currently registered silver-based antimicrobial products, it has determined that in the past they unknowingly approved silver-based pesticidies with nanoscale content. As "treating all of the registered nanosilver products equally is in the public interest, the agency intends to require that "similar data be developed to support the continued registration of these other nanoscale products as well." Accordingly, considerations made in relation to the nanosilver application will have implications for existing and future nanopesticide registrations in the United States.

To help support its decision-making process, EPA convened the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Science Advisory Panel (SAP) in November 2009 to review a number of issues surrounding nanosilver and other metal-based nanopesticides. SAP released its final report in January 2010, which provides much of the current EPA rationale and policy, including:

  • Suggestion that a case-by-case approach be followed due to general lack of data;
  • Recognition that existing data requirements may have to be modified;
  • Information showing toxicity of nanosilver could be higher than conventional silver;
  • Conclusion that there is not enough literature to draw firm conclusions on exposure;
  • Conclusion that existing information on conventional silver would not be sufficient;
  • Suggestion that nanosilver be treated differently in terms of data requirements and risk assessment; and
  • Conclusion that additional data is needed on product chemistry, exposure potential, and potential hazard to human health and the environment.

Taking six months to digest the contents of this final report and perform the necessary research, data review, and risk analysis, the agency was ready to report its findings and decisions. While it granted a four-year conditional registration for the nanosilver application based on a screening level risk assessment for the proposed use pattern, it is expected that the registrant will need to develop study protocols, for EPA review, to generate further data in several major areas (product chemistry, environmental fate and effect, and human toxicity and exposure).

In the product chemistry area, the following data were deemed insufficient:

  • 830.1800 (Enforcement Method); measurement of "total silver" was submitted: however, EPA indicated that it needs "high resolution images of the active." EPA scientists have stated that not one method can provide complete characterization, so the possibility of requiring multiple expensive electron microscopy techniques (SEM, TEM, AFT) exists.
  • 830.6317 (Storage Stability): and 830.6320 (Corrosion Characteristics). "Accelerated methods" will not be accepted, thus all registrants will have to conduct full one-year studies.
  • 830.7520 (Size and Size Distribution): EPA requests size distribution and surface area data on the active ingredient nanoparticles in the composite as well as the composite in the final product. Studies to assess size distribution and surface area are non-guideline. While there is no current EPA-approved protocol for this, "it is anticipated that this study could be accomplished using methods reported in the literature" (Egger et al. [2009] is cited by the agency). A careful reading of the decision document shows EPA has concerns regarding nanoparticles that might be released from the composite in the final product (and thus constitute a potential end user exposure scenario) and has designed a second tier of studies that may also be required depending on the outcome of certain Tier 1 studies.

Additional product chemistry information requested include submission of a sample; additional stability data under a number of different conditions (temperature, metals and metal ions, sunlight, detergents, salinity); and 830.7050 (UV-visible light adsorption) as measured by a method recommended by the November 2009 SAP. This test method helps EPA understand conditions under which photochemical degradation of the technical grade active ingredient may occur and, in this case, will also help verify the presence of nanoscale material(s).

In the environmental fate and effects area, EPA is asking for non-guideline dissolution kinetics study to help the agency determine a fish bioconcentration factor (BCF) value for risk assessment purposes. (Additional Tier 2 testing may be triggered dependent on the results of this study.) With regard to effect, requirements were identified for ecotoxicity studies on fish, birds, algae, and aquatic invertebrates.

In the human exposure and toxicity area, there are several major requirements. An indoor applicator study must be done to confirm the screening level occupational risk assessment findings. With regard to required guideline studies, EPA has requested route-specific subchronic inhalation and dermal toxicity studies, a combined repeat-dose oral toxicity study with reproductive and developmental toxicity screening, and a battery of genetic toxicity studies all using the test material.

For the leaching study, EPA required a sufficiently sensitive test method to differentiate among aggregates of nanoparticles, precipitates of ionic silver, or nanoparticles in fibers or coating fragments. For example, the ion-specific electrode [ISE] method for analyzing wash water for silver ions has a detection limit of 160 ppb; however, EPA suggests using an induction-coupled plasma [ICP] method which has a much lower detection limit of 0.2 ppb. In addition, sufficient magnification for microscopic methods is required. The registrant submitted data using a scanning electron microscopy [SEM] but the magnification was insufficient to be able to accurately visualize and identify silver nanoaprticles in the 1-10 nm size range.

Several interesting data decisions of note were made in the decision document with regard to the submitted toxicological literature. Treatment-related effects from the subchronic inhalation study by Sung et al. (2009) were considered adverse and a no observed adverse effect level (NOAEL) of 133 ug/m3 (1.4x106 particles/cm3; mid-level dose) was determined from this study for use in the screening level risk assessment. Treatment-related effects from the 28-day oral study by Kim et al. (2008) yielded a NOAEL of 30 mg/kg-day (lowest dose) based on increase in alkaline phosphatase and cholesterol—this NOAEL was used to assess oral and dermal risk assessment scenarios. Although no in vivo dermal studies were identified, EPA stated it would be willing to accept "predictive" in vitro studies to calculate a dermal absorption factor (DAF) for use in risk assessment. EPA suggested Larese et al. (2009), which it used to set the DAF at 1% for the dermal scenarios. Of note, route to route extrapolation from the oral study (Kim et al., 2008) was performed for use in the dermal scenarios and this practice will continue until the agency receives dermal studies of sufficient quality. These decision document determinations are important as they represent key "EPA-approved" citations to data for future nanosilver registrations.

EPA noted in all exposure route discussions (oral, inhalation, dermal) that adverse health effects could occur as a result of exposure to "sufficient quantities of silver nanoparticles that break away from the pesticide." This is a central assumption that plays a key role for the agency in determining whether Tier 2 data requirements will be required. Additional data requirements would be triggered by the release of silver nanoparticles in certain Tier 1 studies (including the leaching study). Should this be the case, the agency will request:

  • Additional information on size, size distribution, zeta potential, surface area, solubility, and UV-visible light adsorption;
  • Additional kinetic studies to help refine the fish BCF as well as a new "non-guideline" study to generate data on potential impact to microbial communities;
  • Repeat data on inverts, birds, fish, and algae; and
  • Repeat data on subchronic, repeat dose, and genetic toxicology tests.

Despite the fact that "EPA lacks information to conduct a complete assessment of the potential risks," the protective yet practical approach as outlined in the decision document will require careful attention in the coming months and years to help divine the future with regard to existing and future nanopesticide product registrations.

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