Regulatory Developments

EPA Conditionally Registers Nanosilver As a New Active Ingredient

December 5, 2011

The U.S. Environmental Protection Agency (EPA) announced on December 1, 2011, that it granted a conditional registration for a pesticide product containing nanosilver as a new active ingredient. This memorandum provides additional information regarding this momentous regulatory achievement.

HeiQ AGS-20 is a silver-based antimicrobial pesticide product that will be incorporated into textiles to suppress the growth of bacteria, which EPA states in its December 1, 2011, Decision Document "cause textile odors, stains, and degradation, through the slow release of silver ions." HeiQ AGS-20 is a nanosilver-silica composite where the nanosilver is sintered onto amorphous silicon-dioxide having typical particle diameters of one micrometer (1,000 nanometers). According to EPA, the treated textiles can be manufactured into indoor use articles such as sheets, blankets, towels, napkins, outerwear, sportswear, sleepwear, undergarments, socks and hosiery, and outdoor use articles such as sailcloth, tarps, tents, and awnings. The textiles will be incorporated into the starting materials or treated by application of HeiQ AGS-20 as a surface coating (textile finishing).

In its risk evaluation, EPA used conservative assumptions, overestimating the dose of nanosilver, and maximum values for risk uncertainty factors. Because of EPA's risk concern for occupational exposure to HeiQ AGS-20 powder during mixing and loading operations, HeiQ amended its registration application, and the label now requires workers to wear personal protective equipment (PPE) and use engineering controls when handling HeiQ AGS-20 powder. As a condition of registration, EPA is requiring significant new data development requirements, including route-specific toxicity studies for occupational exposure scenarios and product characterization and stability tests to determine if nanosilver breaks away from HeiQ AGS-20. EPA's Decision Document is available online. The data requirements are set forth in Appendix A, reproduced in part below. The studies listed in Table 1A are considered Tier I because their need is not based on the results of any other studies. Tier II studies may or may not be required based on the results of the Tier I studies. Tier I studies are required to be submitted according to the schedule set forth in the registration.

According to the Decision Document, the basis for conditional registration is that:

  1. HeiQ AGS-20 contains an active ingredient, silver nanoparticles, which is not an active ingredient in any currently registered pesticide (i.e., a "new" active ingredient);
     
  2. Use of HeiQ AGS-20 will not cause unreasonable adverse effects on the environment during the period when newly required data are being developed;
     
  3. Insufficient time has elapsed for HeiQ to generate and submit the newly required data; and
     
  4. Use of HeiQ AGS-20 is in the public interest.

When HeiQ submitted its registration application in September 2008 for HeiQ AGS-20, it did so as a "me too" registration. EPA states that it consulted with the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in November 2009, but could not conclude that the nanoscale material in HeiQ AGS-20 was an active ingredient in any currently registered pesticide. EPA then requested HeiQ register HeiQ AGS-20 as a new active ingredient, which HeiQ did.

In its review, EPA determined that workers, consumers, and the environment could be exposed to:

  • Silver ions released from HeiQ AGS-20 particles;
     
  • HeiQ AGS-20 particles; and
     
  • Nanosilver that might break away from HeiQ AGS-20 particles.

For the purposes of risk from exposure to silver ions, EPA states that it relied on the existing reregistration decision for silver and concluded that the human health or ecological risk from exposure to silver ions derived from HeiQ AGS-20 treated textiles is not of concern. For purposes of risk from exposure to HeiQ AGS-20, HeiQ submitted results from short-term acute animal-toxicity tests completed using high-level doses of HeiQ AGS-20. There were no mortalities or abnormalities in test animals after administration of HeiQ AGS-20 by oral, dermal, and inhalation routes. According to EPA's Decision Document, HeiQ AGS-20 caused moderate to no irritation to the skin and eyes of test animals, and was not a skin sensitizer. Based on these results, the Decision Document states, EPA will require shipping containers filled with HeiQ AGS-20 "to carry a label stating 'CAUTION' where contact with items treated with AGS-20 is restricted for 12 hours after application and AGS-20 does not require child-resistant packaging."

The Decision Document notes that, although there are no intermediate- or long-term human or environmental toxicity studies available for HeiQ AGS-20 or for the nanosilver that might break away, the scientific literature includes intermediate-term toxicity studies for analogous forms of nanosilver. EPA used these data to evaluate the risk from occupational and consumer exposure. In addition, EPA states, because the available exposure data are limited, EPA calculated the daily-dose to workers assuming that all the silver in HeiQ AGS-20 was freely available as nanosilver. For the daily-dose to consumers, EPA assumed that all the silver found in the wash water from color-fast testing of HeiQ AGS-20 treated textiles and during drying of HeiQ AGS-20 treated textiles consisted of nanosilver. These assumptions overestimate the daily-dose of nanosilver that a person could potentially receive when working with HeiQ AGS-20 or wearing HeiQ AGS-20 treated textiles. Because the studies on which EPA relied do not evaluate toxicity over all life stages or evaluate all potential effects, EPA states that it used a maximum 10-fold database uncertainty factor when evaluating the risk from exposure to the nanosilver that might break away from HeiQ AGS-20.

EPA evaluated the impact to the environment based on ecotoxicity studies available in the scientific literature for analogous forms of nanosilver, and assessed environmental exposure by assuming that 300 million people (U.S. population) each purchased one t-shirt treated with HeiQ AGS-20 and that all the silver in those t-shirts was released during a year as nanosilver.

EPA states that, by using conservative assumptions that overestimate the dose of nanosilver that could potentially be derived from HeiQ AGS-20 along with maximum values for risk uncertainty factors, it is able to determine that, for the period of conditional registration, there is a low probability of adverse risk to children and the environment. Thus, EPA concludes that use of HeiQ AGS-20 will not cause unreasonable adverse effects on the environment during the period when newly required data are being developed. EPA notes that it does have a risk concern for occupational exposure when handling HeiQ AGS-20 powder during mixing and loading operations.

As a condition of registration, EPA is requiring HeiQ to conduct a number of studies during the period of conditional registration. The required tests include route-specific toxicity studies for occupational exposure scenarios, as well as product characterization and stability tests to determine if nanosilver breaks away from HeiQ AGS-20. EPA states that, if nanosilver is found to break away from HeiQ AGS-20 or textiles treated with HeiQ AGS-20, then additional testing will be triggered to determine the effect of HeiQ AGS-20 derived nanosilver on humans and the environment. These studies must be completed within a time duration of four years, which EPA chose to allow time for protocol reviews prior to initiation of the studies, completion of the studies, and its review of the study results. EPA intends to evaluate these data as they are submitted to confirm that the use of HeiQ AGS-20 will not cause unreasonable adverse effects to human health and the environment. If HeiQ fails to take appropriate steps to initiate the required studies, or if HeiQ fails to submit the protocols or data, EPA will issue a notice of intent to cancel HeiQ's registration under FIFRA Section 6(e).

Table 1A -- Summary of Tier I Required Data for HeiQ AGS-20

OSCPP Data Requirement (Note 1) Guideline Number: Study Title
Product Chemistry
830.1550: Product Identity and Composition
830.1750: Certified Limits
830.1800: Enforcement Method
830.1900: Submittal of Samples
830.6313: Stability to Normal and Elevated Temperatures, and Metals/Metal Ions
830.6317: Storage Stability
830.6320: Corrosion Characteristics
830.7050: UV-Visible Light Adsorption
830.7840: Solubility
Non-Guideline: Particle Size and Diameter (size) Distribution
Non-Guideline: Surface Area Determination
Human Exposure
875.1200 and 875.1400: Applicator, Indoor Exposure
Non-Guideline: Attrition Study
Non-Guideline: Textile Leaching Study (Confirm Geranio et al., 2009 study results)
Health Effects
870.3465: 90-Day Inhalation Toxicity (Rat) (Replace Sung et al., 2009 study results) Modified to include in vivo bone marrow assay and functional observational battery, motor activity and detailed neuropathology
870.3250: 90-Day Dermal Toxicity (Rat) (Replace DAF of 0.1% and Park et al. 2010 study results)
Modified 870.3550/OECD TG 421: Reproduction/Developmental Toxicity Screening Test
Non-Guideline: in vitro micronucleus (MN) assay
Ecological Effects
850.2100: Avian Acute Oral Toxicity
850.1010: Aquatic Invertebrate Acute Toxicity, Freshwater Daphnids
850.1075: Fish Acute Toxicity Test, Freshwater and Marine
Environmental Fate
Non-Guideline: Dissolution Kinetics Study

Table 2A -- Summary of Tier II Required Data for HeiQ AGS-20

OSCPP Data Requirement (Note 1) Guideline Number: Study Title
Product Chemistry
830.7050: UV-Visible Light Adsorption
Non-Guideline: Particle Size and Diameter (size) Distribution
Non-Guideline: Surface Area Determination
830.7840: Solubility
Non-Guideline: Zeta Potential and Surface Charge Determination
Human Exposure -- No Tier II Studies are Required
Health Effects
870.3100: 90-Day Oral Toxicity (Rat) (Replace Park et al. 2010 study results)
870.3250: 90-Day Dermal Toxicity (Rat) (Replace DAF of 0.1% and Park et al. 2010 study results)
Modified 870.3550/ OECD TG 421: Reproduction/Developmental Toxicity Screening Test
Non-Guideline: in vitro micronucleus (MN) assay
Ecological Effects
850.1850: Modified Aquatic Food Chain Transfer
850.4100: Terrestrial Plant Toxicity
850.4400: Aquatic Plant Toxicity, Tier 2
850.5400: Algal Toxicity, Tier 2
Non-Guideline: Measuring the Chronic Effects of Freshwater Sediment-Associated Contaminants on Chironomus dilutes
Non-Guideline: Measuring the Chronic Effects of Freshwater Sediment-Associated Contaminants on Hyalella azteca
Non-Guideline: Measuring the Chronic Effects of Marine and Estuarine Sediment-Associated Contaminants on Leptocheirus plumulosus
Environmental Fate
Non-Guideline: Rate of Deposition
835.1100: Activated Sludge Sorption Isotherm
835.1230: Adsorption/Desorption (Batch Equilibrium)
835.1240: Leaching Studies (Soil Column Tests)
850.6800: Modified Activated Sludge, Respiration Inhibition Test for Sparingly Soluble Chemicals (Confirm HeiQ screening study)

Note 1: These guidelines only provide general guidance. Protocols shall be submitted prior to conducting these studies.

Commentary

EPA's approval of the HeiQ nanopesticide product is a big deal. Granted, the registrant and many in the pesticide community wish the final approval were swifter, with fewer Tier I and Tier II data requirements, and not time-limited. These should not detract, however, from the bigger picture and HeiQ's success in procuring the first FIFRA approval of a nanopesticide.

Equally important and not to be overlooked is EPA's determination that the use of HeiQ AGS-20 is in the public interest. EPA states that it may lead to less environmental loading of silver as compared to currently registered products with the same use patterns. Importantly, EPA notes HeiQ AGS-20 appears to offer prolonged ability to suppress the growth of odor causing bacteria through the slow release of silver ions as compared to the rapid release of silver ions from registered products containing silver salts. This representation may offer HeiQ an important commercial advantage as EPA specifically notes that "the Agency believes that AGS-20 will allow slow and controlled release of silver ions, potentially resulting in more prolonged antimicrobial activ... Thus, consumers purchasing textiles treated with nanosilver may receive a more durable antimicrobial protection for AGS-20 treated textiles as compared to the alternatives even though there is less total silver in the AGS-20 treated textiles, and such protection is believed to have equal ability to reduce the number of odor causing bacteria as other similar products on the market that contain conventional silvers." This kind of support for HeiQ's product efficacy is valuable.

EPA also, importantly, had some supportive statements for nanotechnology -- all the more important as they came from EPA's Office of Pesticide Programs, which has been criticized by the nano community for its proposed FIFRA Section 6(a)(2) policy, as described in our June 10, 2011, memorandum available online. Specifically, EPA states: "EPA sees the emergence of nanotechnology as offering potential benefits for society in many different fields, including pest control products. The use of nanotechnology in pesticide products may allow for more effective targeting of pests and use of smaller quantities of pesticide. These could contribute to improved human and environmental safety and could lower pest control costs. Therefore, EPA seeks to encourage innovative work to realize these benefits."


 
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