In the August 15, 2019, episode of Bergeson & Campbell, P.C.’s (B&C®’s) All Things Chemical™ Podcast, “All Things Nano with Lisa E. Friedersdorf, Ph.D.,” Lynn L. Bergeson sat down with Dr. Friedersdorf, the Director of the National Nanotechnology Coordination Office (NNCO), to discuss all things nano.  In their conversation, Dr. Friedersdorf breaks down the central goals and challenges of the National Nano Initiative (NNI), a governmental program designed to facilitate research and development in nanotechnology, educate people about nanotechnology, and ensure the responsible development of nano by understanding nano’s potential environmental, safety, and health implications.  Dr. Friedersdorf explains how her work at NNCO helps direct and ensure that the many, many billions of dollars of funding available for nanotechnology applications and implications are allocated in ways that are efficient and invite the greatest return on investment and coordinated with other international nano initiatives.  They also discussed some of the wonderfully surprising and unique applications for nanotechnology, as well as potential future applications of the technology for the field of agricultural and chemical production.

Registration has begun for the National Nanotechnology Initiative’s (NNI) September 10, 2019, webinar on “Respiratory Effects of Engineered Nanomaterials in Relation to Physicochemical Properties.”  The speaker will be Dr. Junfeng (Jim) Zhang, Nicholas School of the Environment and Duke Global Health Institute, Duke University, and Dr. William Boyes, U.S. Environmental Protection Agency, will moderate.  NNI states that the interaction between engineered nanomaterials (ENM) and lung lining fluid and cells may play an essential role in determining lung tissue and lung function effects.  To examine how physicochemical properties of ENMs affect this interaction and consequent biological effects, Dr. Zhang’s team integrated in vitro, in vivo, and computational studies of silver and carbon ENMs.  According to NNI, results show that the interaction between ENMs and the lung lining fluid and cells alters ENM physicochemical properties (e.g., size, charge, dissolution, and sulfidation), consequently affecting cellular uptake, cytotoxicity, and bioreactivity.  The magnitude and profile of biological response depend on physicochemical properties, as well as cell types and animal models.  Some of the responses observed in experimental studies can be predicted using toxico-dynamics models.  Participants will be able to submit questions for Dr. Zhang to answer during the question and answer period.

On August 1, 2019, the German Chemical Industry Association (VCI) announced the availability of a guidance document on the safe recovery and disposal of wastes containing nanomaterials.  According to VCI, wastes containing nanomaterials can be generated in the production or use of nanomaterials.  Such wastes can occur in the production of substances, mixtures, or products; in the processing and repair of products; or in the disposal of products at the end of their life cycle.  The guidance document addresses the following topics:

  • Legal framework;
  • Conclusions from regulatory requirements; and
  • Safe recovery or disposal of wastes containing nanomaterials:
    • Waste recovery or disposal;
    • Gathering information about hazardous properties of substances regarding the waste status;
    • Communication along the supply chain; and
    • Determining the hazardousness of waste.

On August 1-2, 2019, the National Nanotechnology Initiative (NNI) held “The Future of the NNI:  A Stakeholder Workshop.”  The NNI has played a pivotal role in fostering and advancing a dynamic nanotechnology ecosystem in support of the initiative’s four goals:  advance world-class research; foster commercialization; develop and sustain research infrastructure; and support the responsible development of nanotechnology.  Building on this foundation, experts from the nanotechnology community shared their perspectives on the key elements required for the nanotechnology enterprise to thrive over the next 15 years.  NNI has posted the videos of the following sessions:

As reported in our February 1, 2019, blog item, the American Conference of Governmental Industrial Hygienists (ACGIH®) Threshold Limit Values for Chemical Substances (TLV®-CS) Committee included carbon nanotubes on its 2019 list of chemical substances and other issues under study.  Being placed on the under study list indicated that the TLV®-CS Committee had selected carbon nanotubes for development of a threshold limit value (TLV®).  On July 30, 2019, ACGIH® announced the release of its two-tier under study list.  Tier 1 lists the chemical substances and physical agents that may move forward as a notice of intended change (NIC) or notice of intent to establish (NIE) in the upcoming year, based on their status in the development process.  Tier 2 consists of those chemical substances and physical agents that will not move forward, but will either remain on or be removed from the under study list for the next year.  Carbon nanotubes are included in Tier 2.  If carbon nanotubes are included on the 2020 under study list, stakeholders will have an opportunity to submit substantive data and comments.

In May 2019, the Nordic Council of Ministers published a working paper entitled The applicability of the GHS classification criteria to nanomaterials.  The goal of the project was to review the applicability of the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) to manufactured nanomaterials, taking into account the progress of international scientific work.  The report notes that the Organization for Economic Cooperation and Development (OECD) Working Party on Manufactured Nanomaterials (WPMN) has generated and compiled much data on nanomaterials under the Testing Program of Manufactured Nanomaterials.  These data were further assessed for some pre-selected nanomaterials:  single-walled carbon nanotubes (SWCNT), nano silicon dioxide, nano silver, and nano zinc oxide.  Additionally, the appropriateness of the GHS classification criteria for the generated data were evaluated for five health hazard classes for which an initial screening had shown a need for classification.  Finally, if applicable, relevant classifications of the nanomaterials were assessed.  For each of the relevant hazard classes, the available test data of the nanomaterials were summarized and evaluated with respect to:

  • Applicability of the test methods;
  • Applicability of the GHS criteria and proposed classification;
  • Identified data gaps and uncertainties; and
  • Need for revision of GHS criteria or further guidance.

The report lists the following overall observations and reflections:

  • In general, the current GHS classification criteria for the five evaluated hazard classes were found to be applicable to the generated data on SWCNT, nano silicon dioxide, nano silver, and nano zinc oxide.
  • Differences in toxicity exist between the various types/qualities (g., related to production methods (e.g., silicon dioxide) or impurity profile (e.g., SWCNT)) of the same nanomaterials that may result in different classifications of the various types/qualities.
  • Specific target organ toxicity – repeat exposure (STOT RE) is considered a highly relevant hazard class to examine for all the nanomaterials especially considering the lung as the target organ.
  • For voluminous nanomaterials (e., nanomaterials with a relatively high specific surface area and low density), testing at high dose levels may not be technically achievable. Hence, testing in accordance with OECD Test Guideline (TG) methods covering all relevant dose levels for acute toxicity classification and STOT RE classification according to the GHS criteria values may not be possible. This is especially relevant for testing via inhalation route.
  • For acute toxicity and STOT RE, the GHS criteria based on a mass-based dose metric can be applied for voluminous nanomaterials, however, the dose levels corresponding to the less severe hazard categories cannot be technically achieved. It may be examined whether another dose metric (g., specific surface area or particle number concentrations) would be a better metric for enabling differentiation in toxicity and the classification of nanomaterials.
  • It is noted that most testing regarding repeated inhalation exposure has focused on identification of no observed adverse effect concentration (NOAEC)/lowest observed adverse effect concentration (LOAEC) levels and the examination of early signs of toxicity (g., various inflammatory markers) rather than establishing data for STOT RE classification. So mostly very low exposure levels compared to the STOT RE criteria have been used.  Thus, there are data gaps for assessing the proper STOT RE classification of nanomaterials.
  • As support for a STOT RE classification, it should be considered how to use an adverse outcome pathway (AOP) or mode of action (MOA) approach using inflammatory signs/markers or mild/moderate histopathological effects induced in target organs at very low exposure levels for classification purpose.
  • Also, it may be examined how and under which circumstances data from intratracheal instillation or pharyngeal aspiration may be used as support for STOT RE classification if data from inhalation testing are limited or do not cover the relevant dose ranges for classification.

On July 3, 2019, the European Commission (EC) Scientific Committee on Consumer Safety (SCCS) published its final opinion on the solubility of synthetic amorphous silica (SAS). The EC asked whether SCCS considers that SAS materials are soluble (100 milligram per liter (mg/L) or higher) or degradable/non-persistent in biological systems in light of the nanomaterial definition of the Cosmetics Regulation. Having considered the data provided in this dossier and that available in published literature, SCCS concluded that:

  1. The solubility values for hydrophilic SAS materials have been reported to range from 22 mg/L to 225 mg/L for the solubility tests performed in aqueous media, or following the enhanced Organization for Economic Cooperation and Development (OECD) Test Guideline (TG) 105 (0.5 percent ethanol). The latter protocol has been noted to increase the solubility by a factor of ten for some hydrophilic SAS materials.
  2. The solubility values of hydrophobic surface-treated SAS materials have been reported to range from 0.4 to 180 mg/L for solubility tests performed in aqueous media, or following a modified enhanced OECD TG 105 protocol (i.e., using ten percent ethanol). The latter protocol has been noted to increase strongly the solubility of some hydrophobic SAS materials (by a factor up to 173).

The preliminary opinion states that the hydrophilic and hydrophobic SAS materials can therefore be regarded as “insoluble” (i.e., below 100 mg/L) to “very slightly soluble” (i.e., 100 mg/L to 1,000 mg/L) based upon the terminology used in USP 38 and USP 38 NF33. According to the final opinion, in regard to the nanomaterial definition in the Cosmetics Regulation, none of the SAS materials (hydrophilic or hydrophobic) included in the dossier can be regarded as soluble. No data were provided to help establish whether the SAS materials could be regarded as degradable/non-persistent in biological systems.

The EC asked whether SCCS could indicate to which kind of silica this solubility applies. The final opinion states that the solubility values reported in the dossier are applicable when SAS materials are subject to the following conditions:

  • Hydrophilic SAS: Silica and hydrated silica when solubilized in aqueous media containing up to 0.5 percent ethanol;
  • Hydrophobic surface treated SAS: When solubilized in aqueous media containing up to ten percent ethanol;
  • At temperatures between 19.5 to 20.5°C;
  • With a pH level of between three and eight; and
  • Over a period between three days (hydrophilic SAS) up to 49 days (hydrophobic SAS).

The EC asked whether SCCS has any further scientific concerns with regard to the solubility of SAS. SCCS states that the solubility values considered in its opinion may not be valid in situations where the SAS materials are formulated/used under conditions that are different from those used in the solubility tests — e.g., when used in a less/non aqueous formulation, or at a different temperature. According to SCCS, in the context of the definition of nanomaterial under the Cosmetics Regulation, which relates to insoluble materials in conjunction with other size/particle related parameters, the question of solubility of a nano-structured material needs to be seen in perspective for use in cosmetics. For nano-structured materials, with the exception of the materials that are completely soluble, SCCS states that “it is important to establish whether a proportion of these materials would still exist in undissolved form comprising nanoparticles, at the given use level in a cosmetic formulation.” SCCS noted that the protocols used for solubility tests have a strong influence on the solubility of SAS materials.

The National Institute for Occupational Safety and Health (NIOSH) announced on July 10, 2019, the availability of a new Technical Report, The NIOSH Occupational Exposure Banding Process for Chemical Risk Management.  NIOSH describes occupational exposure banding as “a voluntary process that assigns each chemical to a category based on its toxicity and any negative health outcomes associated with exposure to that chemical.”  The Technical Report “provides a process with easy procedures and clear rules for assignment and can be used in a broad spectrum of workplace settings.”  Section 3.14, “Consideration of Special Categories of Aerosols,” includes recommendations for liquid aerosols; fibers, including nanofibers; and nanoparticles:

  • Fibers: The Report notes that fibers and other high-aspect-ratio particles “have unique aerodynamic features that are dependent on their geometry (dimensions) and that influence their deposition in the respiratory tract.”  In addition, the physical shape and size of fibers can directly influence their toxicological properties and the nature of their interactions with target cells.  The Report states:  “These complexities require using a Tier 3 assessment for fibers, and the [occupational exposure band (OEB)] Tier 1 and Tier 2 criteria are not recommended.  Some hazard banding frameworks for nanomaterials recommend assigning the most stringent band for bio-persistent, rigid nanofibers.”
  • Nanoscale solid-phase particles: The Report describes empirical data and mechanistic hypotheses that have been used to support application of the hazard banding procedures within control banding schemes for engineered nanoparticles (g., as applied in various national standards).  Using the same rationale, NIOSH recommends that the occupational exposure banding process be modified as follows when applied to nanoparticles:
    • Poorly-soluble nanoscale particles: If the toxicity data include no observed adverse effect levels (NOAEL) that were developed specifically for the nanoscale form of the chemical substance, then the NIOSH occupational exposure banding process can be used with no modifications;
    • If data are available for only the microscale form of the chemical substance, then the band assignment should be shifted to the next more stringent band, on the assumption that poorly soluble nanoscale substances will likely be more toxic than their microscale equivalents (g., by an order of magnitude). The Report notes that some other banding schemes also recommend a more stringent band (to reduce exposure by an order of magnitude) when data are available on only the microscale form of the substance; and
    • Soluble nanoscale particles: The Report states that data support an association between increased total particle surface area and increased toxicity for poorly soluble nanoscale particles.  As particle solubility increases, there may be less need for the OEB to account for enhanced toxicity due to the nanoparticle-specific characteristics.  The Report notes that in the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) and International Organization for Standardization (ISO) control banding schemes, soluble particles are addressed with regard to the toxicity of the solute, without consideration of nanoparticle-specific toxicity.  Given the uncertainties in the relationship of solubility to particle toxicity, however, NIOSH “recommends that in the absence of data to the contrary, all nanoscale particles should be treated in the same manner without regard to solubility.”  If data are available only for the microscale form of the agent, NIOSH recommends shifting the banding assignment to the next more stringent band.

The Report cautions that because the toxicity of nanoscale fibers and nanoscale tubes may differ substantially from other forms of the compound, the occupational exposure banding process described “may not fully and accurately capture the toxicity of these chemical substances.”  NIOSH states that Tier 1 and Tier 2 should not be used and instead a Tier 3 assessment is required as described for other fibers.  According to the Report, NIOSH is currently evaluating the state of the science for deriving occupational exposure limits (OEL) and OEBs for nanomaterials and is also examining the process and data for developing hazard categories for nanomaterials based on biological mode of action and physical-chemical properties.

The European Chemicals Agency (ECHA) announced on July 3, 2019, that several new features and improvements are now publicly available in its chemicals database, including new information in substance Infocards.  ECHA has updated the substance Infocards with a new nanomaterial form section that shows whether the substance is placed on the European Economic Area (EEA) market in nanoform and provides links to the European Union (EU) Observatory for Nanomaterials (EUON).  As reported in our July 8, 2019, blog item, through EUON’s search tool for nanomaterials, information on over 300 nanomaterials on the EU market can be found and linked to hazard data.  The search uses data from Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation registrations, the cosmetic ingredients notification portal, and the French and Belgian national inventories.

On July 12, 2019, the European Food Safety Authority (EFSA) published in the EFSA Journal its “Scientific opinion on the proposed amendment of the EU specifications for titanium dioxide (E 171) with respect to the inclusion of additional parameters related to its particle size distribution.”  The opinion addresses the assessment of data provided by interested business operators in support of an amendment of the European Union (EU) specifications for titanium dioxide (E 171) with respect to the inclusion of additional parameters related to its particle size distribution.  According to the opinion, titanium dioxide (E 171), which is used as a food additive in food, undergoes no surface treatment and is not coated.  The opinion states that interested business operators have proposed to revise the EU specifications for E 171 to include “a specification of more than 100 nm for median Feret min diameter and less than 50% of the number of constituent particles below 100 nm; measured by EM in both cases.”  The EFSA Panel on Food Additives and Flavorings, after reviewing the data, “concluded that a specification of more than 100 nm for median minimal external dimension, equivalent to less than 50% of the number of constituent particles with a median minimal external dimension below 100 nm, should be inserted in the current EU specifications.”  According to the opinion, the Panel determined that the conclusions made, and the uncertainties identified, in previous EFSA assessments of E 171 remain valid.  The Panel reiterates the need for further research as recommended in previous opinions to decrease the level of uncertainty and acknowledges that interested business operators are carrying out additional studies with characterized E 171.  More information on EFSA’s 2018 review of four new studies on the potential toxicity of titanium dioxide used as a food additive (E 171) is available in our August 6, 2018, blog item.