Nanomaterial Toxicity and Regulatory Framework: Need of the Hour

Abstract

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• Abstract
• Introduction
• Types and Classification of Nanomaterials
• Classification Based on Origins
• Classification of Nanomaterials on the Basis of Dimension
• Properties of Nanomaterials
• Nanoparticles
• Composition
• Toxicity of Nanomaterials Found in Human Environment
• Regulations Framework of Different Countries
• Conclusion
• Acknowledgement
• Conflict of Interest
• References

Nanoparticles (NPs) and Nano-Structured Materials (NSMs) represent a dynamic area of research and a fast-expanding techno-economic sector in diverse applications. Nano-materials exhibit multiple traits that make them suitable for diverse clinical applications. Their defining characteristics include super para-magnetism, high agglomeration and mechanical properties, along with a significant surface area-to-volume ratio. Monometallic nano-structured metal clusters act as precursors for heterogeneous catalysts. Nano Pharmaceuticals (NPs) are characterized as nano-materials that have at least one external dimension, or who’s internal or surface structure is within the nanoscale range (about 1 to 100nm). NPs have distinct physical and chemical properties that affect their toxicity, in contrast to those of larger counterparts. Research into nano-toxicity centers on the detrimental impacts of nano-materials, with the goal of determining their potential threat level to society and the environment. The FDA utilizes a product-focused and science-based regulatory policy that leverages this emerging technology to regulate products. Guidelines cover its physicochemical properties, biological properties and product applications.

Graphical Abstract

Figure 1:Graphical abstract for nanomaterial toxicity and regulatory framework.

Keywords: Nanoparticles; Toxicity; Regulations; FDA; EMEA; Nanomaterials

A nanomaterial is characterized as a “material with any external dimension within the nanoscale or possessing internal structure or surface structure at the nanoscale,” where nanoscale is defined as “the length range approximately from 1nm to 100nm.” This encompasses both nano-objects, which are individual pieces of material and nano-structured materials, which possess internal or surface structures at the nano scale; it is possible for a nano material to belong to both of these categories [1]. Nanoparticles (NPs) and Nano-Structured Materials (NSMs) constitute a burgeoning field of study and a developing technoeconomic sector across various applications [2]. NPs and NSMs have become prominent in technological advancements because of their tunable physicochemical properties, such as melting point, wettability, electrical and thermal conduction and scattering (Figure 2). These characteristics lead to improved performance compared to their bulk counterparts [3]. Various countries having their different opinion regarding nanomaterials which are defined as follows:

Figure 2:Types of nanomaterials [2].

According to European Commission cosmetics directive (EC 2009)

Nanomaterial is defined as follows: ‘Nanomaterial’ refers to an intentionally produced substance that is insoluble or biopersistent, with one or more external dimensions or an internal structure at a scale of 1 to 100nm. As per the definition provided by the European Commission, a nanomaterial is a natural, incidental or manufactured substance that contains particles-either in an unbound state, as aggregates or as agglomerates-and where 50% or more of the particles in its number size distribution have one or more external dimensions ranging from 1nm to 100nm [4].

According to Australian government

Nanomaterial refers to industrial materials that are deliberately produced, manufactured or designed to possess unique characteristics or a specific composition at the nanoscale, which typically ranges from 1nm to 100nm. These materials can be classified as either nano-objects (confined at the nanoscale in one, two or three dimensions) or nanostructured (having structures at the nanoscale on its surface or internally). Aggregates and agglomerates are encompassed and pertain to materials in which 10% or more of the particles, based on number count, fulfill the aforementioned definition [5].

According to Canada

Health Canada defines nanomaterial as any manufactured substance or product, including its component materials, ingredients, devices or structures, that meets one of the following criteria: It has at least one external dimension at the nanoscale; its internal or surface structure is at the nanoscale; it is not at the nanoscale in all dimensions but demonstrates one or more properties or phenomena characteristic of the nanoscale. Nanoscale pertains to characteristics that can be ascribed to the dimensions of the material and size effects [6].

According to USA (United States food and drug administration)

A formal definition of agency does not exist. However, when assessing if an FDA-regulated product contains nanomaterials or involves nanotechnology, the FDA will inquire: Does the engineered material or final product have at least one dimension within the nanoscale range (approximately 1nm to 100nm)? or whether a manufactured material or final product displays characteristics or occurrences, such as physical or chemical properties or biological effects, that can be linked to its dimension(s), even if these dimensions exceed the nanoscale range but are within one micrometer [5,6].

Most current NPs and NSMs can be categorized into four material-based groups: Nanostructured material characterized by a microstructure with a characteristic length scale of a few (typically 1-10) nanometers and NPs, referred to as Nanostructured material [7,8].

Carbon-based nanomaterials

These NMs typically consist of carbon and can be found in forms like hollow tubes, ellipsoids or spheres. Fullerenes (C60), Carbon Nanotubes (CNTs), carbon nano fibers, carbon black, Graphene (Gr) and carbon onions fall under the category of carbon-based NMs. These carbon-based materials (except carbon black) are primarily produced using laser ablation, arc discharge and Chemical Vapor Deposition (CVD) [7].

Inorganic-based nanomaterials

These NMs comprise metal and metal oxide NPs as well as NSMs. NMs like these can be synthesized into various forms, including metals such as Au or Ag NPs, metal oxides like TiO₂ and ZnO NPs, as well as semiconductors such as silicon and ceramics.

Organic-based nanomaterials

This comprises NMs that are primarily composed of organic matter, while excluding carbon-based or inorganic-based NMs. By employing non-covalent (weak) interactions for self-assembly and molecular design, organic NMs can be converted into target structures like dendrimers, micelles, liposomes and polymer NPs.

Composite-based nanomaterials

Composite NMs are multiphase NPs and NSMs where one phase is at the nanoscale. They can consist of combinations of NPs with other NPs, or with larger or bulk materials (e.g., hybrid nanofibers), as well as more complex structures like metal-organic frameworks. The composites can consist of any combinations of carbon-based, metal-based or organic-based NMs with bulk materials made from metal, ceramic or polymer. NMs are produced in various morphologies, as indicated in Figure 3, based on the necessary characteristics for the intended application.

Figure 3:Various types of morphologies of nanomaterials [7].

Apart from dimension and material-based classifications, NPs and NSMs can also be classified as natural or synthetic, based on their origin.
A. Natural nanomaterials are produced in nature either by biological species. The production of artificial surfaces with exclusive micro and nanoscale templates and properties for technological applications are readily available from natural sources [9].
B. Synthetic (engineered) nanomaterials are produced by mechanical grinding, engine exhaust and smoke or are synthesized by physical, chemical, biological or hybrid methods [10].

The Gleiter scheme categorizes nanomaterials based on crystalline forms and chemical compositions. However, it was incomplete due to not considering dimensionality. In Pokropivny et al. [11], developed a new classification scheme for nanomaterials, including 0D, 1D, 2D and 3D composites, reflecting electron movement along dimensions [11].

The small nanomaterials have various dimensions like:
a) Zero dimensions.
b) One dimension.
c) Two dimensions.
d) Three dimensions.

The dimensions of nanomaterials and some of their important characteristics are explained in Figure 4. The nanomaterials have at least one dimension of 1-100nm. The nanomaterials exist in single, aggregated or fused forms with several shapes such as tubular, spherical and irregular. The most common types of nanomaterials are nanofibers, nanotubes, quantum dots and nanosheets. Siegel also classified nanomaterials into four types: zero-dimensional, one-dimensional, two-dimensional and three-dimensional nanostructures [11,12].

Figure 4:Dimensions of nanomaterials and their characteristics.

Nanomaterials have several properties that make them suitable for a variety of clinical applications.
A. One of the major benefits of nanoparticles is their small size of 10-200nm allowing them to circulate the body without disrupting blood flow, as well as being able to avoid clearance by both the renal and complement systems [13].
B. Size of nanomaterials is relevant in treatment of cancer because of enhanced permeability and retention effect was one of the ways that nanoparticles could successfully penetrate tumour tissues. Reference must be in ascending order [14].
C. Nanomedicines are generally simple and cheap to manufacture on the small scale, however, difficulty with scale up and stability on large scale manufacture has been widely experienced [15,16].

Sources of nanomaterial

Sources of nanomaterials can be classified into below main categories based on their origin:
a) Incidental nanomaterials: These are generated as byproducts of industrial processes, including nanoparticles from vehicle engine exhaust, welding fumes, combustion processes and even natural events like forest fires [17].
b) Nanomaterials may be incidentally produced as a byproduct of mechanical or industrial processes: Incidental nanoparticles can originate from vehicle engine exhaust, welding fumes and combustion processes involved in domestic solid fuel heating and cooking. As an example, fullerenes-a category of nanomaterials-are produced by the combustion of gas, biomass and candles [18].

Additionally, it may result from wear and corrosion products (Figure 5). Incidental atmospheric nanoparticles, known as ultrafine particles, are unintentionally generated during deliberate activities and may contribute to air pollution [19,20].

Figure 5:Sources of nanomaterials [19].

Engineered nanomaterials

Human-designed nanomaterials, including carbon black and titanium dioxide nanoparticles, are incremental improvements over colloidal or particulate materials, with specific properties for their intended uses, prior to nanotechnology [21].

Naturally produced nanomaterials

Nanomaterials are found in various organisms, including insects, plants, animals and humans. Natural organic nanomaterials include foraminifera, viruses, wax crystals, silk and more. Inorganic nanomaterials form through crystal growth under earth’s crust, such as clays and opals. Insectal nanomaterials may be a subcategory of natural nanomaterials. Natural inorganic nanomaterials, like clays and opals, form due to complex chemical reactions in fires. Natural sources of nanoparticles comprise combustion products from forest fires, volcanic ash, ocean spray and the radioactive decay of radon gas. Natural nanomaterials can form through the weathering of rocks containing metals or anions and also at locations impacted by acid mine drainage [22].

Advantages of nanomaterials

The nanomaterials’ electrical, magnetic, optical and mechanical properties have led to numerous intriguing applications. Research is ongoing to learn about these properties. The nanomaterials exhibit properties that differ from those of bulk-sized models. The following are some benefits of the nanomaterials:
A. At high temperatures, nanophase ceramics exhibit greater ductility than coarse-grained ceramics.
B. The nanosized metallic powders exhibit a high coldwelding property and ductility, making them highly useful for metal-metal bonding.
C. Solo magnetic particles at the nanoscale exhibit super paramagnetic properties.
D. Nanostructured metal clusters made up of a single metal serve as precursors for heterogeneous catalysts.
E. Nanocrystalline silicon films create a contact that is highly transparent for solar cells.
F. Porous films of nanostructured titanium oxide provide high transmission and enhancement due to their high surface area.
G. The microelectronic industry’s challenges in circuit miniaturization, including inadequate heat dissipation from high-speed microprocessors and low reliability, can be addressed with nanocrystalline materials. These offer excellent thermal conductivity, great durability and long-lasting interconnections.

Disadvantages

Some of disadvantages are as follows:
a) Instability of then a no materials.
b) Poor corrosion resistance.
c) High solubility.
d) When the nanomaterials with the high surface area come in direct contact with oxygen exothermic combustion takes place leading to an explosion.
e) Impurity.
f) Nanomaterials are considered to be biologically harmful.
These have high toxicity which can lead to irritations.
g) Carcinogenic.
h) Difficult to synthesize.
i) No safe disposal available [23].

Toxicology of nanomaterials

Nanotoxicology examines the harmful effects of nanomaterials, focusing on their unique characteristics and potential dangers. Inhalation exposure, skin contact and ingestion are the most concerning. It evaluates the toxicological characteristics of nanoparticles to determine their environmental and societal threats. Nanomaterials have various applications but can also be toxic [24].

Properties that affect toxicity

Size is a key factor in assessing particle toxicity, but other factors like chemical composition, morphology, surface architecture, surface charge, aggregation state, solubility and functional groups also affect toxicity, making generalizations challenging [25].

Metal-based

Metal-based Nanoparticles (NPs) are used in biomedicine for drug delivery systems, but recent advancements in nanotechnology have led to studies evaluating their environmental impact. Researchers have found that certain metal and metal oxide nanoparticles can cause DNA damage, mutations, reduced cell viability, apoptosis, necrosis and reduced proliferation [26].

Carbon-based

As of 2013, the most recent toxicology studies on mice involving Carbon Nanotube (CNT) exposure indicated that MWCNT has a limited pulmonary inflammatory potential at levels that correspond to the average inhalable elemental carbon concentrations found in CNT facilities in the US. According to the study, considerable years of exposure are required for significant pathology to develop [27].

Other

Other classes of nanomaterials include polymers such as nanocellulose and dendrimers.

Size

The size of a nanoparticle can influence its toxicity in various ways. As an illustration, lung deposition and clearance rates vary for particles of differing sizes. The particles’ reactivity and the exact mechanism of their toxicity can also be influenced by size [28].

Dispersion state

Agglomeration or aggregate of nanoparticles in environmental or biological fluids is a common phenomenon, with ISO and ASTM defining it differently. Agglomeration affects nanotoxicity due to its impact on size, surface area and sedimentation characteristics. Mechanical stability of airborne engineered nanoparticle clusters also influences size distribution. Different aerosolization and deagglomeration systems test nanoparticle agglomerates’ stability [29].

Surface chemistry and charge

In their application, nanomaterials are coated and can be assigned positive or negative charges based on their intended purpose. Research has shown that these external elements influence how toxic nanomaterials can be [30].

Respiratory

Nanoparticles in the workplace are primarily inhaled, with their size and shape influencing their deposition in the lungs. Animal studies suggest they can enter the bloodstream and migrate to other organs, including the brain. The risk of inhalation is influenced by the dustiness of the material and its likelihood of being lifted into the air. Carbon nanotubes and carbon nanofibers can cause pulmonary effects like inflammation, granulomas and pulmonary fibrosis. Pulmonary exposure can lead to genotoxic or carcinogenic effects, as well as systemic cardiovascular effects. As of 2013, there were no reported adverse health effects in workers using or producing these nanomaterials [31].

Dermal

Studies suggest that nanomaterials can penetrate the body through unbroken skin during occupational exposure. Particles with diameters less than 1μm can infiltrate mechanically flexed skin and pigs’ skin. Factors like dimensions, morphology, water solubility and surface treatment affect nanoparticle penetration. Current research shows dermal irritation in mice and pro-inflammatory cytokines in human skin cells [32].

Gastrointestinal

Materials can be ingested through inadvertent transfer from hand to mouth. This has been observed with conventional materials and it is a scientifically valid assumption that it could also occur when handling nanomaterials. Particles that are removed from the respiratory tract by the mucociliary escalator can be ingested, which means that ingestion may occur alongside inhalation exposure [33].

Bio-distribution

Nanomaterials, due to their small size, can easily penetrate the human body, but their behavior depends on size, shape and surface reaction. Overwhelming phagocytes could cause inflammation and reduce resistance to pathogens. Nanoparticles can also disrupt biological processes, as they adsorb macromolecules upon contact with tissues and fluids. They can enter the bloodstream through inhalation or ingestion and can be absorbed by various organs and tissues. The composition and concentration of nanomaterials can determine their toxicity, leading to oxidative stress, inflammatory cytokines and cell death [34].

Regulatory framework in India

A nano pharmaceutical is characterized as a pharmaceutical formulation that includes nanomaterials and is designed for internal or external use on the body to provide therapeutic effects, diagnostic purposes or any health benefits. It contains materials measuring between 1 and 100nm in at least one dimension. Furthermore, if the particle size exceeds 100nm, it will still fall within the definition as long as it possesses altered or different pharmaceutical characteristics in relation to the application of nanotechnology compared to those of the API [35]. The “Guidelines for Evaluation of Nanopharmaceuticals in India” categorizes nanopharmaceuticals based on biodegradability, nature, ingredient nanoforms and approval status. It also provides information on toxicological and clinical trial data. The guidelines apply to new drug approvals and clinical trials. Due to the complexities of nanotechnology, a specialized approach is required. The ministry of health regulates nanotechnology applications through its directorate general of health services, overseeing the Central Drugs Standard Control Organization (CDSCO) [36].

Regulatory framework in USA

The FDA has faced numerous risks and uncertainties linked to emerging technologies and nanotechnology is no exception. FDA monitors the fruiting science with robust research agenda in order to help assess the safety and effectiveness of products using nanotechnology [37]. The FDA uses a product-focused regulatory policy based on science and emerging technology, utilizing legal standards for different product categories. It plans to oversee nanotechnology products using current legal authorities, based on specific criteria. The FDA has not established regulatory definitions for terms like “nanotechnology,” “nanomaterial” or “nanoscale” which refer to the engineering of materials with dimensions between 1 and 100 nanometers. Nanotechnology is defined by the National Nanotechnology Initiative Program [34]. To check if FDAregulated product involves the application of nanotechnology, FDA will ask:
A. Whether a material or final product is designed to have at least one external dimension or an internal or surface structure, within the nanoscale range (approximately 1nm to 100nm).
B. Whether a material or final product is designed to display characteristics or phenomena-such as physical or chemical properties or biological effects-that can be linked to its dimensions, even if these dimensions are not within the nanoscale range but extend up to one micrometer (1,000nm) [36].

The USFDA has developed guidance focused on human drug products, including biological products, that contain nanomaterials in their finished dosage form. This guidance addresses Critical Quality Attributes (CQAs), manufacturing processes, stability, Good Manufacturing Practices (GMP), post-marketing controls, clinical and non-clinical developments and potential risks related to their use [19]. The USFDA recommends a risk-based strategy for drug product development containing nanomaterials, emphasizing risk factors. The CQA examines nanomaterials’ chemical composition, particle size, distribution, shape and stability. Standardized methods are being developed for nanomaterial characterization. Manufacturing process and in-process controls must consider nanomaterials in the manufacturing process. For manufacturing process and in-process controls, products containing nanomaterials must be manufactured with reference to:
a) cGMP in section 501(a)(2)(B) of FD&C Act.
b) cGMP regulations in CFR parts 210, 211 and 212.

The clinical development of drug products containing nanomaterials shall follow all policies and guidance with respect to clinical safety and efficacy studies pertaining to the development of IND, NDA, ANDA and BLA submissions [38].

United States

A. The ASTM committee manages the coordination of ASTM standardization and encompasses guidance and standards for nanomaterials in nanotechnology.
B. USFDA oversees a diverse array of products, including drugs, food, cosmetics, etc., that employ nanotechnology [39]. For all the products, they have guidelines. The size of nanomaterials can influence their physicochemical properties. The properties of the same component may differ for their size. Guidelines are provided for its physicochemical properties, biological characteristics and the use of those products.

The FDA activities are:
a) The guidance provided by CDER for nanoparticle development encompasses risk and quality assessments of nanoproducts, along with standards for their identification, physicochemical properties, evaluation and use.
b) To create a regulation that can adapt to changing circumstances.
c) To promote collaboration and alliances with stakeholders.
d) To enhance the knowledge base of regulatory science.
e) To create a product-centric and scientifically grounded method for governing nanomaterials [40,41].

The US Environmental Protection Agency (EPA) was established in 2017 to oversee the health and safety of nanoscale materials, aiming to regulate them as a single class and incorporate this into risk-based principles. A rule was issued in January 2017 mandating one-time reporting and recordkeeping of exposure and health information for nano-sized chemicals [42,43]. This includes,
A. Production volume.
B. Manufacturing method.
C. Processing, uses, exposure and release information.
D. Health and safety data.

Regulatory framework in Europe

Several EU legislative and technical guidance documents have been drafted by the European Commission, containing precise references to nanomaterials [44]. The term ‘nanomaterial’ refers to a natural, incidental or manufactured material that contains particles-either in an unbound state, as aggregates or as agglomerates-and for which 50% or more of the particles in the number size distribution have one or more external dimensions within the range of 1nm to 100nm. Fullerenes, graphene flakes and single-wall carbon nanotubes with one or more external dimensions below 1nm shall be classified as nanomaterials, as defined in the reference [45].

ECHA (European Chemical Agency)

ECHA collaborates with member state competent authorities, the European Commission, stakeholders and international organizations such as the Organization for Economic Cooperation and Development (OECD) [46]. REACH and CLP encompass nanomaterials, involving tasks in various REACH processes (such as registration, evaluation, authorization and restrictions) and CLP processes (including Classification and Labeling) for nanoforms [47].

China

China’s CFDA governs nanomaterial regulations, including nano pharmaceutical production, approval and inspection processes for drugs and medical devices. The CFDA is divided into two areas: Registration and tracking. Medical devices are classified into Class I, Class II and Class III, with Class I being straightforward and Class III being intricate implants. Drugs are categorized into chemical, biological and traditional Chinese medicine or natural drugs according to China’s pharmaceutical classification system [48].

South Korea

South Korea’s drug and medical device approval process is overseen by the Ministry of Food and Drug Safety (MFDS), which also manages pharmaceutical registration and distribution. The Ministry of Health and Welfare (MOHW) makes decisions on coverage, coding and pricing. The Medical Device Act (MDA) governs current regulations, classifying medical devices into four categories based on risk: Class I, Class II, Class III and Class IV [49].

Brazil

ANVISA, the National Health Surveillance Agency, was set up as a financially autonomous entity in Brazil on January 26, 1999. It is associated with the Ministry of Health and overseen by a board of directors composed of multiple members. This agency is tasked with approving food, pharmaceuticals, health services, medical devices and more. ANVISA serves as the overarching authority for medical devices technology, overseeing the guidelines related to medical devices during their development and in the context of drug approval [50,51]. The manufacturer can start their application process before obtaining the GMP certificate and with this, Brazil began the reconstruction and enhancement of its regulatory system.

United Kingdom

For all pharmaceutical companies using nanomaterials, the MHRA oversees the legislation and regulations. It has established standard operating procedures regarding safety, quality and performance [52]. All novel drugs that are newly created receive legislative approval under the MHRA for “first-in-man” studies and review information is recorded through post-market surveillance. Procedures that have received less attention are not governed by any legislative regulations [53-55].

To sum up, despite the promising applications of nanomaterials in diverse areas, their distinctive characteristics can lead to serious health hazards-especially via inhalation and skin contact-which makes it essential to establish strict regulations to guarantee safe usage. To completely comprehend their toxicological effects and to create efficient protective strategies for workers and consumers, it is essential to conduct ongoing research and thorough evaluations.

Author expresses his sincere thanks to all authors for their valuable contribution to carry out this review work.

The authors declare that they have no conflict of interest.

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