Guidance for Industry 
Considering Whether an FDA-Regulated Product Involves 
the Application of Nanotechnology 
 
 
Contains Nonbinding Recommendations 
 
June, 2014 
 
Additional copies are available from: 
Office of Policy 
Office of the Commissioner 
Food and Drug Administration 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
Phone: 301-796-4830 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm 
 
You may submit electronic or written comments regarding this guidance at any time.  Submit 
written comments on the guidance to the Division of Dockets Management (HFA-305), Food 
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  Submit 
electronic comments to http://www.regulations.gov.  All comments should be identified with the 
docket number (FDA-2010-D-0530) listed in the notice of availability that publishes in the 
Federal Register. 
 
 
For questions regarding this document contact: Office of the Commissioner, Food and Drug 
Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, 301-796-4830. 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of the Commissioner 
 
June 2014 
 
1 
  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION AND SCOPE 
 
II.  DISCUSSION 
 
A.  Points to Consider 
 
B.  Rationale for Elements within the Points to Consider 
 
1.  Material or end product that is engineered to have certain dimensions or 
exhibit certain properties (in Points 1 and 2) 
 
2.  Material or end product (in Points 1 and 2) 
 
3.  At least one external dimension, or an internal or surface structure, in the 
nanoscale range (approximately 1 nm to 100 nm) (in Point 1) 
 
4.  Properties or phenomena attributable to dimension(s) (in Point 2) 
 
5.  Dimension(s) of up to one micrometer (1,000 nm) (in Point 2) 
 
III.  CONCLUSION 
 
IV.  REFERENCES  
 
 
2 
  Contains Nonbinding Recommendations 
 
Guidance for Industry 
Considering Whether an FDA-Regulated Product Involves 
1
the Application of Nanotechnology  
 
 
This guidance represents the Food and Drug Administrations (FDAs or the Agencys) current thinking 
on this topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of the 
applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff 
responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call the 
telephone number listed on the title page of this guidance.  
 
 
 
I.  INTRODUCTION AND SCOPE 
 
Nanotechnology is an emerging technology that can be used in a broad array of FDA-regulated 
products, including medical products (e.g. to increase bioavailability of a drug), foods (e.g., to 
improve food packaging) and cosmetics (e.g. to affect the look and feel of cosmetics).  Materials 
in the nanoscale range (i.e., with at least one dimension in the size range of approximately 1 
nanometer (nm) to 100 nm) can exhibit different chemical or physical properties, or biological 
effects compared to larger-scale counterparts.  For example, dimension-dependent properties or 
phenomena may be used for functional effects such as increased bioavailability, decreased 
dosage, or increased potency of a drug product, decreased toxicity of a drug product, better 
detection of pathogens, more protective food packaging materials, or improved delivery of a 
functional ingredient or a nutrient in food (Refs. 1-6).  These effects may derive from altered 
chemical, biological, or magnetic properties, altered electrical or optical activity, increased 
structural integrity, or other unique characteristics of materials in the nanoscale range not 
normally observed or expected in larger-scale materials with the same chemical composition 
(Ref. 7).  Materials or end products may also exhibit similar properties or phenomena attributable 
to a dimension(s) outside the nanoscale range of approximately 1 nm to 100 nm (Refs. 27-30; see 
also discussion in Section II.B.5).  
 
For the purpose of this guidance only, references to products that involve the application of 
nanotechnology or nanotechnology products mean products that contain or are manufactured 
using materials in the nanoscale range, as well as products that contain or are manufactured using 
certain materials that otherwise exhibit related dimension-dependent properties or phenomena.  
Likewise, we use the term nanomaterial generally to refer to both materials in the nanoscale 
                                                 
1 This guidance finalizes the draft guidance, entitled Draft Guidance for Industry: Considering Whether an FDA-
Regulated Product Involves the Application of Nanotechnology, which was issued in June, 2011.  This guidance 
was prepared by FDAs Office of Policy in the Office of the Commissioner, in consultation with FDAs Center for 
Biologics Evaluation and Research, Center for Drugs Evaluation and Research, Center for Devices and Radiological 
Health, Center for Food Safety and Applied Nutrition, Center for Tobacco Products, Center for Veterinary 
Medicine, National Center for Toxicological Research, Office of the Chief Scientist, Office of Foods and Veterinary 
Medicine, Office of Regulatory Affairs, Office of Special Medical Programs, and Nanotechnology Task Force.  
3 
  Contains Nonbinding Recommendations 
 
range and certain materials that otherwise exhibit related dimension-dependent properties or 
phenomena.  Use of these terms is for the purpose of communicating FDAs current thinking 
elaborated in this document only. 
 
As used in this guidance, the word products (or FDA-regulated products) is meant to include 
products, materials, ingredients, and other substances regulated by FDA, including drugs, 
biological products, medical devices, food substances (including food for animals), dietary 
supplements, cosmetic products, and tobacco products.2   
 
The guidance describes FDAs current thinking on determining whether FDA-regulated products 
involve the application of nanotechnology.  This guidance is intended for manufacturers, 
suppliers, importers, and other stakeholders.  (For convenience, the guidance will refer to these 
parties as industry.)  FDAs guidance documents, including this guidance, do not establish 
legally enforceable responsibilities.  Instead, guidance documents describe FDAs current 
thinking on a topic and should be viewed only as recommendations, unless specific regulatory or 
statutory requirements are cited.  The use of the word should in Agency guidance documents 
means that something is suggested or recommended, but not required.  
 
The application of nanotechnology may result in product attributes that differ from those of 
conventionally-manufactured products, and thus may merit particular examination.  However, 
FDA (or we) does not categorically judge all products that involve the application of 
nanotechnology as intrinsically benign or harmful.  FDA will regulate nanotechnology products 
under existing statutory authorities, in accordance with the specific legal standards applicable to 
each type of product under its jurisdiction.  We consider the current framework for safety 
assessment sufficiently robust and flexible to be appropriate for a variety of materials, including 
nanomaterials.  FDA maintains a product-focused, science-based regulatory policy.  Technical 
assessments will be product-specific, taking into account the effects of nanomaterials in the 
particular biological and mechanical context of each product and its intended use.  As such, the 
particular policies for each product area, both substantive and procedural, will vary according to 
the statutory authorities and relevant regulatory frameworks (Ref. 8).  We believe that this 
regulatory policy allows for tailored approaches that adhere to applicable legal frameworks and 
reflect the characteristics of specific products or product classes and evolving technology and 
scientific understanding.   
  
This guidance provides an overarching framework for FDAs approach to the regulation of 
nanotechnology products.  It identifies two points to consider when determining whether the 
FDA-regulated product involves the application of nanotechnology.  An affirmative finding to 
either of the Points to Consider, elaborated in section II below, might suggest the need for 
particular attention by the Agency and/or industry to the product to identify and address potential 
implications for safety, effectiveness, public health impact, or regulatory status of the product. 
 
This guidance does not address, or presuppose, what ultimate regulatory outcome, if any, will 
result in a particular case where the use of these points may indicate that an FDA-regulated 
product involves the application of nanotechnology.  Issues such as the safety, effectiveness, 
                                                 
2 Nanotechnology may also be applied to combination products (as defined at 21 CFR 3.2(e)). 
4 
  Contains Nonbinding Recommendations 
 
public health impact, or the regulatory status of nanotechnology products are currently addressed 
on a case-by-case basis using FDAs existing review processes.3   
 
This guidance also does not establish regulatory definitions.  Rather, it is intended to help 
industry and others identify when they should consider potential implications for regulatory 
status, safety, effectiveness, or public health impact that may arise with the application of 
nanotechnology in FDA-regulated products.  We advise industry to consult with FDA early in 
the development process to facilitate a mutual understanding of the specific scientific and 
regulatory issues for their nanotechnology products. 
 
FDA will provide further guidance to industry, as needed, to address the application of 
nanotechnology as applicable to specific FDA-regulated products or classes of products (such as 
human foods, drugs, or cosmetics), consistent with existing federal policies (Refs. 9, 10).  As 
appropriate, FDAs product-specific guidance documents will address issues such as the 
regulatory status, safety, effectiveness, performance, quality, or public health impact of 
nanotechnology products.4   
 
 
II.  DISCUSSION 
 
FDA has not established regulatory definitions of nanotechnology, nanomaterial, 
nanoscale, or other related terms.  These terms are commonly used in relation to the 
engineering (i.e., deliberate manipulation, manufacture or selection) of materials that have at 
least one dimension in the size range of approximately 1 nanometers (nm) to 100 nm.  For 
example, the National Nanotechnology Initiative Program defines nanotechnology as the 
understanding and control of matter at dimensions between approximately 1 and 100 
nanometers, where unique phenomena enable novel applications (Ref. 11).  Various published 
definitions mention other factors such as function, shape, charge, the ratio of surface area to 
volume, or other physical or chemical properties.     
 
Based on our current scientific and technical understanding of nanomaterials and their 
characteristics, FDA believes that evaluations of safety, effectiveness, public health impact, or 
regulatory status of nanotechnology products should consider any unique properties and 
behaviors that the application of nanotechnology may impart.  This guidance identifies two 
Points to Consider that should be used to evaluate whether FDA-regulated products involve the 
application of nanotechnology.  These points address both particle dimensions and dimension-
dependent properties or phenomena.  Product-specific premarket review, when required, offers 
an opportunity for FDA to apply these points and, where products are not subject to premarket 
review, industry should consider these points.  If either point applies to a given product, industry 
                                                 
3 It bears noting that the application of nanotechnology may also affect the classification of a product. For example, 
nanomaterials used in medical products may function through different modes of action than larger-scale materials 
with the same chemical composition, which may affect the classification of the product, for example as a drug or 
device. 
4 FDAs guidance documents relevant to nanotechnology, including product-specific guidance documents that focus 
on nanotechnology applications in specific product sectors, can be found at: 
http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/default.htm    
5 
  Contains Nonbinding Recommendations 
 
and FDA should consider whether the evaluations of safety, effectiveness, public health impact, 
or regulatory status of that product have identified and adequately addressed any unique 
properties or behaviors of the product.    
 
These two Points to Consider are intended to provide an initial screening tool that can be broadly 
applied to all FDA-regulated products, with the understanding that these points are subject to 
change in the future as new information becomes available.  In particular, FDA may further 
refine these points, either as applicable broadly to all FDA-regulated products or as applicable to 
particular products or classes of products, as justified by scientific information.  This may 
include refining particle size parameters or introducing additional parameters such as those 
related to particle size distribution or specific properties.5  We will consider future revisions to 
our approach, including developing regulatory definitions relevant to nanotechnology, as 
warranted and in keeping with evolving scientific understanding.  As previously indicated, FDA 
also may provide additional guidance, including product-specific guidance documents, to address 
issues such as the regulatory status, safety, effectiveness, performance, quality, or public health 
impact of nanotechnology products. 
 
A.  Points to Consider 
 
At this time, when considering whether an FDA-regulated product involves the application of 
nanotechnology, FDA will ask:  
 
1.  Whether a material or end product is engineered to have at least one external dimension, or 
an internal or surface structure, in the nanoscale range (approximately 1 nm to 100 nm); 
 
In addition, as we explain in more detail below, because materials or end products can also 
exhibit related properties or phenomena attributable to a dimension(s) outside the nanoscale 
range of approximately 1 nm to 100 nm that are relevant to evaluations of safety, effectiveness, 
performance, quality, public health impact, or regulatory status of products, we will also ask: 
 
2.  Whether a material or end product is engineered to exhibit properties or phenomena, 
including physical or chemical properties or biological effects, that are attributable to its 
dimension(s), even if these dimensions fall outside the nanoscale range, up to one 
micrometer (1,000 nm).6   
 
                                                 
5 At this time, we do not have an adequate basis on which to determine a particle number threshold or a list of 
unique or novel properties that are applicable across the range of FDA-regulated products.  In addition, 
challenges related to measurement methods and biological effects add further complexity to recommending use of 
particle number, weight, or surface area as the most appropriate units of measure.  FDA intends to actively follow 
scientific developments on this issue and provide additional guidance, as appropriate.  
6 As explained in section II.B.5. below, the use of 1,000 nm as a reference point should not be interpreted to mean 
that materials or products with dimensions above 1,000 nm cannot exhibit dimension-dependent properties or 
phenomena of importance to safety, effectiveness, public health impact, or regulatory status of the material or 
product.  See further discussion on this issue in section II.B.5. below. 
6 
  Contains Nonbinding Recommendations 
 
These considerations apply not only to new products, but also when changes to manufacturing 
processes alter the dimensions, properties, or effects of an FDA-regulated product or any of its 
constituent parts.7   
 
B.  Rationale for Elements within the Points to Consider  
 
1.  Material or end product that is engineered to have certain dimensions or exhibit 
certain properties (in Points 1 and 2) 
 
The term engineered, used in both Points 1 and 2, is used to distinguish products that have 
been deliberately manipulated by the application of nanotechnology from those products that 
contain materials that naturally occur in the nanoscale range.  FDA is particularly interested in 
the deliberate and purposeful manipulation and control of dimensions to produce specific 
properties, because the emergence of these new properties or phenomena may raise questions 
about the safety, effectiveness, performance, quality or public health impact that may warrant 
further evaluation.  FDAs interest in materials or products engineered to have nanoscale 
dimensions or related dimension-dependent properties or phenomena is distinct from the more 
familiar use of biological or chemical substances that may naturally exist at small scales, 
including at the nanoscale, such as microorganisms or proteins.   
 
The term engineered is also used to distinguish products that have been deliberately 
manipulated by the application of nanotechnology from products that may unintentionally 
include materials in the nanoscale range.   
For example, the incidental presence of particles in the nanoscale range in conventionally-
manufactured products8 is not covered under the scope of this guidance.9 
 
2.  Material or end product (in Points 1 and 2) 
 
The phrase material or end product, referred to in both Points 1 and 2, is used to cover 
different types of articles that are regulated by FDA, such as products, materials, ingredients, and 
other substances regulated by FDA.  This includes finished products (e.g., a drug tablet for 
administration to a patient) as well as materials that are intended for use in a finished product 
(e.g., a food additive added to a food during processing).  In determining whether a material or 
end product satisfies either Point 1 or Point 2, FDA will examine the material or end product, 
and may also consider the constituent parts of the material or end product.  Therefore, relevant 
considerations include whether a material or end product contains or involves in its manufacture 
the use of materials that meet either Point 1 or Point 2.  
 
                                                 
7 These Points to Consider are not intended to apply to products that have been previously reviewed or approved by 
FDA and where no changes are made to manufacturing processes that would alter the dimensions, properties or 
effects of the product or its constituent parts. 
8 For example, small amounts of particles in the nanoscale range have been reported to be present in foods 
manufactured using conventional food manufacturing practices (Ref. 12).  
9 However, evaluations of conventionally-manufactured products may include a consideration of the effects, if any, 
of such incidental presence of particles in the nanoscale range on the safety, effectiveness, or public health impact of 
a product.  
7 
  Contains Nonbinding Recommendations 
 
3.   At least one external dimension, or an internal or surface structure, in the 
nanoscale range (approximately 1 nm to 100 nm) (in Point 1) 
 
A size range of approximately 1 nm to 100 nm is commonly used in various working definitions 
or descriptions regarding nanotechnology proposed by the regulatory and scientific 
community.10  In this size range, materials can exhibit new or altered physicochemical properties 
that can enable novel applications (Refs. 11, 13-15).  Accordingly, per Point 1, if a material or 
end product is engineered to have at least one external dimension in the range of 1 nm to 100 nm, 
or is engineered to have an internal or surface structure in the range of 1 nm to 100 nm, industry 
and FDA should consider any unique characteristics or biological effects exhibited by the 
product that may influence its safety, effectiveness, public health impact, or regulatory status.  
Primary particles engineered with at least one external dimension within the nanoscale range are 
covered in Point 1.  This Point also covers any aggregates or agglomerates formed by such 
nanoscale primary particles.  In addition, coated, functionalized, or hierarchically-assembled 
engineered structures that include internal or surface discrete and functional nanoscale entities, 
such as where such entities are embedded or attached to the surface, are encompassed within 
Point 1.11  Such engineered structures with discrete and functional nanoscale entities embedded 
or attached to the surface may have altered properties or phenomena that may affect product 
safety or effectiveness (Ref. 16).  The inclusion of particles, objects, or structures with internal, 
surface, or external dimension(s) in the nanoscale range is consistent with approaches taken by 
other scientific and regulatory bodies (Refs. 17-23).  
 
4.  Properties or phenomena attributable to dimension(s) (in Point 2) 
 
While size alone, for very small particles, is suggestive of the presence of properties meriting 
further examination, the identification and assessment of specific dimension-dependent 
properties and phenomena are ultimately more relevant for purposes of FDA regulatory review 
and oversight.  Point 2, therefore, focuses on the properties of the material and its behavior in 
biological systems.12  The phrase exhibits properties or phenomena . . . that are attributable to 
its dimension(s), is used because properties and phenomena of materials in the nanoscale range 
enable applications that can affect the safety, effectiveness, performance, quality, public health 
impact, or regulatory status of FDA-regulated products.  For example, as noted above, 
dimension-dependent properties or phenomena may be used for various functional effects such 
as increased bioavailability or decreased toxicity of drug products, better detection of pathogens, 
                                                 
10 For example, a size range of approximately 1 nm to 100 nm is used in definitions, working definitions, or 
descriptions published by the National Nanotechnology Initiative (Ref. 11); Environmental Protection Agency 
(http://www.epa.gov/pesticides/regulating/nanotechnology.html); European Commission (Ref. 17); Health Canada 
(Ref. 19); International Standards Organization (Ref. 20); Organization for Economic Cooperation and 
Developments Working Party on Nanotechnology and Working Party on Manufactured Nanomaterials 
(http://www.oecd.org/sti/nano/); National Cancer Institute (http://www.cancer.gov/dictionary?cdrid=445071); and 
American National Standards Institute (http://nanostandards.ansi.org/tiki-index.php). 
11 This is not intended to include any incidental presence of internal or surface features with dimensions in the 
nanoscale range that may be present in conventionally-manufactured substances (for example, internal porosity, 
surface roughness or surface defects).   
12 Consistent with Policy Principles for the U.S. Decision-Making Concerning Regulation and Oversight of 
Applications of Nanotechnology and Nanomaterials, Office of Science and Technology Policy, Office of 
Management and Budget, and Office of the United States Trade Representative, June 9, 2011 (Ref. 10).  
8 
  Contains Nonbinding Recommendations 
 
improved food packaging materials, or improved delivery of nutrients.  These effects may derive 
from altered or unique characteristics of materials in the nanoscale range that are not normally 
observed or expected in larger-scale materials with the same chemical composition (Ref. 7).  
However, such changes may raise questions about the safety, effectiveness, performance, quality 
or public health impact of nanotechnology products.  In addition, considerations such as routes of 
exposure, dosage, and behavior in various biological systems (including specific tissues and 
organs) (Refs. 13, 24) are critical for evaluating the safety, effectiveness, public health impact, or 
regulatory status of a wide array of products under FDAs jurisdiction. Such evaluations should 
include a consideration of the specific tests (whether traditional, modified, or new) that may be 
needed (Refs. 25, 26) to determine the physicochemical properties and biological effects of a 
product that involves the application of nanotechnology.  
 
5.  Dimension(s) of up to one micrometer (1,000 nm) (in Point 2) 
 
Materials or end products can also exhibit properties or phenomena attributable to a dimension(s) 
outside the nanoscale range of approximately 1 nm to 100 nm.  Physical and chemical properties 
and biological behavior that are relevant to evaluations of safety, effectiveness, performance, 
quality, public health impact, or regulatory status of products have been observed at dimensions 
outside the nanoscale range of approximately 1 nm to 100 nm (Refs. 27-30).  Therefore, Point 2 
focuses on the importance of considering properties or phenomena attributable to dimensions, 
even where such dimensions may be outside the nanoscale range of approximately 1 nm to 100 
nm.  FDAs consideration of materials with dimension(s) outside the nanoscale range of 
approximately 1 nm to 100 nm is consistent with approaches taken by other scientific and 
regulatory organizations.13   
                                                 
13 For example, the Joint Research Centre and the Scientific Committee on Emerging and Newly Identified Health 
Risks of the European Commission concluded: In order to base a nanomaterials definition for regulatory purposes 
on size alone, the upper nanoscale limit should ideally be high enough to capture all types of materials that would 
need particular attention for regulation due to their nanoscale size. Upper limits which are often used in existing 
definitions, for example 100 nm, may require the introduction of one or more qualifiers based on structural features 
or properties other than size, in order to capture structures of concern (for example agglomerates or aggregates) with 
a size larger than 100 nm in the regulation (Ref. 22); The upper size limit for one or more external dimensions of 
100 nm is complicated by the potential exclusion of aggregates, agglomerates and multicomponent assemblies that 
would have external sizes greater than this (Ref. 23); and An upper limit of 100 nm is commonly used by general 
consensus but there is no scientific evidence to support the appropriateness of this value (Stated as SCENIHR 
conclusions in the European Commission Recommendation on the definition of nanomaterial, Ref. 17).  The 
European Commission further noted that it may be necessary to include additional materials, such as some 
materials with a size . . . greater than 100 nm in the scope of application of specific legislation or legislative 
provisions suited for a nanomaterial (Ref. 17). In addition, the International Organization for Standardization (ISO) 
acknowledged that health and safety considerations associated with intentionally produced and incidental nano-
objects do not abruptly end at dimensions of 100 nm. As knowledge expands, it is abundantly clear that a robust 
terminology will need to capture and convey effectively the performance aspects of intentionally produced nano-
objects and nanostructured materials in their definitions, apart from their fundamental size and shape (Ref. 20).  
More recently, Health Canada adopted a working definition of nanomaterial that, in part, reflects that it is possible 
for nanoscale properties/ phenomena to be exhibited outside the 1 nm to 100 nm size range, such as select quantum 
devices (Ref. 19). Finally, in its second regulatory review on nanomaterials, the European Commission noted that 
fullerenes, graphene flakes and single wall carbon nanotubes with one or more external dimensions below 1 nm 
should be considered as nanomaterials. Several types of nanomaterials were identified as not matching the EU 
definition, with an acknowledgment that there are an increasing number of particles which are engineered to have 
internal nanoscale features. Examples are core-shell particles and nano-encapsulates. These particles may be 
designed, for example for pharmaceutical applications, where the inner core particle is released in a certain 
9 
  Contains Nonbinding Recommendations 
 
 
At the present time, available scientific information does not establish a uniform upper boundary 
above 100 nm where novel properties and phenomena similar to those seen in materials with 
dimensions in the nanoscale range cease for all potential materials or end products.  For this 
reason, at this time, FDA finds it reasonable to consider evaluation of materials or end products 
engineered to exhibit properties or phenomena attributable to dimensions up to 1,000 nm, as a 
means to screen materials for further examination and to determine whether these materials 
exhibit properties or phenomena attributable to their dimension(s) and associated with the 
application of nanotechnology.14  An upper limit of one micrometer (1,000 nm) applied in the 
context of properties or phenomena attributable to dimensions serves both to: (1) include 
materials with dimension(s) outside the nanoscale range of approximately 1 nm to 100 nm that 
may exhibit dimension-dependent properties or phenomena associated with the application of 
nanotechnology and distinct from those of macro-scaled materials; and (2) exclude macro-scaled 
materials that may have properties attributable to their dimension(s) but are not likely associated 
with the application of nanotechnology.   
 
An upper limit of 1,000 nm, combined with the presence of dimension-dependent properties or 
phenomena similar to those seen in materials with dimensions in the nanoscale range, provides 
an initial screening tool to help identify materials or products with properties or phenomena of 
particular relevance for regulatory review.  The use of 1,000 nm as a reference point in this 
context should not be interpreted to mean that materials or products with dimensions above 
1,000 nm cannot exhibit dimension-dependent properties or phenomena of importance to safety, 
effectiveness, public health impact, or regulatory status of the material or product.  As noted 
above, we may further refine these Points to Consider, including this upper limit, either as 
applicable broadly to FDA-regulated products or as applicable to specific products or product 
categories.  
 
 
III.  CONCLUSION 
 
The two Points to Consider elaborated in this guidance should be applied when considering 
whether an FDA-regulated product involves the application of nanotechnology.  An affirmative 
finding to either of the Points to Consider, elaborated in this guidance, might suggest the need for 
particular attention to the product by FDA and/or industry for potential implications for safety, 
effectiveness, public health impact, or regulatory status of the product.  We will consider future 
revisions to our approach, including developing regulatory definitions relevant to 
nanotechnology, as warranted and in keeping with evolving scientific understanding.   
 
There remains a need to learn more about the potential role and importance of dimensions in the 
physical and chemical characteristics and biological effects exhibited by FDA-regulated products 
                                                                                                                                                             
environment. Some of these materials have an external diameter smaller than 100 nm, matching the EU 
nanomaterial definition, others have an external diameter larger than 100 nm, not matching the EU nanomaterial 
definition (Ref. 31).  
14 However, as noted previously, FDA will consider further refinement of these Points to Consider for particular 
products or classes of products, as scientific information becomes available, including refining particle size 
parameters.  
10 
  Contains Nonbinding Recommendations 
 
that involve the application of nanotechnology.15  Product-specific premarket review, when 
required, offers an opportunity for FDA to better understand the properties and behavior of 
products that involve the application of nanotechnology.  Where products that involve the 
application of nanotechnology are not subject to premarket review, we urge industry to consult 
with the Agency early in the product development process.  In this way, any questions about the 
products regulatory status, safety, effectiveness, or public health impact can be appropriately 
and adequately addressed.  FDA has and, as needed, will continue to provide additional guidance 
to industry in more targeted guidance documents to address these considerations. 
 
 
IV.  REFERENCES 
 
We have placed these references on display in the Division of Dockets Management, Food and 
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  You may see them at 
that location between 9 a.m. and 4 p.m., Monday through Friday.  As of June 1, 2014, FDA had 
verified the Web site addresses for the references it makes available as hyperlinks from the 
Internet copy of this guidance, but FDA is not responsible for any subsequent changes to Non- 
FDA Web site references after June 1, 2014. 
 
1.  Merisko-Liversidge EM and Liversidge GG. Drug nanoparticles: formulating poorly 
water-soluble compounds. Toxicologic Pathology, 36:43-48, 2008. 
 
2.  Paciotti GF, Myer L, Weinreich D, et al. Colloidal gold: a novel nanoparticle vector for 
tumor directed drug delivery. Drug Delivery, 11:169-183, 2004. 
 
3.  Kaittanis C, Santra S, Manuel PJ. Emerging nanotechnology-based strategies for the 
identification of microbial pathogenesis. Advanced Drug Delivery Reviews 62:408-423, 
2010. 
 
4.  Chaudhry Q, Scotter M, Blackburn J, et al. Applications and implications of 
nanotechnologies for the food sector. Food Additives and Contaminants 25:241-258, 
2008. 
 
5.  Institute of Medicine. Nanotechnology in food products: Workshop Summary. 
Washington, DC: The National Academies Press, 2009.  
 
6.  Chen L, Remondetto GE, Subirade M. Food protein-based materials as nutraceutical 
delivery systems. Trends in Food Science & Technology 17:272-283, 2006. 
 
7.  Nanotechnology. A Report of the U.S. Food and Drug Administration Nanotechnology 
Task Force, July 25, 2007; available online at: 
http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/UCM2006659.htm  
                                                 
15 FDAs nanotechnology regulatory science program aims to further enhance FDAs scientific capabilities, 
including developing necessary data and tools to identify and measure dimension-dependent properties and assess 
their potential impact on safety or effectiveness. See 
http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm273325.htm  
11 
  Contains Nonbinding Recommendations 
 
 
8.  FDAs Approach to Regulation of Nanotechnology Products; available online at: 
http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm301114.htm  
 
9.  Office of Science and Technology Policy, Office of Management and Budget, and the 
United States Trade Representative. Principles for Regulation and Oversight of Emerging 
Technologies, March 11, 2011; available online at: 
http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-agencies/Principles-for-
Regulation-and-Oversight-of-Emerging-Technologies-new.pdf 
 
10. Office of Science and Technology Policy, Office of Management and Budget, and the 
United States Trade Representative. Policy Principles for the U.S. Decision-Making 
Concerning Regulation and Oversight of Applications of Nanotechnology and 
Nanomaterials, June 9, 2011; available online at: 
http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-agencies/nanotechnology-
regulation-and-oversight-principles.pdf 
 
11. National Nanotechnology Initiative Strategic Plan, February 2014; available online at 
http://nano.gov/sites/default/files/pub_resource/2014_nni_strategic_plan.pdf  
 
12. Palashuddin M, Jaiswal A, Paul A, et al. Presence of amorphous carbon nanoparticles in 
food caramels. Scientific Reports 2(383):1-5, 2012. 
 
13. Kunzman A, Andersson B, Thurnherr T, et al. Toxicology of engineered nanomaterials: 
Focus on biocompatibility, biodistribution and biodegradation. Biochimica et Biophysica 
Acta 1810:361-373, 2011. 
 
14. Myers JD, Doane T, Burda C, and Basilion JP. Nanoparticles for imaging and treating 
brain cancer. Nanomedicine 8(1):123-143, 2013. 
 
15. Powers KW, Brown SC, Krishna VB, et al. Research Strategies for Safety Evaluation of 
Nanomaterials. Part VI. Characterization of Nanoscale Particles for Toxicological 
Evaluation. Toxicological Sciences 90: 296303, 2006. 
 
16. Small is Different: A Science Perspective on the Regulatory Challenges of the Nanoscale. 
Report of the Expert Panel on Nanotechnology. The Council of Canadian Academies, 
September, 2008; available online at: 
http://www.scienceadvice.ca/en/assessments/completed/nanotechnology.aspx. 
 
17. European Commission Recommendation on the definition of nanomaterial, October, 
2011; available online at: 
http://ec.europa.eu/environment/chemicals/nanotech/pdf/commission_recommendation.p
df 
 
18. Communication from the Commission to the European Parliament, the Council and the 
European Economic and Social Committee, Second Regulatory Review on 
12 
  Contains Nonbinding Recommendations 
 
Nanomaterials, October 2012; available online at: 
http://ec.europa.eu/nanotechnology/pdf/second_regulatory_review_on_nanomaterials_-
_com(2012)_572.pdf  
 
19. Policy Statement on Health Canadas Working Definition for Nanomaterial, 2011; 
available online at: http://www.hc-sc.gc.ca/sr-sr/pubs/nano/pol-eng.php 
 
20. International Organization for Standardization/Technical Specification, 
Nanotechnologies-Vocabulary-Part 1: Core terms, 2010 (ISO/TS 80004-1:2010). 
 
21. Australias National Industrial Chemicals Notification and Assessment Schemes 
working definition of industrial nanomaterial, 2010; available online at: 
http://nanotech.lawbc.com/2010/10/articles/international/other/australia-announces-
adjustments-to-nicnas-new-chemicals-processes-for-industrial-nanomaterials/ 
 
22. Considerations on a Definition of Nanomaterial for Regulatory Purposes, Joint Research 
Centre, 2010; available online at: 
http://ec.europa.eu/dgs/jrc/downloads/jrc_reference_report_201007_nanomaterials.pdf 
 
23. Scientific Basis for the Definition of the Term Nanomaterial, Scientific Committee on 
Emerging and Newly Identified Health Risks, 2010; available online at: 
http://ec.europa.eu/health/scientific_committees/emerging/docs/scenihr_o_030.pdf  
 
24. Nel AE, Madler L, Velegol D, et al. Understanding biophysicochemical interactions at 
the nano-bio interface. Nature Materials 8:543-557, 2009.  
 
25. Khushf G and Siegel RA. What is unique about nanomedicine? The significance of the 
mesoscale. Journal of Law, Medicine, & Ethics 40(4)780-794, 2012. 
 
26. Mauer-Jones MA and Haynes CL. Toward correlation in in vivo and in vitro 
nanotoxicology studies. Journal of Law, Medicine, & Ethics 40(4)795-801, 2012. 
 
27. Etheridge ML, Campbell SA, Erdman AG, et al. The big picture on nanomedicine: the 
state of investigational and approved nanomedicine products. Nanomedicine: 
Nanotechnology, Biology, and Medicine 9:1-14, 2013. 
 
28. Almeida JPM, Chen AL, Foster A, and Drezek R. In vivo biodistribution of 
nanoparticles. Nanomedicine 6(5):815-835, 2011. 
 
29. Sonavane G, Tomoda K, and Makino K. Biodistribution of colloidal gold nanoparticles 
after intravenous administration: effect of particle size. Colloids and Surfaces B: 
Biointerfaces 66:274-280, 2008. 
 
30. Liu Z, Chen K, Davis C, et al. Drug delivery with carbon nanotubes for in vivo cancer 
treatment. Cancer Research 68(16):6652-6660, 2008. 
 
13 
  Contains Nonbinding Recommendations 
 
31. European Commission Staff Working Paper, Types and uses of nanomaterials, including 
safety aspects, October, 2012; available online at: 
http://ec.europa.eu/nanotechnology/pdf/second_regulatory_review_on_nanomaterials_-
_staff_working_paper_accompanying_com(2012)_572.pdf  
 
 
 
14