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Guidance for Industry 
Safety of Nanomaterials in Cosmetic 
Products 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
You may submit either electronic or written comments regarding this guidance at any time.   
Submit electronic comments to http://www.regulations.gov.  Submit written comments to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this document contact the Center for Food Safety and Applied 
Nutrition (CFSAN) at 240-402-1130. 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
 
 
June 2014 
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Table of Contents 
 
 
I.        Introduction  
II.      Background  
III.    Discussion 
  A.  General Framework for Assessing the Safety of Cosmetic 
Products 
 
 
  B.  Points to Consider in Assessing the Safety of Nanomaterials in 
Cosmetic Products 
1.  Nanomaterial Characterization 
a. Physicochemical Properties  
b. Impurities 
2.  Toxicology Considerations 
a. Routes of Exposure 
b. Uptake and Absorption  
c. Toxicity Testing 
 
 
C.  Summary of Recommendations 
 
 
IV.    How to Contact FDA About this Guidance 
 
 
V.      References
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1
Guidance for Industry
 
Safety of Nanomaterials in Cosmetic Products 
 
This guidance represents the Food and Drug Administration's (FDAs) 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 
 
This document provides guidance to industry and other stakeholders (e.g., academia, other 
regulatory groups) on FDAs current thinking on the safety assessment of nanomaterials in 
cosmetic products.  The guidance document is intended to assist industry and other 
stakeholders in identifying the potential safety issues of nanomaterials in cosmetic products 
and developing a framework for evaluating them.  This guidance also provides contact 
information for manufacturers and sponsors who wish to discuss safety considerations 
regarding the use of specific nanomaterials in cosmetic products with FDA.  This guidance is 
not applicable to other products regulated by FDA, including over-the-counter and 
prescription drugs and medical devices. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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 our guidances means that 
something is suggested or recommended, but not required. 
 
II.  Background 
 
Nanomaterials are used in a variety of FDA-regulated products because of their unique 
properties, imparting potential advantages to products considered for development.  Such 
materials, due to their nanoscale size, can have chemical, physical, and biological properties 
that differ from those of their larger counterparts.  Such differences may include altered 
magnetic properties, altered electrical or optical activity, increased structural integrity, or 
altered chemical or biological activity (Ref. 1).  These new or altered properties may affect 
the performance, quality, safety, and/or effectiveness, if applicable, of a product that 
incorporates that nanomaterial. 
                                                           
1  This guidance has been prepared by the Office of Cosmetics and Colors in the Center for Food Safety and 
Applied Nutrition at the U.S. Food and Drug Administration. 
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In July of 2007, FDA issued a report prepared by its Nanotechnology Task Force (Task 
Force).  The Task Force report presented an assessment of scientific and regulatory 
considerations relating to the safety and effectiveness of FDA-regulated products containing 
nanomaterials and made recommendations in light of these considerations (Ref. 2).  
Specifically, with respect to cosmetic products, the Task Force recommended that we issue 
guidance describing safety issues that manufacturers should consider to ensure that 
cosmetic products made with nanomaterials are safe and not adulterated.  We are issuing 
this guidance as part of our ongoing efforts to implement the Task Force recommendations 
(Ref. 2). 
 
The Task Force also recommended that FDA request submission of data and other 
information addressing the effects of nanomaterials in those products that are not subject to 
premarket authorization, such as cosmetic products.  On September 8, 2008, FDA held a 
public meeting to discuss such data and information, along with related scientific and 
regulatory issues concerning nanotechnology.  FDA considered the information obtained at, 
and subsequent to, the public meeting in developing this guidance.  We also considered 
information provided by the cosmetic industry to the International Cooperation on 
Cosmetics Regulations (ICCR), publications and information regarding recent advances in 
nanotechnology, and other authoritative guidance/ reports regarding the safety of 
nanomaterials (Refs. 3, 4, 5, 6).  This guidance also refers to other relevant reports, such as 
the Organization for Economic Co-operation and Development (OECD) Working Party on 
Manufactured Nanomaterials Preliminary Review of OECD Test Guidelines for their 
Applicability to Manufactured Nanomaterials (Ref. 7), the Scientific Committee on 
Consumer Safety (SCCS) Guidance on the Safety Assessment of Nanomaterials in 
Cosmetics (Ref. 8), and relevant ICCR reports, such as on the Currently Available 
Methods for Characterization of Nanomaterials, and Principles of Cosmetic Product 
Safety Assessment. (Refs. 9, 10).  
 
FDA has not established regulatory definitions of nanotechnology, nanomaterial, 
nanoscale, or other related terms.  In  June 2014, FDA issued a guidance for industry titled 
Considering Whether an FDA-Regulated Product Involves the Application of 
Nanotechnology (Ref. 1). As described in that guidance, 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); and (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). We will apply these considerations broadly to all FDA-
regulated products, including cosmetic products. 
 
The application of nanotechnology may result in product attributes that differ from those of 
conventionally-manufactured products, and thus may merit particular examination.  
However, we do not categorically judge all products containing nanomaterials or otherwise 
involving application of nanotechnology as intrinsically benign or harmful. Rather, for 
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nanotechnology-derived and conventionally-manufactured cosmetic products alike, we 
consider the characteristics of the finished product and the safety for its intended use.  Our 
consideration of nanotechnology applications in cosmetic products in this document is 
consistent with the agency guidance (Ref. 1) and with the broader federal guidance on 
regulatory oversight of emerging technologies (Ref. 11) and nanotechnology (Ref. 12). 
 
III. Discussion 
 
 
A.    General Framework for Assessing the Safety of Nanomaterials 
  in Cosmetic Products 
 
Section 301(a) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 
331(a)) prohibits the marketing of adulterated or misbranded cosmetics2 in interstate 
commerce.  The FD&C Act does not subject cosmetics or cosmetic ingredients (with the 
exception of color additives) to FDA premarket approval in order to be marketed legally in 
the United States.  Except for color additives and those ingredients that are prohibited or 
restricted from use in cosmetics by regulation, a manufacturer may use any ingredient in the 
formulation of a cosmetic provided that the use of the ingredient does not otherwise cause 
the cosmetic to be adulterated (section 601 of the FD&C Act (21 U.S.C. 361)) or 
misbranded (section 602 of the FD&C Act (21 U.S.C. 362)).3 
 
Cosmetic product manufacturers must ensure that the product is not misbranded or 
adulterated.  The FD&C Act does not give us the authority to require that safety data be 
submitted to us or to approve a cosmetic product before it is marketed.  Nevertheless, 
manufacturers or distributors are responsible for obtaining all data and information needed 
to substantiate the safety of their products before introducing them into the marketplace.   
 
 
In the Federal Register of March 3, 1975 (40 FR 8912 at 8916), we advised that the safety 
of a product can be adequately substantiated through (a) reliance on already available 
toxicological test data on individual ingredients and on product formulations that are similar 
in composition to the particular cosmetic, and (b) performance of any additional 
toxicological and other tests that are appropriate in light of such existing data and 
information.  Although satisfactory toxicological data may exist for each ingredient of a 
cosmetic product, it will still be necessary to conduct some toxicological testing with the 
complete formulation to assure adequately the safety of the finished cosmetic. 
 
We believe that these general principles are applicable to the safety substantiation of 
cosmetic products whether they contain nanomaterials or conventionally manufactured 
                                                           
2 The FD&C Act defines cosmetics by their intended use as articles intended to be rubbed, poured, 
sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, 
promoting attractiveness or altering the appearance, and articles intended for use as a component of any such 
articles; except that such term shall not include soap (section 201(i) of the FD&C Act). 
3 The name of each ingredient must be declared on the label of the cosmetic product, as required by 21 CFR 
701.3. 
 
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ingredients.  In applying these principles, however, it may be important to give particular 
consideration to the fact that a material at nanoscale may show changes in, or have novel, 
physicochemical properties, behaviors, and/or effects that could be different from a larger 
scale material with the same chemical composition (Refs. 2, 8).   
 
For example, the small particle size of a nanomaterial has the potential to alter the 
distribution and bioavailability of that material compared to a larger scale material with the 
same chemical composition.  The small size leads to increased surface area relative to the 
mass of the particle, which could result in increased biological interactions.  In addition, 
the uptake, absorption, and biodistribution of the material may be altered, leading to 
potential systemic exposure (Refs. 5, 8).   
 
In some cases, the traditional testing methods that have been used to determine the safety 
of cosmetic ingredients and finished products may not be fully applicable due to a 
nanomaterials distinctive properties and behavior.  Such distinctive physicochemical 
characteristics or biological interactions may affect the results or interpretation of results 
obtained from traditional toxicology testing, which form an integral part of safety 
substantiation.  In Section III.B of this document, we highlight key scientific 
considerations relevant to the assessment of the safety of nanomaterials used in cosmetic 
products. 
 
If you wish to use a nanomaterial in a cosmetic product, either a new material or an 
altered version of an already marketed ingredient, we encourage you to meet with us to 
discuss the test methods and data that might help substantiate the products safety, 
including short-term toxicity and long-term toxicity data, as appropriate. We encourage 
you to contact us to discuss any aspect of the safety assessment of cosmetic ingredients or 
finished products. 
 
B.  Points to Consider in Assessing the Safety of Nanomaterials in 
  Cosmetic Products 
 
We consider the current framework for safety assessment sufficiently robust and flexible to 
be appropriate for a variety of materials, including products containing nanomaterials.  Just 
as the traditional safety assessment includes material characterization and toxicology 
considerations, safety evaluations of cosmetic products containing nanomaterials should also 
take these considerations into account.  As noted in section III.A, nanomaterials may exhibit 
new or altered physicochemical properties that may affect biological interactions, which 
may raise questions about the safety of the product containing nanomaterials.  Any such 
unique properties or biological effects of nanomaterials should be identified and 
appropriately addressed during safety evaluations.    
 
With respect to nanomaterial characterization, safety should be assessed through fully 
describing the nanomaterial and evaluating a wide range of physical and chemical 
properties, as well as through the assessment of impurities, if present.  The toxicology and 
absorption, distribution, metabolism, and excretion considerations for nanomaterials in 
cosmetic products can be informed by addressing the routes of exposure, the uptake and 
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absorption, and toxicity testing.   In addition, any distinctive properties and biological 
behavior of nanomaterials should be considered in determining the suitability of traditional 
testing methods for toxicity testing of cosmetic products containing nanomaterials.  As 
needed, traditional toxicity testing methods should be modified or new methods developed 
to address: (1) the key chemical and physical properties that may affect the toxicity profile 
of nanomaterials and (2) the effects of those properties on the function of the cosmetic 
formulation.  The toxicological testing should include consideration of toxicity of both the 
ingredients and impurities; dosimetry for in vitro and in vivo toxicology studies, if needed; 
clinical testing, if warranted; and toxicokinetics and toxicodynamics.  The overall package of 
data and information should substantiate the safety of the product under the intended 
conditions of use.  These considerations are discussed in greater detail in sections III.B.1 and 
III.B.2 below. 
 
1.  Nanomaterial Characterization 
 
Nanomaterials vary widely in composition, morphology, and other characteristics and 
cannot be considered a uniform group of substances.  These substances may have physical, 
chemical, or biological properties that are different from those of larger scale material with 
the same chemical composition.  As stated earlier, such differences may include altered 
magnetic properties, altered electrical or optical activity, increased structural integrity, or 
altered chemical or biological activity (Ref. 6). 
 
As discussed in the FDA Task Force report, studies indicate that various attributes of a 
particular nanoscale material, including increased surface-area-to-volume ratio, 
morphology, surface features, and charge, can affect the distribution of that material in the 
body and that materials interaction with biological systems (Ref. 2, 8).  Therefore, 
thorough characterization of nanomaterials can form an integral part of the safety 
assessment.  This would include proper identification of the chemical composition as well 
as impurities, structure, and configuration of the nanomaterial(s) used in the cosmetic 
product.  In addition, characterization of the nanomaterial(s) as present in the raw 
material, formulation, test media, and in the relevant biological environment for 
toxicological testing should be considered to help determine potential biological 
interactions and effects (Ref. 8).  In addition, stability of the nanomaterial under testing 
conditions and in a formulation under intended conditions of use should be determined.   
 
a.  Physicochemical Properties 
 
As with any cosmetic ingredient, the nanomaterial should be fully described, including: 
 
  the nanomaterial name, 
 
  the Chemical Abstracts Service (CAS) number, 
 
  the structural formula, 
 
  the elemental and molecular composition including: 
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the degree of purity, and 
o 
 
any known impurities or additives. 
o 
 
A thorough understanding of the details of the manufacturing process will help identify 
residual additives and impurities, as well as certain other physical and chemical properties. 
A wide range of physical and chemical properties should be evaluated to help determine if a 
substance produced with nanotechnology is safe for the proposed use (Refs. 7, 13, 14, 15).  
Proper characterization should include, as appropriate: 
 
  measurement of particle size and distribution, 
  aggregation and agglomeration characteristics, 
  surface chemistry, including: 
zeta potential/surface charge,  
o 
surface coating, 
o 
  functionalization, and 
o
catalytic activity 
o 
  morphology including: 
shape, 
o 
surface area, 
o 
surface topology, and 
o 
crystallinity 
o 
  solubility, 
  density, 
  stability, and 
  porosity.  
 
Although a wide range of analytical techniques are available for measurement of 
physicochemical properties of materials (Refs.  8, 9, 16), many of these methods have not 
been validated for the evaluation of nanomaterials in cosmetic products.  Therefore, 
appropriate analytical methods suitable for the specific nanomaterial and the cosmetic 
product formulation should be chosen, and results obtained from such tests appropriately 
interpreted and reported for adequate characterization of the material. 
 
b.  Impurities 
 
As with any cosmetic ingredient, a change in the starting material used to prepare a 
formulation will likely result in altered composition of the final product, which may result in 
different impurities.  Variables such as altered purity or changes in the starting material 
should be considered.  A manufacturer should assess the identity and quantity of impurities 
and how they may affect the overall safety of the end product. 
 
It is also important to understand how the nanomaterial is manufactured.  Nanoscale 
impurities may arise from the manufacturing process.  Changes in the manufacturing 
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process, including use of different solvents, time/temperature conditions and changes to the 
starting chemicals (e.g., alternative starting materials, different purity levels or different 
concentrations of the chemicals used in the process) may change the types and/or quantities 
of impurities in the final product. Additional agents, such as dispersing agents and surface 
modifiers, are often used in the manufacture of nanomaterials.  These additional agents and 
impurities should be considered in the safety substantiation for nanomaterials in cosmetic 
products. 
 
2.  Toxicology Considerations 
 
The appropriateness of toxicological testing depends on the intended use, exposure levels, 
and degree of concern for potential toxicity of an ingredient or formulation.  In determining 
what toxicological testing may be appropriate, manufacturers should consider each 
ingredients chemical structure and composition, and physicochemical properties, 
purity/impurities, agglomeration and size distribution, stability, conditions of exposure, 
uptake and absorption, bioavailability, toxicity, and any other qualities that may affect the 
safety of the product for its intended use.   Manufacturers should address both short-term 
and long-term toxicity of nanomaterials (Ref. 8), and consider the need to evaluate the 
possibility of ingredient-ingredient interactions or ingredient-packaging interactions. 
 
Where traditional toxicity test methods are used, manufacturers should consider the 
applicability of the test methods and, as needed, modify them with respect to such factors as 
appropriate solvents and dosing formulations, solubility, agglomeration and aggregation of 
particles, and stability conditions associated with the cosmetic product containing 
nanomaterials (Refs. 2, 17, 18). For example, whether a nanomaterial is soluble, insoluble, 
or partially-soluble may affect the suitability of a traditional toxicity test method.  Some 
traditional in vivo test methods may be suitable for only soluble nanomaterials (Ref. 17).  
Some traditional in vitro and in vivo test methods may need to be adjusted for testing 
insoluble or partially-soluble nanomaterials (Refs. 7, 18).  These considerations are 
important because nanoparticles tend to stick to each other to form larger 
agglomerates/aggregates that may be insoluble.  Therefore, in a dosing or test medium, 
nanomaterials may be present as a nano-dispersion rather than in solution (Refs. 7, 18).  
Agglomeration and aggregation of particles is another factor that may affect the suitability 
of traditional toxicity testing methods, and manufacturers should ensure that testing 
appropriately reflects the range of free particles and any aggregates or aggolomerates found 
in the cosmetic product formulation.  Toxicological testing may need to be conducted 
separately on the free nanoparticles and the agglomerated/aggregated nanoparticles because 
they will likely have different chemical and biological properties.  Due to their high surface 
energy, nanomaterials may also interact with the testing medium or bind to different 
substances, including proteins, in the test medium, resulting in an altered biological activity 
(Refs. 8, 19, 20, 21).  Thus, manufacturers should consider and make necessary adjustments 
to traditional toxicity testing methods, taking into account the specific characteristics of the 
nanomaterial as it is intended to be used in the cosmetic product.  In instances where 
traditional toxicity testing methods cannot be satisfactorily modified, FDA recommends 
developing new methods to adequately assess the toxicity of the nanomaterial in the 
cosmetic product and ensure the product is safe.  
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It is also important to mention that the dose metrics currently used for toxicological testing 
of  conventionally manufactured chemicals (measured and expressed in mass, volume or 
number of particles such as mg/kg, or mg/L) may not be appropriate for nanomaterials 
because of their large surface area per particle mass or volume (Refs. 5, 8).  In addition to 
weight/volume metrics, evaluations of the safety of nanomaterials should also consider 
alternative metrics, such as weight/volume concentration, particle number concentration and 
surface area, until suitable parameters for dose metrics become available.   
 
a.  Routes of Exposure 
 
The safety of an ingredient is based in part on the potential for exposure and the relevant 
routes of exposure that are determined by its intended use and its application.  Although 
most cosmetic products are applied directly to the skin, some products may be applied by 
spray presenting the possibility of inhalation exposure.  Additionally, some cosmetic 
products are applied in an area where there is the possibility of oral exposure.  Additionally, 
systemic absorption can result from dermal, inhalation, ocular and oral exposures (Refs. 22, 
23).  Therefore, for nanomaterials, the dose to the primary exposure organs as well as the 
dose to any secondary target organs should be considered in developing or modifying 
toxicological testing methods and for evaluating the test data (Ref. 5). 
 
b.  Uptake and Absorption 
 
As stated above, some nanomaterials have unique physicochemical properties that may alter 
the potential toxicity of a compound (e.g. reduction in particle size could increase the ability 
for the compound to be absorbed).  Therefore, the safety assessment should address whether 
there will be an increase in uptake, absorption, transport into cells, and transport across 
barriers (e.g. blood-brain barrier) or altered bioavailability or biological half-life. For 
example, there may be an increase in the dose delivered to sensitive tissues due to the 
increased ability of the nanomaterial to pass through the blood-brain barrier (Ref. 24). 
 
Nanomaterials used in cosmetic products can be divided into two groups: (1) soluble and/or 
biodegradable nanoparticles, which disintegrate into their molecular components (e.g. some 
liposomes and nanoemulsions) upon application to skin and thus may not raise safety 
questions, and (2) insoluble, sufficiently stable and/or biopersistent nanoparticles (e.g. 
titanium dioxide (TiO ), fullerenes, and quantum dots).  Some insoluble, partially-soluble or 
2
sufficiently stable nanomaterials, particularly those in the lower nanoscale range and with 
certain surface characteristics, may be able to cross biological membrane barriers (Ref. 25) 
and may have harmful effects due to the potential interaction with organs and cellular 
compartments.  Thus, when there is evidence of systemic exposure to nanomaterials, 
manufacturers should consider including absorption, distribution, metabolism, and excretion 
(ADME) parameters in safety assessments of the nanomaterial in the cosmetic product (Ref. 
8).   
 
For exposure via dermal absorption, studies should be conducted with both intact skin and 
impaired skin (e.g. sunburned, atopic, eczematous, psoriatic, or systematically damaged skin) 
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to address the possibility of an increased rate of penetration and ability of the ingredient to 
become systemically absorbed.  The passive transport of many nanomaterials may not occur 
through intact skin, but there is an increased probability for entry of nanomaterials through 
skin with an impaired barrier layer (Refs. 26, 27).  A variety of techniques used to study and 
quantify skin penetration of chemicals are discussed in the literature (Refs. 28, 29).  We 
recognize that there are limitations to using impaired skin models for conducting dermal 
absorption studies as there is currently no standard or established method(s).  We encourage 
manufacturers to develop appropriate impaired skin models for dermal absorption studies.  
 
The use of aerosolized cosmetic products can also result in exposure to nanomaterials via 
the respiratory tract.  The deposition of nanomaterials in the respiratory system depends 
on their aerosol properties and interactions with respiratory epithelium.  The soluble 
nanoparticles may be dissolved, metabolized and transported to other organs and blood 
whereas the insoluble nanoparticles may be either retained in the airways and result in 
pulmonary effects or swallowed by coughing and cleared.  As discussed earlier, the 
physical characteristics, including surface properties of nanomaterials, are important 
factors that warrant careful attention, particularly for inhaled nanoscale particles.  Studies 
have indicated that decreasing the size of particles and increasing the surface area can 
result in potential adverse effects not only in the respiratory system, but also in the heart 
and blood vessels, the central nervous system, and the immune system (Ref. 30). 
 
Exposure via the oral route is generally limited to those products that are introduced into or 
applied near the mouth (e.g., mouthwash, lipsticks).   Limited evidence suggests that the 
uptake of nanomaterials and systemic absorption depends on their size, surface charge, and 
surface ligand modification (Ref. 30).  Additional studies have indicated that nanomaterials 
have limited uptake in the gastrointestinal tract, but the translocation to certain regions of 
the intestinal barrier can be substantially increased (Refs. 31, 32). 
 
Therefore, we recommend that the safety assessment process for nanomaterials include the 
issues of toxicokinetics and toxicodynamics with reference to different exposure routes. 
 
c.  Toxicity Testing 
 
The initial step in the evaluation of the safety assessment of cosmetic products is to 
conduct toxicity testing based on a toxicological profile of the ingredients and their routes 
of exposure.  There are several guidelines (Refs. 4, 33, 34) for conducting toxicity testing 
(tiered testing strategy) of chemicals that can be used as a starting point in evaluating 
toxicity of nanomaterial ingredients. Consistent with the guidelines issued by the 
Cosmetic, Toiletry and Fragrance Association (CTFA) (Ref. 33) and the Organization for 
Economic Co-operation and Development (OECD) (Ref. 3), we recommend, at a 
minimum, testing for acute toxicity, skin irritation, ocular irritation, dermal photoirritation, 
skin sensitization, mutagenicity/ genotoxicity, repeated dose (21-28 days) toxicity, and 
subchronic (90 days) toxicity (Ref. 34).  We also recommend phototoxicity testing (Ref. 
35) for a cosmetic product that is intended to be used on sun-exposed skin.  Results 
obtained from this basic test battery may indicate a need for additional testing.  Where 
available, other relevant data, such as toxicological data on individual ingredients that are 
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similar in composition to the nanomaterial or data on a larger scale material with the same 
chemical composition as the nanomaterial, can also be considered. 
  
As stated previously, in designing tests for use with nanomaterials in cosmetics products, 
manufacturers should consider modifying traditional toxicity testing with respect to such 
factors as appropriate solvents and dosing formulations, agglomeration of particles, purity 
and stability conditions, and other variables.  New methods may also need to be developed if 
traditional tests cannot be modified satisfactorily.  For example, the Ames test, 
recommended as part of a battery of genotoxicity testing for conventional chemicals, may 
not be suitable for insoluble or partially-soluble nanomaterials used in cosmetic products 
because the bacterial cell wall may create a possible barrier for many nanomaterials (Ref. 
36). 
 
Toxicity testing in vivo has long been considered indispensable for obtaining information 
on translocation, biodistribution, accumulation, and clearance (Ref. 37).  As mentioned 
earlier, while conducting in vivo toxicity testing for nanomaterials, careful attention should 
be paid to the issue of dose metrics (mass, volume or number of particles).  The 
manufacturer should consider the surface area and number of particles, as well as mass 
concentration in the study design of in vivo toxicity testing.  For in vivo studies via the 
dermal route of administration, the test substance should be applied directly to the skin, 
and for the oral route of administration, the test substance should be given either by gavage 
or in the diet.  Agglomeration or aggregation characteristics of nanomaterials in the topical 
vehicle, gavage or feed matrix are other important factors to assess prior to conducting 
these studies for safety assessment.  Additionally, the potential for nanomaterials to 
penetrate through the skin or be absorbed through the gut and becoming available for 
biodistribution, should be addressed while estimating the risks associated with the 
exposure to nanomaterials. 
 
There has been recent emphasis on the development of validated methods for in vitro 
testing of cosmetic products by the Interagency Coordinating Committee on the Validation 
of Alternative Methods (ICCVAM) and the European Center for the Validation of 
Alternative Methods (ECVAM).  The seventh amendment to Directive 2003/15/EC of the 
European Parliament and of the Council (Ref. 38) instituted a ban on animal testing of 
cosmetic products in 2004 and a ban on certain animal tests with validated alternatives in 
March 2009.  We recommend validation of in vitro methods for safety testing of cosmetic 
products and ingredients and optimizing these models for nanomaterials, with particular 
attention being paid to the issues of cytotoxicity and precipitation of insoluble ingredients. 
Nanomaterials can settle, diffuse, and aggregate differentially according to their size, 
density, and surface chemistry (Ref. 39).  Thus, the assessment of the agglomeration or 
aggregation of nanomaterials in the media used in the in vitro system should be addressed. 
 
Alternative testing methods currently under consideration that can be optimized for a 
specific nanomaterial and might be useful to help determine ingredient safety include: 
 
1.  Reconstructed human skin such as EpiskinTM and Epiderm TM for skin 
irritation and corrosion testing; 
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2.  Phototoxicity testing via 3T3 NRPT (3T3 fibroblasts neutral red 
uptake phototoxicity testing) applicable to ultra violet (UV) absorbing 
substances; 
3.  Human/pig skin in a diffusion cell for dermal absorption; 
4.  Bovine Corneal Opacity and Permeability (BCOP) and the Isolated Chicken 
  Eye (ICE) for ocular irritation; and 
5.  Genotoxicity testing using a battery of recommended tests covering the 
endpoints of gene mutation, and structural and numerical aberrations. While 
conducting genotoxicty tests, the nanomaterials specific properties should 
be taken into account to understand the mechanism of nanomaterials 
genotoxic effects (Ref. 36). 
 
Finally, we note that in vivo studies may be more suitable for nanomaterials with limited 
solubility properties (Ref. 8). 
 
C.  Summary of Recommendations 
 
In summary, nanomaterials can have chemical, physical, and biological properties that differ 
from those of larger scale particles with the same chemical composition, and the use of 
nanomaterials in cosmetic products may raise questions about the safety of the product for 
its intended use.  As with any cosmetic product that has new or altered properties, data needs 
and testing methods should be evaluated to address any unique properties and function of the 
nanomaterials used in the cosmetic products as well as the questions that continue to remain 
about the applicability of traditional safety testing methods to products that involve 
nanotechnology.  We recommend that the safety assessment for cosmetic products using 
nanomaterials should address several important factors, including: 
 
  the physicochemical characteristics, 
  agglomeration and size distribution of nanomaterials under the conditions of 
toxicity testing and as expected in the final product, 
  impurities, 
  potential routes of exposure to the nanomaterials,  
  potential for aggregation and agglomeration of nanoparticles in the final product, 
  dosimetry for in vitro and in vivo toxicology studies, and 
  in vitro and in vivo toxicological data on nanomaterial ingredients and their 
impurities, dermal penetration, potential inhalation, irritation (skin and eye) and 
sensitization studies, mutagenicity/genotoxicity studies. 
 
We expect that the science surrounding nanomaterials will continue to evolve and be used 
in the development of new testing methods. 
 
The safety of a cosmetic product should be evaluated by analyzing the physicochemical 
properties and the relevant toxicological endpoints of each ingredient in relation to the 
expected exposure resulting from the intended use of the finished product.  If you wish to 
use a nanomaterial in a cosmetic product, either a new material or an altered version of an 
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already marketed ingredient, we encourage you to meet with us to discuss the test methods 
and data needed to substantiate the products safety, including short-term toxicity and other 
long-term toxicity data, as appropriate.  We welcome your questions relating to the use of 
nanomaterials in cosmetic products. 
 
IV.  How to Contact FDA About this Guidance 
 
Contact the Office of Cosmetics and Colors at 240-402-1130 if you have questions or would 
like to meet with us. You may also contact FDA by email at industry.cosmetics@fda.gov. 
 
V.  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 3rd , 
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 23rd , 2014. 
 
1. FDA. 2013. Guidance for Industry. Considering Whether an FDA-Regulated Product 
Involves the Application of Nanotechnology, available at  
http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm.  
2.  FDA. 2007. A Report of the U.S. Food and Drug Administration Nanotechnology 
Task Force.  As of the date of this guidance, this Web site is an active site that adds 
information over time to provide the most current information about this topic.  
Persons who access this Web site after June 23rd may find more information than the 
information we placed in the Division of Dockets Management. 
3.  Scientific Committee on Emerging and Newly-Identified Health Risks Opinion on the 
Appropriateness of the Risk Assessment Methodology in accordance with the 
Technical Guidance Documents for New and Existing Substances for Assessing the 
Risks of Nanomaterials. 2007 June 7; 1-68. 
4.  Organization for Economic Co-operation and Development (OECD) Guidelines for 
Testing of Chemicals: Section 4 Health Effects Guidelines. 
5.  Scientific Committee on Consumer Products Opinion on Safety of Nanomaterials in 
Cosmetic Products. 2007 Dec. 18; 1-63. 
6.  International Organization for Standardization, International Electrotechnical 
Commission, National Institute of Standards and Technology and OECD International 
Workshop on Documentary Standards for Measurement and Characterization for 
Nanotechnologies, Final Report, 2008 June; 1-40. 
7.  OECD Working Party on Manufactured Nanomaterials Preliminary Review of OECD 
Test Guidelines for their Applicability to Manufactured Nanomaterials, 
ENV/CHEM/NANO(2009)6/REV1, Environment Directorate Organization For 
Economic Co-Operation and Development Paris, 2009. 
8.  Scientific Committee on Consumer Safety Opinion Guidance on the Safety 
Assessment of Nanomaterials in Cosmetics. 2012 June. 26-27; 1-62. 
9.  ICCR (2011a) Currently Available Methods for Characterization of Nanomaterials, 
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Contains Nonbinding Recommendations 
                                                    
ICCR Report of the Joint Regulator - Industry Ad Hoc Working Group, available at 
http://ec.europa.eu/consumers/sectors/cosmetics/files/pdf/iccr5_char_nano_en.pdf. 
10. ICCR (2011b) Principles of Cosmetic Product Safety Assessment, A Report prepared 
for ICCR, available at 
http://ec.europa.eu/consumers/sectors/cosmetics/files/pdf/iccr5_safety_en.pdf.  
11. Principles for Regulation and Oversight of Emerging Technologies, March 11, 2011, 
available at, http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-
agencies/Principles-for-Regulation-and-Oversight-of-Emerging-Technologies-
new.pdf. 
12. Policy Principles for the U.S. Decision-Making Concerning Regulation and Oversight 
of  Applications of Nanotechnology and Nanomaterials, June 9, 2011, available at, 
http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-
agencies/nanotechnology-regulation-and-oversight-principles.pdf. 
13. OECD Environment, Health and Safety Publications Series on the Safety of 
Manufactured Nanomaterials No. 27, List of Manufactured Nanomaterials and List of 
Endpoints for Phase One of the Sponsorship Programme for the Testing of 
Manufactured Nanomaterials: Revision 2010 December 1; 1-16. 
14. Oberdorster, G., Maynard, A., Donaldson, K., Castranova, V., Fitzpatrick, J., Ausman, 
K., Carter, J., Karn, B., Kreyling, W., Lai, D., Olin, S., Monteiro-Riviere,  N., 
Warheit, D., Yang, H; Principles for characterizing the potential human health effects 
from exposure to nanomaterials: elements of a screening strategy. Particle and Fibre 
Toxicology. 2005; 2:8 (doi:10.1186/1743-8977-2-8). 
15. Powers, K.W., Brown, S.C., Krishna, V.B., Wasdo, S.C., Moudgil, B.M., Roberts, 
S.M; Research Strategies for Safety Evaluation of Nanomaterials. Part VI. 
Characterization of Nanoscale Particles for Toxicological Evaluation. Toxicological 
Sciences. 2006; 90 (2): 296-303. 
16. FDA, 2010. Center for Drug Evaluation and Research MAPP. Office of 
Pharmaceutical Science. Reporting Format for Nanotechnology.   
17. Rocks, S.S., Pollard, R.D., Levy, L., Harrison, P., and Handy, R. (2008), Comparison 
of risk assessment approaches for manufactured nanomaterials, Defra, London. 
18. Chaudhry, Q., Bouwmeester, H. and Hertel, R.F. (2010) The Current Risk  Assessment 
Paradigm in Relation to Regulation of Nanotechnologies, In. G.A. Hodge, D.M. 
Bowman and A.D. Maynard (eds), International Handbook on Regulating 
Nanotechnologies. Cheltenham:  Edward Elgar, 124-143. 
19. Cedervall T., Lynch I., Lindman S., Berggard T., Thulin E., Nilsson H., Dawson K.A., 
Linse S; Understanding the nanoparticle-protein corona using methods to quantify 
exchange rates and affinities of proteins for nanoparticles. 2007: PNAS 104, 2050-
2055. 
20. Simon, P. and Joner, E; Conceivable interactions of biopersistent nanoparticles with 
food matrix and living systems following from their physicochemical properties. 
Journal of Food and Nutrition Research. 2008; 47, 51-59. 
21. Lynch I. and Dawson K.A; Protein- nanoparticle interactions. Nano Today. 2008; 3, 
4047. 
22. Rouse, J.G., Yang, J., Ryman-Rasmussen, J.P., Barron, A.R., Monteiro-Riviere, N.A; 
Effects of mechanical flexion on the penetration of fullerene amino acid-derivatized 
peptide nanoparticles through skin. Nano Lett. 2007; 7 (1):155-160. 
  15     
 
Contains Nonbinding Recommendations 
                                                    
23. Oberdorster, G; Pulmonary effects of inhaled ultrafine particles. Int Arch Occup 
  Environ Health. 2001; 74 (1):1-8. 
24. Lockman P.R., et al. Nanoparticle surface charges alter blood-brain barrier integrity 
and permeability, J. Drug Target. 2004; 12(9-10): 635-641. 
25. Geiser M., Kreyling W.G; Deposition and biokinetics of inhaled nanoparticles.   
  Particle Fiber Toxicol; 2010:7:2. 
26. Larese, F.F., Agostin, F.D., Crosera, M., Adami, G., Renzi, N., Bovenzi, M., Maina, 
G; Human skin penetration of silver nanoparticles through intact and damaged skin. 
Toxicology 2009; 255: 33-37.27. 
27. Gratieri, T., Schaefer U.F., Jing L., Gao, M., Kostka, K.H., Lopez, R.F., Schneider, M. 
Penetration of quantum dot particles through human skin. J Biomed Nanotechnol, 
2010; 5: 586-595. 
28. Sekkat, N., Guy, R.H; Biological models to study skin permeation. Chapter in 
Pharmacokinetic Optimization in Drug Research. Biological, Physiochemical and 
Computational Strategies. 2001; 155-172. 
29. OECD 428 Guidelines for the Testing of Chemicals: Skin Absorption: In Vitro    
  Method. 
30. Oberdorster, G., Oberdorster, E., Oberdorster, J; Nanotechnology: An Emerging 
Discipline Evolving from Studies of Ultrafine Particles. Environ Health Perspect. 
  2005b; 113 (7):823-839. 
31. Eldridge, J.H., Hammond, C.J., Meulbroek, J.A., Staas, J.K., Gilley, R.M., Tice, T.R; 
Controlled vaccine release in the gut-associated lymphoid tissues. I. Orally 
administered biodegradable microspheres target the peyers patches. J Control 
Release. 1990; 11: 205-214. 
32. Shakweh, M., Besnard, M., Nicolas, V., Fattal, E; Poly(lactide-co-glycolide) particles 
of different physiochemical properties and their uptake by Peyers patches in mice. 
Eur j Pharma Biopharma. 2005; 61 (1-2):1-13. 
33. CTFA (currently known as PCPC) Safety Evaluation Guidelines, 2007. 
34. FDA  Redbook 2000. Toxicological Principles for the Safety Assessment of Food 
Ingredients. Updated July 2007. 
35. U.S. Food and Drug Administration, Guidance for Industry: Photosafety Testing, 
May 2003. 
36. Landsiedel, R., Kapp, M.D., Schulz, M., Wiench, K., Oesch, F.; Genotoxicity 
investigations on nanomaterials: methods, preparation and characterization of test 
materials, potential artifacts and limitations  Many questions, some answers Mutat 
Res. 2009; 681: 241-258. 
37. PCPC comments submitted in response to the FDAs Nanotechnology public meeting.     
September 2008. 
38. Directive 2003/15/EC of The European Parliament and of the Council of 27 February 
2003 amending Council Directive 76/768/EEC on the approximation of the laws of the 
Member States relating to cosmetic products. Official Journal L66, 11/03/2003 p.26.  
39. Teeguarden, J.G., Hinderliter, P.M., Orr, G., Thrall, B.D., Pounds, J.G.; 
Particokinetics In Vitro:  Dosimetry Considerations for In Vitro Nanoparticle Toxicity 
Assessments. Toxicol Sciences. 2007; 95(2): 300-312. 
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