#220 
 
Guidance for Industry 
 
Use of Nanomaterials in Food for Animals
 
 
Submit comments on this guidance at any time.  Submit  electronic comments on the guidance 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 No. FDA-2013-D-1009. 
 
For further information  regarding this document, contact Dragan Momcilovic,  Center for 
Veterinary Medicine, Division  of Animal Feeds (HFV-226), Food and Drug Administration, 
7519 Standish Place, Rockville,  MD 20855, 240-402-5944;  email: 
dragan.momcilovic@fda.hhs.gov. 
 
Additional  copies of this guidance document may be requested from the Policy and Regulations 
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration,  7519 Standish 
Place, Rockville,  MD 20855, and may be viewed on the Internet at either 
http://www.fda.gov/AnimalVeterinary/default.htm  or http://www.regulations.gov. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
August 2015  Contains Nonbinding Recommendations 
Table of Contents 
 
I.  INTRODUCTION ............................................................................................................. 3 
II.  SCOPE ............................................................................................................................. 3 
III.  LEGAL AUTHORITY................................................................................................... 4 
IV.  DISCUSSION ................................................................................................................. 5 
A.  Nanotechnology and Food for Animals........................................................... 5 
B.  Physicochemical Properties of Nanomaterials in Food for Animals ............... 6 
C.  Nanotechnology and GRAS Substances in Food for Animals......................... 7 
V.  RECOMMENDATIONS FOR NANOMATERIAL ANIMAL FOOD INGREDIENT 
FAPS   .................................................................................................................................... 8 
A.  Identity ............................................................................................................ 8 
B.  Manufacturing Methods and Controls ........................................................... 8 
C.  Intended Use, Use Level, and Labeling ........................................................... 9 
D.  Analytical Methods ......................................................................................... 9 
E.  Safety Evaluation and Proposed Tolerances for the Food Additive ............. 10 
F.  Proposed Regulation ..................................................................................... 10 
G.  Environmental Assessment ........................................................................... 10 
VI.  CONCLUSION............................................................................................................. 11 
 
2  Contains Nonbinding Recommendations 
Guidance for Industry 
 
Use of Nanomaterials in Food for Animals 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page. 
 
I.  Introduction 
 
This guidance describes the Food and Drug Administrations  (FDAs) current thinking  regarding 
the use of nanomaterials or the application  of nanotechnology  in food for animals.  It is intended 
to help industry and other stakeholders identify potential issues related to the safety or regulatory 
status of food for animals containing  nanomaterials or otherwise involving  the application  of 
nanotechnology. 
 
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 Agency guidances means that something is suggested or 
recommended, but not required. 
 
II.  Scope 
 
In this document, the term animal food means food for animals.  This guidance is applicable to 
food ingredients  that are intended for use in animal food and that (1) consist entirely of 
nanomaterials,  (2) contain nanomaterials as a component, or (3) otherwise involve  the 
application  of nanotechnology.1 
 
   
                                              
1 In its evaluation of such materials, FDA intends to apply the principles outlined in the agencys 
guidance document entitled, Considering Whether an FDA-Regulated Product Involves the Application 
of Nanotechnology, which is available online at:  
http://www.fda.gov/regulatoryinformation/guidances/ucm257698.htm. In addition, FDA issued a 
guidance related to the use of nanotechnology in food in June 2014 entitled, Guidance for Industry:  
Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging Technologies, 
on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food 
Ingredients that are Color Additives, which is available online at:  
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm300661.h
tm. 
3  Contains Nonbinding Recommendations 
Medicated feed contains new animal drugs approved for use in or on animal food.  This guidance 
does not apply to a nanomaterial form of a new animal drug or drug component (e.g., drug 
carrier) in medicated feed; however, it does apply to nanomaterial animal food ingredients  in 
medicated feed. 
 
This guidance is not intended to call into question the regulatory status of products that naturally 
exist in the nanoscale range or that contain incidental  amounts of particles in the nanoscale 
range, and that have already been determined to be GRAS or approved in response to a food 
additive petition. 
 
We are particularly  interested in materials or end products that involve  the application  of 
nanotechnology  to deliberately  manipulate or control particle size in order to produce specific 
technical effects. 
 
Materials or end products that naturally occur or naturally contain substances in the nanoscale 
range and are not further manipulated  or engineered are not within the scope of this guidance. 
Examples of such substances include microorganisms  or proteins that naturally exist at small 
scales. 
 
We recognize that conventional  manufacturing processes, such as milling  or general combustion, 
may sometimes result in the animal food containing  particles of varying sizes, including  particles 
in the nanoscale range.  This guidance is not intended to apply to the incidental  presence of 
particles in the nanoscale range that may occur in animal food as a result of conventional 
manufacturing processes. 
 
III.  Legal Authority 
 
FDA regulates foods and substances added to food under the Federal Food, Drug, and Cosmetic 
Act (FD&C Act).  Many substances added to foods are food additives.  Section 201(s) of the 
FD&C Act (21 U.S.C.  321(s)) defines a food additive as any substance the intended use of 
which results or may reasonably be expected to result, directly or indirectly,  in its becoming a 
component or otherwise affecting the characteristics of any food[.]  Section 201(s) of the FD&C 
Act excludes from this definition  any substance that is generally recognized as safe (GRAS) 
among qualified  experts under the conditions  of its intended use, or that qualifies  for any of the 
other exemptions from the food additive definition  (e.g., new animal drug, color additive,  etc.).2 
 
Food additives require premarket approval based on data demonstrating safety.  FDA issues food 
additive regulations specifying  the conditions  under which an additive has been demonstrated to 
be safe and, therefore, may be lawfully  used.  See section 409(a)(2) of the FD&C Act (21 U.S.C. 
 348(a)(2)).  A food that contains an unapproved food additive is deemed to be unsafe under 
                                              
2 Under section 201(s) of the FD&C Act, the following types of substances are excluded from the food 
additive definition:  (1) pesticide chemical residues in or on a raw agricultural commodity or processed 
food; (2) pesticide chemicals; (3) color additives; and (4) substances used in accordance with a prior 
sanction (i.e., a sanction or approval granted prior to the enactment of the Food Additives Amendment of 
1958 under the FD&C Act, the Poultry Products Inspection Act, or the Meat Inspection Act). 
4  Contains Nonbinding Recommendations 
section 409(a) of the FD&C Act (21 U.S.C.  348(a)) and adulterated under section 
402(a)(2)(C)(i) of the FD&C Act (21 U.S.C.  342(a)(2)(C)(i)). In general, adulterated foods 
cannot be legally imported or marketed in the United States (21 U.S.C.  331(a)).  Therefore, to 
use a food additive in animal food, FDA must issue a food additive regulation prescribing the 
conditions  under which the additive may be safely used (21 U.S.C.  348(c)(1)(A)).  Section 
409(b) through (g) of the FD&C Act provides for a petition process to establish that a use of a 
food additive is safe. 
 
Pursuant to section 409(j) of the FD&C Act, a food additive,  or food containing  a food additive, 
intended for investigational  use may be exempt from the requirements of section 409 of the 
FD&C Act under the conditions  set forth in Title 21 of the Code of Federal Regulations  section 
570.17 (21 CFR 570.17). 
 
Under section 201(s) of the FD&C Act, the use of a food substance may be shown to be GRAS 
either through scientific procedures or, for a substance used in food before 1958, through either 
scientific procedures or experience based on common use in food.  General recognition  of safety 
based upon scientific procedures requires the same quantity and quality of scientific evidence as 
is needed for approval of a food additive petition  (FAP).  21 CFR 570.30(b).  The implementing 
regulations for eligibility  for GRAS classification  and affirmation of GRAS status for animal 
food are found at 21 CFR 570.30 and 21 CFR 570.35. FDAs Center for Veterinary Medicine 
(CVM) is also accepting notifications  of GRAS determinations for animal food substances 
through a pilot program.3 
 
IV.  Discussion 
 
A. Nanotechnology  and Food for Animals 
 
Nanotechnology  involves manipulation  of materials on an atomic or molecular scale. It is an 
emerging technology  that has the potential to be used across the spectrum of FDA-regulated 
products, including  animal food. 
 
FDA has not established regulatory definitions  of nanotechnology,  nanomaterial, 
nanoscale, or other related terms.  In June 2014, FDA issued a guidance for industry 
entitled, Considering  Whether an FDA-Regulated Product Involves the Application  of 
Nanotechnology. 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).  
                                              
3 This program was announced in the Federal Register of June 4, 2010 (75 FR 31800). More information 
about the GRAS Notification Program for animal food is available online at: 
http://www.fda.gov/AnimalVeterinary/Products/AnimalFoodFeeds/GenerallyRecognizedasSafeGRASNo
tifications/default.htm.   
5  Contains Nonbinding Recommendations 
These considerations apply broadly to all FDA-regulated products, including  to food for 
animals. 
 
The application  of nanotechnology  may result in product attributes that differ from those of 
conventionally-manufactured  products, and thus may merit examination. However, FDA does 
not categorically judge all products containing  nanomaterials or otherwise involving  the 
application  of nanotechnology  as intrinsically  benign or harmful. Rather, for nanotechnology-
derived and conventionally-manufactured  animal food products alike, FDA considers the 
characteristics of the finished product and its safety for its intended use. FDAs consideration 
of nanotechnology  applications  in animal food is consistent with the agencys guidance4 and 
with the broader federal guidance on regulatory oversight of emerging technologies5 and 
nanotechnology6. 
 
B.  Physicochemical Properties of Nanomaterials in Food for Animals 
 
Available scientific evidence indicates that materials manipulated  on the nanoscale level 
through the use of nanotechnology  may result in the materials possessing novel 
physicochemical  properties.  The physical characteristics of a particular nanomaterial, 
including  increased surface area-to-volume ratio, morphology,  surface features, and charge, 
can affect the biological  behavior of the material.7 
 
In addition,  materials manipulated  on the nanoscale level through the use of nanotechnology 
may affect the biodistribution,  biocompatibility,  or toxicity  of the material.8  For example, 
changing the particle size of a material may affect its absorption and transport in the body.9 
Thus, the bioavailability  of a nanomaterial animal food ingredient  may be significantly 
different from that seen or expected in a larger-scaled material with the same chemical 
composition,  which may alter the minimum  amount of the animal food ingredient  necessary 
to achieve the intended technical or nutritional  effect. 
 
                                              
4  FDA issued guidance in June 2014 entitled, Guidance for Industry. Considering Whether an FDA-
Regulated Product Involves the Application of Nanotechnology. 
http://www.fda.gov/regulatoryinformation/guidances/ucm257698.htm 
5 The White House Emerging Technologies Interagency Policy Coordination Committee (ETIPC). 2011.  
Memorandum for the Heads of Executive Departments and Agencies: Principles for Regulation and 
Oversight of Emerging Technologies.  http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-
agencies/Principles-for-Regulation-and-Oversight-of-Emerging-Technologies-new.pdf 
6 The White House Office of Science and Technology Policy (OSTP). 2011.  Memorandum for the Heads 
of Executive Departments and Agencies: Policy Principles for the U.S. Decision-Making Concerning 
Regulation and Oversight of Applications of Nanotechnology and Nanomaterials. 
http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-agencies/nanotechnology-regulation-and-
oversight-principles.pdf  
7 FDAs Nanotechnology Task Force Report 2007 can be accessed at 
http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/UCM2006659.htm 
8 Ibid. 
9 Ibid. 
6  Contains Nonbinding Recommendations 
Similarly,  two animal food ingredients  of the same chemical composition,  but of different 
particle size, shape, or other morphological  feature, may exhibit different physicochemical 
properties. For example, some tea polyphenols  are anti-oxidants  in their bulk form, but the 
same tea polyphenols  are pro-oxidants  in their nanoscale form10. 
 
Because the application  of nanotechnology  may result in new or different physicochemical 
properties, specific data should be used as evidence to show that the use of the nanomaterial 
version of the animal food ingredient  is safe for its intended use, even if it shares the same 
chemical composition  as a larger-scaled animal food ingredient  that is determined to be 
GRAS for that intended use or is a food additive approved for that intended use. 
 
There are animal food ingredients that are approved as food additives or that are GRAS for 
their intended uses that could be manufactured to significantly  alter their particle size or size 
distribution  into the nanoscale range.  In some instances, these changes could result in a 
material with different properties.  In such cases, manufacturers should conduct safety 
assessments that are based on data and information  relevant to the nanomaterial  version and 
not rely entirely on the data and information  used to determine the safety of a larger-scaled 
material with the same chemical composition. 
 
C.  Nanotechnology  and GRAS Substances in Food for Animals 
 
A determination  that a particular use of a substance is GRAS (unless established by common 
use before 1958) requires both technical evidence of safety and a basis to conclude that this 
technical evidence of safety is generally known and accepted (i.e., general recognition  of 
safety).  At present, for nanotechnology  applications  in animal food, there are questions 
related to the technical evidence of safety as well as the general recognition  of that safety that 
are likely  to be sufficient to warrant formal premarket review and approval by FDA, rather 
than to satisfy criteria for GRAS status. When questions about the safety of the use of an 
animal food ingredient are raised and experts would need additional  data that are not 
generally available to answer those questions,  then the general recognition  of safety criteria 
for GRAS status would not be satisfied for that use of that animal food ingredient.  At this 
time, we are not aware of any animal food ingredient  engineered on the nanometer scale for 
which there is generally available safety data sufficient to serve as the foundation  for a 
determination  that the use of such an animal food ingredient  is GRAS. 
 
Furthermore, where there is a lack of general recognition  of the safety of a nanomaterial 
animal food ingredient for its intended use, it is likely  that a GRAS notice for such a 
nanomaterial animal food ingredient would not meet the criteria of CVMs pilot GRAS 
notification  program. Therefore, premarket review and approval of the animal food ingredient 
by FDA may be warranted. We recommend that you consult with us even if you believe that 
the generally available data and information  could form a basis for a determination  of GRAS 
status of an animal food substance that involves  nanotechnology. 
                                              
10 Alotaibi, et al. 2013.  Tea phenols in bulk and nanoparticle form modify DNA damage in human 
lymphocytes from colon cancer patients and healthy individuals treated in vitro with platinum-based 
chemotherapeutic drugs. Nanomedicine (Lond). Mar; 8(3):389-401. 
7  Contains Nonbinding Recommendations 
V.  Recommendations for Nanomaterial Animal Food Ingredient FAPs 
 
Following  a determination  that an FAP is warranted, you should submit the FAP for your 
nanomaterial animal food ingredient to FDA. When developing  a submission  to the agency, 
please consult CVM Guidance for Industry (GFI) #221, Recommendations  for Preparation and 
Submission  of Animal Food Additive  Petitions. 11 CVM intends GFI #221 to provide guidance 
for meeting the FAP requirements established in 21 CFR part 571. The recommendations 
provided in GFI #221 apply generally to all food additives for animal food, including  those that 
involve  the use of nanotechnology. 
 
When developing  a submission  for a FAP for a nanomaterial animal food additive,  we 
recommend that you consider the following: 
 
A. Identity 
 
As with all other food additives,  the FAP for a nanomaterial animal food additive must 
include information  which identifies and characterizes the nanomaterial animal food additive. 
See section 409(b)(2) of the FD&C Act (21 U.S.C 348(b)(2)).  The FAP must include the 
name and all pertinent information  concerning the nanomaterial  animal food additive, 
including  chemical identity  and composition  of the food additive,  its physical,  chemical, and 
biological  properties, and specifications prescribing the minimum  content of the desired 
component(s) and identifying  and limiting  the reaction byproducts and other impurities  (21 
CFR 571.1(c)).  Where such information  is not available,  a statement as to the reasons why it 
is not should be submitted. 
 
The name of the nanomaterial animal food additive,  like the name of a conventionally-scaled 
food additive,  is identified  in the relevant food additive regulation. 
 
B.  Manufacturing Methods and Controls 
 
For any animal food additive,  it may be important to provide information  regarding the 
presence of byproducts and impurities  associated with its manufacturing.  Toxicity  may be 
associated with byproducts and impurities  resulting from the manufacture of a nanomaterial 
food ingredient.12 
 
Nanomaterials may agglomerate or aggregate and interact with other ingredients in animal 
food matrices. FAPs involving  nanomaterials should provide data on the stability  of the 
nanomaterials in the proposed formulations  and under the proposed conditions  of use. 
 
                                              
11 See GFI #221, Recommendations for Preparation and Submission of Animal Food Additive 
Petitions. 
http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustr
y/UCM367746.pdf  
12 J.J. Scott-Fordsmand, et al. 2008. The toxicity testing of double-walled nanotubes-contaminated food to 
Eisenia veneta earthworms. Ecotoxicology and Environmental Safety 71 (2008) 616 619. 
8  Contains Nonbinding Recommendations 
If a nanomaterial ingredient  is intended to be distributed  uniformly  throughout an animal 
food matrix, then you should provide information  demonstrating that the nanomaterial 
ingredient  can be mixed to a uniform content in a representative animal food matrix. 
 
The physicochemical  properties of nanomaterials may change in liquid  media. The effects of 
a particular liquid  medium on the physicochemical  properties of a nanomaterial animal food 
ingredient  approved for use in dry animal foods are uncertain.  For example, the stability  of a 
nanomaterial animal food additive approved for use in dry animal foods may change when 
the same nanomaterial animal food additive is proposed for use in a liquid  animal food. CVM 
generally will not assume a nanomaterial animal food additive approved for use in dry animal 
foods is safe nor has the same technical effect when used in liquid  media. As a result, 
information  related to changes in physicochemical  properties may be needed to demonstrate 
safety or technical effect before an animal food additive,  approved for use in dry animal 
food, is approved for use in a liquid  medium. 
 
C.  Intended Use, Use Level, and Labeling 
 
The regulations at 21 CFR parts 501 and 502 provide requirements for labeling  and naming of 
animal foods and ingredients.  In addition,  FDA may require the label or labeling  of an animal 
food additive,  including  a nanomaterial food additive for animal food, to include any 
information  necessary to ensure the safe use of the food additive.  See section 409(c)(1)(A) of 
the FD&C Act (21 U.S.C 348(c)(1)(A) and 21 CFR 571.100(a)).  Foods that do not bear 
such required labeling  may be deemed misbranded under sections 403 and 201(n) of the 
FD&C Act. 
 
D. Analytical Methods 
 
Scientifically  valid analytical  methods that are capable of determining  the chemical 
composition  and the amount of the nanomaterial  animal food additive contained in various 
animal food matrices should be used.  The analytical methods should correctly identify  the 
nanomaterial animal food ingredient by its relevant physical properties (e.g., 3-dimensional 
properties such as size and/or shape). 
 
Complexities  of detection and characterization of nanomaterials pose particular challenges to 
analytical methods.  A detailed description of the analytical methods used to determine the 
identity,  purity,  quality,  and strength of the nanomaterial animal food additive  should be 
provided.  Such analytical methods should be described in sufficient detail and specificity as 
to permit the reviewer to determine the validity  of the methods to verify the purity,  quality, 
and strength of the nanomaterial animal food additive. Analytical  methods may need to be 
performed as the animal food additive is produced, after it is purified,  in its marketed 
packaged matrix, and in a representative animal food matrix. 
 
   
9  Contains Nonbinding Recommendations 
E.  Safety Evaluation  and Proposed Tolerances for the Food Additive 
 
As part of the FAP process, FDA examines safety data provided by the petitioner to show 
whether the food additive will  be safe for its intended use.  Both human food safety and target 
animal safety must be addressed in any FAP for a substance intended for use in food for 
animals that are raised for food production. See 21 CFR part 571.  As with all other food 
additives,  these two sections of an FAP for nanomaterial animal food additives should contain 
the scientific data necessary to demonstrate the safety of the nanomaterial animal food 
additive for humans and target animals under the conditions  of intended use. 
 
The information  needed to demonstrate human food safety for a nanomaterial animal food 
additive may differ from that needed for a larger-scaled material with the same chemical 
composition.   For example, you may need to provide a specially designed assay (see 
Analytical  Methods above) to characterize the distribution  and accumulation  of the 
nanomaterial in the edible tissues (including  milk and eggs) derived from food-producing 
animals. 
 
The information  needed for demonstrating  target animal safety for a nanomaterial animal 
food additive may differ from that needed for larger-scaled material with the same chemical 
composition.  For example, if the bioavailability  of a nanomaterial animal food ingredient 
differs from its larger-scaled counterpart, then the toxicological  profile for the larger-scaled 
counterpart may not be adequate to ensure the target animal safety of the nanomaterial animal 
food additive. In this example, you may need to provide a toxicological  profile that is specific 
for the nanomaterial animal food additive for its proposed use. 
 
F.  Proposed Regulation 
 
The proposed regulation section of an animal food additive petition should include 
information,  including  technical specifications,  that is necessary for proper identification  of 
the nanomaterial animal food additive.  If applicable,  the proposed regulation  should have 
proposed limitations  on the conditions  of use to ensure safety. 
 
G. Environmental  Assessment 
 
The potential adverse environmental  impact of a nanomaterial  may differ from that of a 
larger-scaled material with the same chemical composition.  Impact on the environment may 
occur at various stages of the ingredients  life cycle, including  manufacture, storage, use, and 
disposal. We recommend contacting CVM13 early in product development  to determine 
whether the approval of a FAP for the nanomaterial animal food additive  would qualify for a 
categorical exclusion,  or if it would not qualify for a categorical exclusion,  to determine the 
appropriate scope of an environmental  assessment. 
 
   
                                              
13See contact information on title page. 
10  Contains Nonbinding Recommendations 
VI.  Conclusion 
 
We recommend that you contact CVM early in the product development  process so that a 
determination  can be made as to whether your animal food product involves  the application  of 
nanotechnology  and so that any questions related to safety and regulatory status can be 
appropriately  addressed. To facilitate the efficient development and approval of FAPs for 
nanomaterial animal food additives,  CVM encourages pre-petition consultations  with our 
Division  of Animal Feeds. 
11