Contains Nonbinding Recommendations  
Draft-Not for Implementation  
Dietary Supplements:  New Dietary  
Ingredient  Notifications  and Related  Issues:  
Guidance for  Industry  
Draft Guidance 
This guidance is being distributed for comment purposes only.  
Although you can comment  on any guidance  at  any time (see  21 CFR  10.115(g)(5)),   to ensure  
that FDA  considers your  comment on this draft  guidance  before  we  begin work on the final  
version of the guidance,  submit  either  electronic  or written comments  on the draft guidance  
within  60  days of publication  in the  Federal Register  of the  notice  announcing the  availability 
of the draft guidance.  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  FDA-2011-D-0376,  which is  listed in the  notice of  
availability  that publishes   in the  Federal Register.  
For  questions regarding this  draft document,  contact  the  Food and Drug Administration,  Office  
of  Dietary Supplement  Programs, 5001 Campus Drive  (HFS-810),  College  Park, MD 20740,  
Toll  Free (855)  543-3784,   or 240-402-2375.   
U.S. Department of  Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
March 2024  
Replaces  revised draft  guidance 
issued August 2016   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
Table  of Contents  
I.  Introduction 
II.  Background 
III.  Goals  and Public   Health Importance  of the Guidance 
IV.  Determining  Whether  a New Dietary Ingredient (NDI) 
Notification  Is  Required 
A.  What  Is a  New Dietary Ingredient? 
1.  What  do the terms  dietary ingredient  and new dietary ingredient  mean? 
2.  Can a  substance that  is not  a dietary ingredient   be an NDI? 
3.  Must  I submit  an  NDI  notification  for a dietary ingredient   marketed in the U.S. 
prior  to October 15,  1994? 
4.  Is an ingredient   that was  used to make a conventional  food marketed before 
October 15,  1994,  an  NDI? 
a.  Is  an  NDI  notification  required for  a  dietary supplement containing  an  NDI  if 
the supplement  contains  only dietary ingredients  that have been present in 
the  food supply as  articles used for  food in a  form in which the  food has  not 
been chemically  altered? 
b.  Does the adulteration standard in 21 U.S.C.  342(f)(1)(B)  apply to a dietary 
supplement containing  an NDI  even when an  NDI notification  is  not 
required? 
5.  Is a  substance that was  a component  of a conventional  food marketed before 
October 15,  1994,  an  NDI  if  the  component  was not  a dietary ingredient 
marketed in the  U.S.  before October  15, 1994? 
6.  Is a substance that was  an ingredient   in  a  dietary supplement  marketed before 
October 15,  1994,  an  NDI? 
7.  What does  marketing  a dietary ingredient   mean? 
8.  Is a  dietary ingredient   marketed outside  the U.S.  prior  to October 15,  1994, 
considered to be  an  NDI  if it was  not  marketed in the U.S. before that date? 
9.  What documentation  does  FDA recommend  to show  that a  dietary ingredient 
was  marketed prior  to October 15,  1994? 
10. Is  marketing an ingredient   for any use prior  to October 15,  1994, sufficient  to 
conclude  that  it is not  an NDI? 
11. Is there  an authoritative   list  of dietary ingredients  that were  marketed prior  to 
October 15,  1994 (a so-called grandfathered list  or  old dietary ingredient 
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list)?  
12. If I  change  the manufacturing process for a  dietary ingredient  that  was  marketed 
in the U.S. prior  to October 15,  1994,  does  that make the ingredient   an  NDI? 
13. Should I submit  a  new NDI  notification  if  I change the manufacturing process 
for an  NDI  that is  the subject  of a notification  for  which I have received an 
acknowledgment without objection from  FDA? 
B.  Exception to Notification Requirement for Certain NDIs with a History 
of Use in Conventional Food 
1.  When is  a  notification  not required for  an  NDI? 
2.  Am  I required to submit  an  NDI  notification  for a  dietary  ingredient  that  is an 
NDI, but has been (a) listed or affirmed by FDA as  generally  recognized  as safe 
(GRAS) for direct  addition  to food  or  (b) approved as a direct  food additive  in 
the  U.S.? 
3.  Does the adulteration standard in 21 U.S.C.  342(f)(1)(B) apply to  an  NDI  that 
has been listed  or affirmed by FDA as  GRAS  for direct  addition  to food  or 
approved as a direct  food additive  in the  U.S.? 
4.  What are examples  of processes  that chemically  alter  an article of food present 
in the food supply? 
5.  What  processes for  manufacturing a dietary ingredient  from an article of food 
present  in the food supply do not result in chemical  alteration? 
C.  Other Questions About When an NDI Notification Is Necessary 
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient Notification 
Procedures and Timeframes: Guidance for Industry" (first paragraph of response).
2.  If I  submit  an NDI  notification  for  a  dietary supplement  that I manufacture  or 
distribute  and then decide to manufacture  or distribute  a  different  supplement 
that contains  the same NDI,  should  I submit  another  NDI notification? 
3.  If a  dietary supplement  manufacturer  or  distributor   has submitted an NDI 
notification  prior  to marketing a  dietary supplement with the  NDI,  and I intend 
to market  a  dietary supplement  containing  the same  NDI, should I also submit  an 
NDI  notification? 
4.  When I  submit  an NDI  notification,   may I rely on data from  another NDI 
notification   or master file? 
5.  Can FDA provide  an explanation  and examples  to help distinguish  situations   in 
which separate notifications   are required for  dietary supplements  containing  the 
same NDI  from  situations  in which the same NDI  notification  covers multiple 
dietary supplements? 
6.  Should I  notify FDA  about a  microbial  ingredient   in my dietary supplement? 
7.  If I  want to market a dietary supplement  containing  several  pre-DSHEA 
ingredients  that  havent previously  been marketed together,  do I have to submit 
an NDI notification? 
8.  Can FDA  provide visual  aids  to help me decide  whether I  should submit  an  NDI 
notification? 
D.  Additional  Issues to Consider Before Submitting an NDI Notification 
1.  What is  a dietary ingredient? 
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2.  May  a contaminant  that is  found in the  food supply  be  a dietary ingredient? 
3.  Under what circumstances  does FDA consider  synthetically  produced  substances 
to be dietary ingredients  under  the FD&C Act? 
4.  Are food contact  substances and other  indirect  food additives  dietary 
ingredients?   What  about secondary direct food additives? 
5.  If I  alter  the chemical  structure of a dietary  ingredient,  is  the new substance still 
a dietary ingredient? 
6.  In what forms  may a dietary supplement  containing  my NDI be  sold? 
7.  When  FDA reviews an  NDI  notification,   does the agency consider  whether the 
prohibition  in section 301(ll)   of the FD&C Act  applies  to the  use of  the  NDI in  a 
dietary supplement? 
8.  May  an ingredient   that has  not been marketed  as a  food  or as a dietary 
supplement,   but has  been approved as a  new drug or  licensed as a biologic,  be 
used as  an NDI  in a  dietary supplement? 
9.  May  I use an ingredient  in a  dietary supplement  if  it  has been clinically  tested as 
a drug but  has not  been approved as a  drug in the  U.S.? 
10. How  do I determine  whether  a dietary ingredient   is an article  that  is approved or 
authorized for investigation  as a new  drug? 
11. May  a dietary ingredient   that was  authorized for investigation  as a  new  drug in 
the past  be  used as an  NDI  in a dietary supplement  if the IND  was withdrawn or 
the ingredient   is  no longer  being investigated  as a new  drug? 
12. May  I manufacture and sell  a dietary supplement  containing  a  dietary ingredient 
that was  marketed as  a food or dietary supplement  before it  was approved as  a 
drug,  licensed  as a  biologic,   or  authorized  for investigation  under  an IND? 
V.  NDI Notification  Procedures and Timeframes 
A.  Procedure for Submitting  an NDI Notification 
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
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RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
B.  What Happens After an NDI Notification Is Submitted? 
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
VI.  What  to Include   in an  NDI  Notification 
A.  Identity Information about the NDI and the Dietary Supplement 
1.  What  is the  purpose of including  information  about  the identity of the  NDI  and 
the  dietary supplement  containing  the NDI  in my notification? 
2.  What types  of identity information  should I include  in my NDI  notification? 
3.  How  much detail  should my description of  the  manufacturing  process  contain? 
4.  What  is  a specification? 
5.  What  specifications  for my process  and ingredients  should I  include in the 
notification? 
6.  What additional   information  should I submit  if  my NDI  is  a discrete chemical  
entity (e.g.,  a vitamin,   mineral,  amino  acid,  or a  constituent  or a metabolite of 
another dietary ingredient)? 
7.  What additional   chemistry information  should I submit  if my NDI  is  a salt? 
8.  What additional   chemistry information  should I submit  if my NDI  is  an enzyme? 
9.  What additional   chemistry information  should I  submit  if my NDI  is  a covalently 
modified  derivative  of  a dietary ingredient? 
10. What  information  should I  submit if  my notification  relies on history of use or 
other evidence of  safety for a  substance or product  that is  similar  to,  but not 
exactly  the same as, my  NDI or dietary supplement? 
11. What  additional   identity  information  should I  submit  if my product  contains a 
mixture  of ingredients? 
12. What  additional   identity  information  should I submit  if  my NDI  is  a botanical  or 
is derived from a  botanical? 
13. Should I describe  the  production  methods for  my botanical  NDI? 
14. How should the identity section of my NDI  notification  deal  with toxins  in 
related plants or  microorganisms? 
15. How should I  describe  an extract or concentrate of a  botanical  or a dietary 
substance? 
16. What additional   information  should I include  if  my NDI  is produced using 
fermentation? 
17. What  additional   information  should I  include  if my NDI  is  a live  microbial 
dietary ingredient? 
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18. What  information  should I  provide in  my notification  if  the labeling  of the NDI 
or dietary supplement  containing  the  NDI will  include  an expiration  date or  use 
by date? 
19. What information  should  I submit  to  describe  the  conditions   of  use that  I intend 
to recommend or suggest  in the labeling  of my dietary supplement? 
B.  History of Use or Other Evidence of Safety 
1.  What safety information  is  required to support  an  NDI  notification? 
2.  Should  I submit  both a  history of safe  use and  safety  testing data for the NDI? 
3.  What data and information  should I  submit  to substantiate  an  NDIs history of 
safe use? 
4.  What documentation  of  an  NDIs history of use should I  submit? 
5.  Am I required to submit  a  comprehensive  survey of  every historical  use of the 
NDI? 
6.  How do I  determine  whether historical  use was  daily chronic  or 
intermittent? 
7.  Should I estimate  the  intake  of  historically   consumed materials  related to  my 
NDI  if  I am relying on  those related  materials  to establish  a  history of  safe use, 
and should this  estimate  be  included  in my NDI  notification? 
8.  Where may I find information  on how  to estimate  consumer  intake? 
9.  How is  the reliability  of history of  use  data evaluated? 
10. Should  I cite the history of use of  an NDI  in traditional  medicine? 
11. Does  FDA recommend submitting   additional   animal  and human studies  to 
supplement  evidence of a history of  safe  use  by humans? 
12. What  factors  are  helpful in evaluating whether to submit  animal  or human safety 
studies  in addition  to history of use data? 
13. Should  I use toxicology  or clinical  studies  published  by others,  or unpublished 
studies  I have performed,  if those studies used test  articles  that  are similar   but 
not  identical  to the NDI  or the  dietary supplement  containing  the NDI? 
14. Are there scenarios in which  FDA considers additional  safety data  unnecessary 
if  the proposed use  of  the NDI  leads  to intake  levels  that  are  the same  as or  less 
than the  levels consumed historically? 
15. What types  of data does FDA recommend to  assess safety if  the dietary  
supplement  containing  the  NDI  is intended for  daily chronic use, the  NDI has a 
documented history  of  safe  intermittent  use,  and the proposed use of the NDI 
leads  to intake levels  that are the same as  or  less than the levels  consumed 
historically? 
16. What types  of data  does FDA recommend to  assess safety if  the dietary  
supplement  containing  the  NDI  is intended for  daily chronic use, the  NDI has a 
documented history  of  safe  daily chronic  use,  and the proposed use of the NDI 
leads  to intake levels  that are greater than the levels  consumed  historically? 
17. What types  of data does FDA recommend to  assess safety if  the dietary  
supplement  containing  the NDI  is intended for  daily chronic use, the  NDI has a 
documented history  of  safe  intermittent  use,  and the proposed use of the NDI 
leads  to intake levels  that are greater than the levels  consumed  historically? 
18. What types  of data does FDA recommend to  assess safety if  the dietary  
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supplement  containing  the NDI  is  intended for intermittent   use, the  NDI  has a  
documented history  of  safe  intermittent  use,  and the proposed use of the NDI  
leads  to intake levels  that are greater than the levels  consumed  historically?  
19. What types  of data does FDA recommend to  assess safety if  the dietary  
supplement  containing  the NDI  is  intended for intermittent   use, the  NDI  has a 
documented history of  safe daily  chronic  use,  and the proposed use of the NDI 
leads  to intake levels  that are  greater than the levels  consumed historically? 
20. What types  of data does FDA recommend to  assess safety if  there  is no history 
of use of the NDI  that can be  relied on to provide  evidence  of safe  use in dietary 
supplements? 
21. Am I required to use only FDA-published  safety test protocols? 
22. What  are some  sources of  safety testing protocols  that  can be  used in testing 
NDIs  and dietary supplements? 
23. What is  the appropriate  highest  dose of  an  NDI  to use in animal  and human 
safety studies? 
24. What should I do to justify the use of a  particular  protocol? 
25. How  will I  identify a  potential hazard using a  standard genetic  toxicity test, and 
what  should I do after identifying  a potential  genetic  toxicity hazard? 
26. Should the NDI notification  discuss  the history of use or other  evidence of safety 
that forms  the basis  for my conclusion  that a  genotoxic  dietary ingredient  can 
reasonably be expected to be safe? 
27. Where can I find good examples  of genotoxicity  protocols  that can be used in 
conducting animal and human studies  on NDIs? 
28. What  is the  purpose of a  subchronic  oral  toxicity study? 
29. What is  the appropriate  duration for a  subchronic  oral  toxicity  study? 
30. Where can I find more  information  and examples  of a subchronic  oral  toxicity 
study? 
31. What  is the  purpose of reproductive  toxicity   and  teratology studies? 
32. Should I include  a  discussion  of the reproductive  and teratology studies  in my 
NDI notification? 
33. Should I  identify the  No  Observed Adverse Effect Level  (NOAEL) for all  test 
substance-related changes  in both reproductive  and teratology test endpoints? 
34. Where can I find sample  protocols  for reproductive  and teratology studies? 
35. What  is the  purpose of repeat-dose toxicity  testing? 
36. Am I required to conduct  human clinical  studies  to assess  the  safety of my NDI 
or the dietary supplement  containing  my NDI? 
37. What  kinds  of human clinical  studies  are  useful  to assess  the safety of  an  NDI  or 
dietary supplement  containing  an NDI? 
38. What is  the purpose  of  repeat-dose  human studies,  and how are such studies 
classified? 
39. Where can I find more  information  and examples  of clinical  protocols  that can 
be used in conducting human studies  for NDIs  and dietary supplements? 
40. What information  should I  submit  to demonstrate  the safety of  an  NDI  produced 
by fermentation using microorganisms   like  bacteria or yeast? 
41. What information  should I  submit  to demonstrate  the safety of a microbial  NDI 
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(live  or killed)?  
42. What should I do to demonstrate  the safety of  an  NDI  that contains 
nanomaterials  or otherwise  involves   the application  of nanotechnology? 
C.  Summary of the Basis  for Your Conclusion of Safety 
1.  Should my notification  include  separate safety  profiles  for the NDI and the 
dietary supplement  in which  the NDI  will be used? 
2.  What should I include  in my comprehensive  safety profile  for the NDI? 
3.  What should I include  in my dietary supplement  safety narrative? 
4.  What  is  the difference between a NOEL and  a NOAEL,  and which should I use? 
5.  What safety factors  should be used if  only animal  toxicity  studies  are  available? 
6.  Does  FDA recommend including  margin of  safety discussions  in NDI 
notifications? 
7.  What is  the difference between  a safety  factor and a margin  of safety? 
8.  When is  the ratio of the EDI  to the  ADI  adequate to support  the conclusion  that a 
dietary supplement  containing  an  NDI  will reasonably  be  expected to  be safe? 
9.  What is  an example of a  common error about  margin of safety in NDI 
notifications   that have been submitted to FDA for review? 
10. Are the recommendations   in section VI  requirements  for safety information  to 
include  in an NDI notification? 
VII.  Definitions 
VIII. Appendix:   Decision Tree for NDI Notification 
Document History 
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Dietary Supplements:  New Dietary   
Ingredient  Notifications and Related 
1 
Issues:  Guidance for Industry  
This  draft guidance,  when finalized,   will  represent the Food and Drug Administration's   (FDA's)  
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 
Under section 413(a)(2)  of the Federal  Food,  Drug,  and Cosmetic  Act (FD&C  Act) (21 U.S.C.  
350b(a)(2)),  the manufacturer or  distributor   of a new  dietary ingredient  (NDI) that has not  been 
present in the  food supply as  an article  used for food,  or a  dietary supplement  containing  such an 
NDI,  must  submit  a  premarket  safety notification  to FDA  at least 75 days before introducing  the  
product  into  interstate commerce.   This guidance  is intended to  help  manufacturers  and distributors  
of  dietary ingredients  and dietary supplements  (you)  decide whether  to submit  a premarket safety  
notification  to FDA (we  or us) for  a product that  is  or contains  an  NDI.   These premarket  
safety notifications   are commonly  referred to as NDI  notifications.   The  guidance  is  also  intended 
to help you  to prepare  NDI notifications   that we  will  be able to review  more efficiently  and respond 
to more  quickly.   
The guidance  answers frequently asked questions  about  NDI notifications   and related issues.   The  
major  topics it  addresses  are:  
  What  qualifies   as an  NDI; 
  When an  NDI  notification  is  required; 
  What are the procedures  for submitting  an  NDI  notification; 
1  This guidance has  been prepared by the Office of Dietary Supplement Programs in the Center for Food Safety and  
Applied Nutrition at the U.S. Food and Drug Administration.  
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   What  types  of data and information  FDA  recommends  you consider when you  evaluate 
the safety of  NDIs and  dietary supplements  containing  an  NDI; and  
   What  FDA recommends  you  include in an  NDI  notification.     
 
In addition,   the guidance  contains  questions  and answers about  parts  of  the  definition  of dietary 
supplement2  that can affect  whether a particular  substance may be marketed  as  a dietary  ingredient  
in a  dietary supplement.   We  encourage  you  to consult this guidance during your  safety review  of  
dietary  supplements  that contain an  NDI  and when you prepare  NDI notifications.     
 
The guidance  focuses on interpreting  the FD&C Acts  requirements  relating  to NDIs and dietary 
supplements  that contain an NDI.  It  does not  discuss  other parts of  the FD&C  Act that may affect  
the regulatory status of  a  particular  ingredient   or product,  such as  provisions  of  the FDA Food 
Safety  Modernization  Act (FSMA)3  that may  apply to dietary ingredients   and/or dietary 
supplements.  
 
FDAs  guidance documents,  including  this  guidance,  do not establish legally  enforceable  
responsibilities.   Instead,  guidances  describe  our  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  FDA  guidances means  that something is suggested or  recommended,  but not  
required.  
 
II.   Background    
On October 25,  1994,  the Dietary Supplement  Health  and Education Act  of  1994 (DSHEA) (Pub.  
L. 103-417) was  signed into law.   DSHEA  amended the  FD&C  Act  by adding,  among other  
provisions,   (1) section 201(ff)  (21 U.S.C. 321(ff)),  which defines  the term dietary supplement;  
and (2) section 413 (21 U.S.C.  350b),  which defines the  term  new dietary ingredient  and requires  
the manufacturer  or distributor   of  an NDI,  or of the dietary supplement  that  contains  the  NDI, to 
submit  a premarket  notification  to FDA at  least 75 days before introducing  the  product  into 
interstate  commerce or delivering  it  for introduction  into interstate  commerce,  unless  the NDI and 
any other  dietary ingredients   in the dietary supplement  have been present in the food supply as  an 
article used for food in a  form in which the  food has  not  been chemically  altered (21 U.S.C.  
350b(a)(1)).    
 
The notification  must  contain the information,   including  any citation to published  articles,  which 
provides  the  basis on which the  manufacturer or  distributor   of  the  NDI  or dietary supplement  (the  
notifier)  has concluded that the dietary supplement  containing  the NDI  will  reasonably be expected 
to be safe  (21 U.S.C. 350b(a)(2)).  If  the required premarket  notification  is not  submitted to FDA,  
section 413(a)  of the FD&C Act  (21 U.S.C. 350b(a))  provides that  the dietary supplement  
containing  the NDI is deemed to be adulterated under  section 402(f)  of the FD&C Act  (21 U.S.C.  
                                              
2 Dietary supplement  is defined in 21 U.S.C.  321(ff).  Available at: https://www.gpo.gov/fdsys/pkg/USCODE-2014-
title21/pdf/USCODE-2014-title21-chap9-subchapII-sec321.pdf  
3   Pub. L. No.  111-353,  124 Stat.  3886 (2011).    
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342(f)).  Even if  the notification  is  submitted as  required,  the dietary supplement  containing  the  
NDI  is  adulterated under  section 402(f) unless there  is a  history of use  or other  evidence of safety 
establishing  that  the NDI, when used under  the conditions   recommended or  suggested in the  
labeling  of the dietary supplement,  will  reasonably be expected to be safe.   
 
To help  industry comply with DSHEA,  we  issued a regulation  in  21 CFR 190.6 (  190.6 or the NDI  
regulation)   to implement   the FD&C Acts  premarket notification  requirements  for  dietary 
supplements  that contain an NDI  (62 FR 49886;  September  23,  1997).  The NDI regulation 
specifies  the  information  the  manufacturer or  distributor   must include  in its premarket NDI  
notification  (21 CFR 190.6(b)):4    
 
   The name and complete  address of the manufacturer  or distributor   that is  submitting  the  
notification.  
   The name of  the NDI  that is  the subject  of  the premarket notification.   For botanicals,  
the Latin binomial   name must  be given,  including  the author  citation (the name of the  
scientist who gave  the  botanical its  Latin binomial   name).  
   A description of the dietary supplement  that contains  the NDI, including:  
  the level  of the NDI in the dietary supplement,  and  
o 
  the conditions   of  use  recommended or suggested in the labeling  of the dietary 
o 
supplement,   or if  no conditions   of use are  recommended or suggested in the  
supplements  labeling,   the ordinary conditions   of use  of the  supplement.  
   The  history of use  or other  evidence of safety establishing  that  the  dietary ingredient,  
when used under  the conditions   recommended in the labeling  of the dietary supplement,  
will  reasonably  be expected to be safe.  
   The signature  of  a  person authorized by the  manufacturer or  distributor   to sign the  
notification  on its behalf.  
In addition  to the requirements  for the content  of NDI notifications,   the NDI regulation establishes  
the administrative   procedures for these notifications.   Section 190.6(c)  defines  the filing  date  of a  
notification  as the  date  we  receive  it and, consistent  with section 413(a)(2) of the  FD&C Act, 
prohibits   the manufacturer  or distributor   of  the dietary supplement  that contains  the NDI  from  
introducing   the product  into  interstate commerce, or delivering  it  for introduction   into interstate  
commerce,  for 75 days after  the filing  date  (21 CFR 190.6(c)).    If  the  manufacturer or distributor  
submits additional   substantive information  in support of  the  original  NDI notification,    190.6(d)  
provides  that the  date  of this supplemental  submission  to FDA  becomes the  new notification  filing  
date,  and  the 75-day period  restarts.  Consistent  with section 413(a)  of the FD&C Act,    190.6(e)  
provides  that FDA  will  not disclose  the  existence of,  or the information  contained in,  an NDI  
notification  for 90 days after  the filing  date  of  the notification.   Section 190.6(e)  further  provides  
that after  the 90th  day,  the entire notification,   except trade secrets  and confidential  commercial  
information,   will  be  placed on public  display,   as  prescribed in section 413(a) of  the  FD&C  Act.   
Finally,     190.6(f)  states  that FDAs failure  to respond to an NDI  notification  does not  constitute  a  
                                              
4 Please see question V.A.2 for a  recommended template for the format and content of an NDI notification, and section  
VI.A  for detailed recommendations on what to include in the identity section of an NDI notification.  
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finding  by the agency that the NDI or the dietary supplement  containing  the  NDI is  safe or  is  not  
adulterated under section 402 of  the  FD&C  Act  (21 U.S.C.  342).  
On January 4,  2011,  the President  signed into law the FDA Food Safety Modernization  Act  
(FSMA)  (Pub. L.  111-353).   Section 113(b) of  FSMA  requires FDA  to publish,   not  later than 180 
days  after  the date of enactment, guidance that  clarifies  when  a dietary  supplement  ingredient  is an  
NDI, when the manufacturer  or distributor   of a  dietary ingredient  or  dietary supplement  should 
submit  an NDI  notification  to FDA under  section 413(a)(2)  of the FD&C  Act,  the evidence  needed 
to document  the safety of an NDI, and appropriate  methods  for  establishing  the identity  of an NDI.   
In July 2011,  we  published  a draft  guidance  to comply with section 113(b)  of FSMA  (see 76 FR  
39111; July 5,  2011).   This  revised  draft guidance replaces the July 2011 draft guidance.  
 
III.   Goals  and Public   Health Importance  of the Guidance  
One key goal  of this  guidance  is  to improve  the rate  of  compliance  with the NDI notification 
requirement.  In 2012, FDA estimated  that the number  of dietary supplements  on the market was  
55,600 and that  5,560 new dietary supplement  products  come on the market each year.5  This  is in  
contrast  to the  approximately  4,000 products  that were  on the market in 1994,  when  DSHEA was 
enacted.6    As of December  2014,  we had  received and completed our evaluation of  just over 750 
NDI  notifications   since  the first  notification  was  received in 1995.7   These  figures, coupled with 
recent concern  about  the presence  of undeclared active ingredients   in products  marketed as  dietary 
supplements,  highlight   the importance  of submitting  NDI  notifications   as a  preventive  control  to 
ensure that consumers  are  not exposed to unnecessary public   health risks in the  form of  new  
ingredients  with unknown safety profiles.8   To improve  public  understanding  of the NDI  
notification  requirement,  this guidance  includes  an in-depth  discussion  of  the scope of the  
requirement,  along with detailed examples of  situations   in which a notification  would or  would not  
be required.    
 
A second goal  of the guidance  is  to improve  the quality of NDI notifications.    Our aim  in  issuing  
the  NDI  regulation  in 1997  was  to ensure that NDI  notifications   contain the information  that  is  
necessary for  FDA to evaluate  whether a  dietary supplement  containing  an  NDI  is reasonably 
expected to be safe, and that  aim  remains  the same today.  After  many years  of  experience with  
reviewing NDI notifications   and answering questions  from  industry, we have concluded that  a 
guidance  on NDI issues  is needed  to help the dietary supplement  industry understand and  comply 
with section 413 of the FD&C Act  and the  NDI regulation.  We hope  that the additional  
                                              
5  Dietary Supplement Labeling Requirements and Recommendations Under the Dietary Supplement and  
Nonprescription Drug Consumer Protection Act, 77 FR  35687  (June 14, 2012). 
6 Dietary Supplement Health and Education Act of 1994, Pub. L.  103-417,  2(12)(C),  108 Stat. 4326. Available at: 
http://www.fda.gov/regulatoryinformation/legislation/significantamendmentstothefdcact/ucm148003.htm 
7  Memorandum to File from  Fred A. Hines, Consumer Safety Officer, FDA (December 17,  2014).    
8 See, e.g., NDI Notification Response - E.  coli Nissle strain (Oct. 28, 2011)  Available at: 
https://www.regulations.gov/document?D=FDA-2012-S-1178-0014; NDI Notification Response - Human placenta 
extract (Apr. 6, 2011).  Available at: https://www.regulations.gov/document?D=FDA-2011-S-0933-0133    
12   Contains Nonbinding Recommendations  
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explanation  in this  guidance will  help you decide when an NDI  notification  is  required  and what  
that notification  should contain.   
 
DSHEA does not  specify  the type  or amount  of evidence  that must  be included in an  NDI  
notification.    Accordingly,   this guidance  explains  how  to submit  a  premarket notification   and 
makes  detailed  recommendations   on the  type and amount  of evidence  to include.   As set forth  in  
more detail in  the  rest  of  this guidance,  we recommend including  in  your  NDI notification   the  
following:    
 
    A  full description of  the identity and composition  of the NDI  and the dietary 
supplement  in which the NDI  will  be marketed;   
   A  discussion of  the basis  for  your  conclusion  that the substance  is  an  NDI;   
   A  description of  the conditions   of use recommended or suggested in the  labeling  of the  
dietary supplement,   or  if  no conditions   of use are  recommended or suggested  in the  
labeling,   the ordinary conditions   of use of the supplement;  and  
   An explanation  of  how  the  history of  use or other  evidence  of safety in the notification 
justifies  your  conclusion  that the  dietary supplement  containing  the NDI will reasonably 
be expected to be safe.  
 
 
IV.   Determining  Whether  a New Dietary Ingredient  (NDI)  
Notification  Is  Required  
A.   What  Is a New Dietary Ingredient?  
1.   What  do the terms  dietary ingredient  and new dietary ingredient 
mean?  
As  defined  in  section 201(ff)(1) of the FD&C Act (21 U.S.C.   321(ff)(1)),  a dietary  
ingredient  is  any one  of the following:  
(A)  A vitamin;  
(B) A mineral;  
(C) An herb or other  botanical;  
(D) An amino acid;  
(E) A  dietary substance for use by man to supplement  the diet  by increasing the  
total dietary intake; or  
(F) A concentrate, metabolite,   constituent,  extract,  or combination  of any 
ingredient   described in (A), (B),  (C), (D),  or (E).  
An  NDI  is  defined as  a dietary ingredient   that was  not  marketed in the U.S.  before  
October 15,  1994  (21 U.S.C. 350b(d)).   Thus,  to be an NDI, a  substance must  be a  
dietary ingredient.  
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2.   Can a  substance that is not a  dietary  ingredient be an NDI?  
No.  Because  new dietary ingredient  is  defined to mean a dietary ingredient   that  
was not  marketed in the U.S.  before  October 15,  1994,  a  substance cannot  be a  new  
dietary ingredient   unless it is also a  dietary ingredient.  
3.   Must  I submit  an  NDI  notification for  a  dietary  ingredient marketed in the  
U.S. prior  to October 15, 1994?  
No.  Dietary ingredients   marketed prior  to October  15, 1994 (pre-DSHEA dietary  
ingredients)  are not  NDIs and,  therefore,  do not require  an  NDI  notification.   See  
questions  IV.A.4, IV.A.7  and IV.A.10  for more on how FDA interprets  the terms  
marketed  and dietary ingredient   in the definition  of  an  NDI  (21 U.S.C. 350b(d)).  
4.   Is an ingredient that was  used to make  a conventional food marketed before  
October 15, 1994, an NDI?  
It depends.  The  use  of an ingredient   in  a conventional  food before October 15,  
1994,  does not  determine  whether the  ingredient  is  an  NDI.  What matters is  whether  
the  ingredient   was marketed  as  a dietary ingredient     meaning  that  it  was marketed  
in or  as a dietary supplement,  or  for use  in a dietary supplement    in the U.S.  
before October 15,  1994.   Therefore, an ingredient   that was  used to make a  
conventional  food before October  15, 1994,  is  still  an  NDI  unless  the ingredient   was  
also  marketed as a dietary  ingredient  in the U.S.  before  October 15,  1994.   For  
example, an  ingredient   used to color  a conventional   food before October 15,  1994,  
would be  an  NDI  unless  it  was  also  marketed  before October 15,  1994,  in or  as a 
dietary supplement,   or as a  dietary ingredient   for use in a dietary supplement.   
We recognize  that the present definitions   of dietary supplement  and dietary 
ingredient  were not  added to  the FD&C Act until after  October 15,  1994,  and that  
many products now marketed as  dietary ingredients   for  use  in dietary supplements  
were marketed under  other  product  categories,  such  as foods for special dietary use  
or  food additives.   Therefore,  we interpret  dietary ingredient   to refer to ingredients  
that  (1) if  marketed today, would qualify as  dietary ingredients  under  21 U.S.C. 
321(ff)(1);  and (2)  when marketed before October 15,  1994,  were  intended for use  
as  or  in a  product that  would now  be  a  dietary supplement  as  defined in 21 U.S.C.  
321(ff) and that would not also meet the definition  of  a drug.   See questions  IV.A.7  
and IV.A.10  for more about  FDAs views  on the meaning of marketing  and 
dietary ingredient  in the  NDI  definition.  
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a.   Is  an  NDI  notification  required  for a  dietary supplement  containing  an  
NDI if  the supplement contains only dietary  ingredients that have been 
present in the food supply  as articles used for food in a  form  in which 
the food has not  been chemically altered?  
No, an NDI  notification  would not be  required in this  situation  because of  the  
exception to the  notification  requirement  for dietary supplements  that contain 
only dietary ingredients  that have  been present in the food supply as  articles  
used for food in a form in which the food has  not  been chemically  altered  (21 
U.S.C. 350b(a)(1)).  See questions IV.B.4  and IV.B.5  for FDAs view on  
what chemically   altered means.   
 
Example:  Ingredient  X is  a  food additive  that  was approved for  use to 
sweeten baked goods  in 1993 and was  marketed for that use  before October  
15, 1994,  but was  not marketed for use  as  a  dietary ingredient   in dietary 
supplements  before that date.   ABC Company wants to market  a  supplement  
that  contains Ingredient X,  and  it  plans  to use the same  form  of  Ingredient  X  
used as  a sweetener  in baked goods.   Ingredient  X  will  be the only dietary 
ingredient   in the supplement,   which will  be called X-cellent.  Although 
Ingredient X  is  an  NDI  because it was  not marketed as  a dietary ingredient  
before October 15,  1994, ABC Company  is  not  required  to submit  an NDI  
notification  for  X-cellent  because Ingredient  X  has  been present in the food 
supply as  an article used for food  in a  form in which the  food has  not been 
chemically  altered, and it is the  only dietary ingredient   in the  supplement.      
b.   Does the adulteration standard in 21 U.S.C. 342(f)(1)(B)9  apply to  a 
dietary  supplement containing  an NDI even when  an  NDI notification is  
not required?  
Yes.   The  adulteration standard in 21 U.S.C.  342(f)(1)(B) applies to  all  
dietary supplements  that  contain an NDI, even in situations  when  no 
notification  is required because  the supplement contains  only dietary 
ingredients  that  have been present in the food supply as articles  used for food 
in a  form in which the  food has  not been chemically altered.  See section  
IV.B  for  more information  about  chemical alteration and  the  exception to the  
NDI  notification  requirement  for certain NDIs that have been present in the  
food supply as conventional  foods.    
                                              
9 Under 21 U.S.C. 342(f)(1)(B),  a dietary supplement containing an NDI is adulterated unless there is adequate  
information to provide reasonable assurance that the NDI does not present a significant or unreasonable risk of illness  
or injury.  
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5.   Is a substance that was a component of a conventional food marketed before  
October 15, 1994, an NDI if  the component was not  a dietary ingredient  
marketed in the  U.S. before October 15, 1994?  
Yes, assuming the component  meets  the  definition  of a  dietary ingredient.  The mere 
presence of a substance as  a component  of a conventional  food that  was marketed  
before October 15,  1994,  does not  establish  that the substance was  marketed  as  a 
dietary ingredient   before that date.   Similarly,  the fact that  a minor  component may 
have been isolated  as  part of an analytical  chemical  procedure to examine the 
composition  of the previously  marketed food before October 15,  1994,  is not  
sufficient to establish that the component  is  a  pre-DSHEA dietary ingredient   or  even 
that  it is a  dietary ingredient  at all.   If  it is not a  dietary  ingredient,   it is ineligible   to  
be  an  NDI.   If the  food component  fits  into one  of the dietary ingredient   categories  
(for example,  if it  is a  metabolite or extract  of  another dietary ingredient)  but was  
not  marketed as a dietary ingredient  before October 15,  1994,  it would be  an  NDI.   
On the other  hand,  if  the substance was marketed as  a dietary  ingredient  before that  
date (in addition  to its  marketing for conventional  food use), then it is not  an  NDI.   
(See questions  IV.A.4, IV.A.7, and IV.A.10  for FDAs  views on the  meaning of  
marketing  and dietary ingredient   in the NDI  definition.)  
6.   Is a  substance  that was an ingredient in  a dietary supplement  marketed  
before October 15, 1994, an NDI?  
The answer  depends  on whether the substance was  used as a  dietary ingredient  or  for 
some other  purpose  (e.g., excipient  or processing aid)  in the  pre-DSHEA dietary 
supplement.  If  the substance  was added to  the  supplement as  a dietary ingredient,   it  
is  not  an NDI  and may be used in dietary supplements  without  submitting  an NDI  
notification  to FDA.     
If the substance was  not  added to the  pre-DSHEA dietary supplement  as a  dietary 
ingredient,   however, the analysis  becomes more complicated.   If the substance was  
directly added  to  the pre-DSHEA dietary supplement,   intended to become  a  
component  of the  finished dietary supplement  and  have a technical  effect in  it,  and 
was  GRAS  or  approved as a food additive  for that use, the substance  would be an 
NDI.   However,  because most  secondary direct food additives,10   indirect food 
additives,11   food contact substances,12  and other indirectly  added substances  are not  
                                              
10  Secondary direct food additives are added during the manufacturing of a food to achieve a technical effect, but they  
have no technical effect in the finished food.   See FDA, Food Ingredients and Packaging Terms. Available at: 
http://www.fda.gov/Food/IngredientsPackagingLabeling/Definitions/default.htm (accessed April 22,  2015). 
11  Indirect food additives come into contact with food as part of packaging, holding, or processing, but they are not  
intended to be added directly to, become a component of, or have a technical effect in or on the food.   Before the FDA  
Modernization Act of 1997, indirect food additives were approved by regulation.   Now, new indirect food additives are  
authorized through the food contact substance notification program. In addition, indirect food additives may be  
authorized through the threshold of regulation exemption process in 21 CFR 170.39.   See FDA, Food Ingredients and  
 
16   Contains Nonbinding Recommendations  
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intended  to  have a technical  effect in  or  become components  of  the finished food  
(see question  IV.D.4), you would first  have  to consider whether  such a substance fits  
into  one of  the  dietary ingredient   categories in section 201(ff)(1)  of the FD&C Act  
(21  U.S.C. 321(ff)(1))  to determine  whether it  is  an NDI.  If  the substance does  not  
fit into any of  the  dietary ingredient   categories, it would not be  either  an NDI  or a  
pre-DSHEA dietary ingredient.    Rather, it could not be  used as a  dietary ingredient  
in a  dietary supplement  at all.   
7.   What  does  marketing  a dietary ingredient mean?  
FDA considers  marketing  a  dietary ingredient  to mean selling  or offering the  
dietary ingredient   for sale  (1) as  or in  a dietary supplement,   (2) in bulk as  a dietary 
ingredient   for use in dietary supplements,   or (3) as  an ingredient   in a blend or  
formulation  of dietary ingredients   for use in dietary supplements.  A  dietary 
ingredient   may be marketed  by offering the article  for sale  online  or  at a retail  
establishment,   listing  it for sale  in a  catalog or  price  list, or  through advertising or  
other  promotion,   if the  promotion  makes clear that the article  is  available  for  
purchase.  Coming soon  advertisements  would not  qualify.    
 
If  a dietary supplement  containing  an NDI  is sold before  the manufacturer  or  
distributor   submits  a required NDI notification   or less  than 75 days after  the  
notification  is submitted,  the  sale  of the  product is not evidence  that the dietary 
supplement  or NDI was  lawfully marketed.   
8.   Is a dietary ingredient marketed outside the U.S. prior to October 15, 1994,  
considered to be  an NDI if  it  was not  marketed in the U.S. before that  date?  
Yes.  Submitting  documentation  that the ingredient   was  marketed in any other  
country before this  date does not  establish that the  ingredient  is  not  an  NDI.  The  
only kind of  marketing that  is relevant to  whether a dietary ingredient   is  an  NDI  is  
marketing in the  U.S.  before October  15, 1994.13   
9.   What documentation does FDA recommend to show that a  dietary 
ingredient was  marketed prior to October 15, 1994?  
Documentation to show that a dietary ingredient   is not  an  NDI  should consist of  
written business  records,  promotional  materials,  or press`  reports  with a  
                                                                                                                                                       
Packaging Terms. Available at: http://www.fda.gov/Food/IngredientsPackagingLabeling/Definitions/default.htm  
(accessed April 22,  2015). 
12  A food contact substance is a substance intended for use as a component of materials used in manufacturing, packing,  
packaging, transporting, or holding food if that use is not intended to have any technical effect in the food.   21 U.S.C.  
348(h)(6).  
13  For  evidence of marketing in another country as evidence of safety, especially when considering the differences in  
dietary consumption  between countries, see question VI.B.3.  
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contemporaneous date  prior  to October  15, 1994.   Examples  include  sales records,  
bills   of lading,  sales contracts,  manufacturing  records,  commercial invoices,  
magazine advertisements,  mail  order catalogs,  or sales brochures.    
Documentation should  include  adequate information  to establish that marketing took 
place in  the U.S.:   the  identity  (e.g., chemical  or botanical name)  of the marketed 
ingredient,  including  its  form (e.g.,  ground herb,  water extract,  oil),  and whether  the  
ingredient   was marketed  as  a dietary ingredient   or for some  other purpose.   For  
example, advertising  in body building  magazines could be  adequate evidence of  
marketing as  a  dietary ingredient.  On the other hand,  advertising or  other references  
in gardening or landscaping  magazines  would not  likely  serve  as adequate evidence  
of the marketing of  a botanical  or herb  as a  dietary ingredient.   
We would also consider  GRAS  and food additive  regulations in  the  Code of Federal  
Regulations  as documentation that  an ingredient  was marketed as a  dietary 
ingredient   before October 15,  1994,  if  the regulation covers use of the substance as a  
nutrient supplement,  became effective before October 15,  1994,  and contains  
identity  specifications  that the ingredient   meets. Although  references  published 
before October 15,  1994,  such as  the 1992 edition  of  Herbs of Commerce,14  may be  
supportive,   we are unlikely  to regard a listing  in Herbs of Commerce  as being solely 
determinative  of  whether  a dietary ingredient   was marketed as  such before October  
15, 1994  because this listing   may  not specify necessary information  such as  the plant  
part and/or  extract type.   If you rely on Herbs of Commerce  as evidence  that your  
dietary ingredient   is  not  an NDI, we  recommend that you maintain  additional  
documentation  showing that  the botanical  was  marketed  as a  dietary ingredient  
before  October  15,  1994.   The documentation  should specify the plant  part  from  
which the  botanical dietary ingredient was  derived,  and for botanical  extracts  it  
should also specify  the extract type.  
Affidavits  attesting to recollection of  when a dietary ingredient  was  first marketed  
generally would  not  be  adequate to show  that an ingredient  was  marketed prior  to 
October 15,  1994, unless  supported by contemporaneous  written records.   Because 
memory can be  unreliable,  especially when the  event  in question took place more  
than thirty  years ago,  we  are not  likely  to  regard  such an affidavit  alone, without any 
sort of objective,   verifiable  documentation  from  the time  of  marketing,  as  an 
adequate basis  to establish pre-DSHEA  marketing  of a substance as  a dietary  
ingredient   for use in  or as  a dietary  supplement.  
                                              
14  Moley, Timothy, Steven Foster, and Dennis Awang.  Herbs of Commerce. Austin, TX: American Herbal Products  
Association, 1992.   
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10.   Is marketing an ingredient for any use  prior to October 15, 1994, sufficient  
to conclude that  it  is  not  an  NDI?  
No.   FDA  does not consider the marketing of an ingredient  as a  conventional  food,  
as  a drug,  or for any other non-food use,  to be  evidence  that an ingredient  is not  an  
NDI.  Unless the ingredient  was  marketed  as a dietary  ingredient  for  use in or as  a 
dietary supplement  prior  to October  15, 1994,  it is  an  NDI.    
11.  Is there an authoritative  list of  dietary  ingredients that were marketed prior 
to October 15, 1994 (a so-called grandfathered list or  old dietary  
ingredient  list)?  
Not  currently.  Some trade associations and other  industry groups have  compiled 
lists of  old dietary ingredients,   15  though FDA is unable  to verify  the accuracy of  
these lists because we  have  not  seen documentation  showing  that the ingredients   on 
such  lists  were marketed  as dietary ingredients   prior  to October 15,  1994.  The lists  
contain ingredients  FDA believes  are unlikely   to have been marketed  as  dietary  
ingredients,  like acetaminophen or  pharmaceutical glaze,  and mixtures  that  are only 
vaguely described,  like sterol complete premix.   Moreover, the  introduction  to one  
trade association  list16  states  that the association did not independently  verify that  
the substances  on  the list  were in use  before October 15,  1994.   The cover page of  
the list  specifically  states,  This list  is compiled solely for  reference  purposes and 
does not  constitute  verification  that any specific  dietary ingredient  was  or was not  
marketed as a dietary supplement  before  October  15,  1994.  The trade associations 
introduction  to the  list  also  states,  There is no definitive   list  of  grandfathered 
dietary ingredients.   The best policy  is for  any company to maintain its  own records  
confirming  long-term  use of an ingredient.   Because  of the uncertainty about  the  
existence  of supporting  evidence,  FDA  does not  accept  the inclusion  of an 
ingredient   on an industry  list  of pre-DSHEA dietary ingredients  as  proof  that the  
ingredient   is not  an  NDI.  However,  in response  to comments,  we are prepared  to 
develop an authoritative   list  of pre-DSHEA ingredients,   based on independent  and 
verifiable data.  Because  FDA does not  generally have access to marketing  records  
for dietary ingredients  and dietary supplements,  the  documentation   of pre-DSHEA 
marketing  would have to be supplied   by industry.  
                                              
15  See, e.g.,  National Nutritional Foods  Association, NNFA List of Dietary Supplement Ingredients In Use Before 
October 15, 1994 (April 26,  1996).   Docket No. FDA-2005-P-0259 [Document ID: FDA-2005-P-0259-0012].  
Available at: 
https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Tan%20Sheet/19/50/111212_UNPA_ 
ODI_List.pdf   
16  Council for  Responsible Nutrition, CRN List of  Dietary Ingredients Grandfathered Under DSHEA (September  
1998).   Docket No. FDA-2005-P-0259 [Document ID: FDA-2005-P-0259-0010].  Available at: 
http://www.fda.gov/ohrms/dockets/dockets/05p0305/05p-0305-cr00001-04-Council-For-Responsible-Nutrition-
vol1.pdf  
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FDAs current thinking  is that  the two main factors  for placing an ingredient   on an 
authoritative   list  of pre-DSHEA ingredients  would be:  (1) adequate documentation 
of marketing for use  as or  in a  dietary supplement  in the U.S.  before October 15,  
1994:  and (2) a precise  description  of  the  identity  of  the ingredient  marketed.  
Records offered to support  an items  inclusion  on the list  should specify the date of  
marketing in the  U.S. and clearly identify  the  ingredient  marketed on that  date.  
Documentation of an ingredients   identity should be sufficiently  precise to uniquely 
identify the  ingredient.   See question IV.A.9  for the kinds  of documentation  FDA  
recommends  to show that a dietary ingredient   was  marketed prior  to October 15,  
1994.    
Including  an ingredient   on FDAs  list of  pre-DSHEA dietary ingredients  would 
represent  our  view  that  the evidence  is adequate  to conclude  that the dietary 
ingredient   in question is not  new and,  therefore,  not subject to the  NDI  
notification   requirement.  The mere  fact that an ingredient  is  not  on the list  would 
not, however,  establish that  the ingredient   is  an NDI  or that dietary supplements  
containing  that dietary ingredient  are  adulterated for failure  to notify.   Rather,  the  
omission  of an ingredient   from  the list  would be regarded as  neutral  and would not  
affect the ingredients  regulatory status.   Whether  FDA would investigate  dietary 
ingredients  not on the  list  to determine whether  an NDI notification  should have  
been submitted would typically  depend on factors  relating to public  health, such as  
potential for  risk,  extent  of public  exposure  to the ingredient,   and association with 
adverse events.    
Although only one instance  of marketing as  a dietary ingredient   before October 15,  
1994 (pre-DSHEA marketing)  need be shown to establish that an ingredient  is  not  
an NDI, each dietary supplement manufacturer  and  distributor   is responsible  for  
determining  whether  each  dietary ingredient  in each of  its  dietary supplements  is an  
NDI and ensuring that  the firm  complies  with the NDI  notification  requirements, if  
applicable.  For ingredients   that are  not on FDAs  list  of pre-DSHEA dietary  
ingredients,  a  firm could either maintain its own records  of  the  pre-DSHEA 
marketing of a  dietary ingredient  or rely on another  firm  or organizations   records,  
with that entitys permission.     
12. If Ichange the manufacturing  process for a dietary ingredient that  was  
marketed in the U.S. prior  to October 15, 1994, does that make the  
ingredient  an  NDI?  
The answer  depends  on the extent to which the manufacturing  process  change  
affects  the  resulting ingredient.   As discussed  in a  separate FDA  guidance  on 
manufacturing changes,17  such changes  may affect  the identity of the food substance  
                                              
17  FDA, 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,  
 
20   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
or its  safety and suitability  for certain conditions   of use.   Manufacturing  changes  
may also affect  the purity of a food substance,  such as  the amounts  of impurities   and 
contaminants  in the  food substance.    
Any  changes  in your manufacturing  process  that alter the identity   of the ingredient  
will  convert a  previously  marketed dietary ingredient   into  an  NDI.  Manufacturing 
changes that alter  the physicochemical  structure or  properties,  purity and impurities,  
or biological   properties  (such as  bioavailability  or toxicity)  of  the ingredient  result  in 
an NDI.18   For example,  using a solvent  to prepare  an extract from  a pre-DSHEA 
dietary ingredient  creates  an  NDI  because the final  extract contains  only a  
fractionated subset  of the constituent  substances  in the original  dietary ingredient.   A 
manufacturing change which changes the ingredient   in a  way that leads  to alteration 
of the serving level  or conditions   of use of the product  is another  example of a 
significant   change  which is  likely  to create an NDI.  
In addition,   changes that alter  the  identity  of  the source  material  for an  ingredient  
may  create an NDI.   For example,  using  a  different  part of a plant  (e.g., using an 
extract of plant  leaves where the root  extract from  the same plant  is  a pre-DSHEA 
dietary ingredient)   would create an  NDI.   If the  ingredient   produced by the new  
manufacturing process  is  an NDI, an NDI  notification  is  required unless  the NDI has  
been present in the food supply as  an article  used for food in a form in which the  
food  has not  been chemically  altered (see Section  IV.B).   On the other hand,  if the  
manufacturing changes do not  alter the identity  of the  ingredient  (e.g.,  there are no  
changes in physicochemical   structure or properties  and no changes in purity,  
impurities   or  biological   properties such as  bioavailability  or  toxicity)   then the  
regulatory status of  the  pre-DSHEA ingredient  does not  change and  no NDI  
notification  is needed.   
Note that the question of whether a manufacturing change creates  an NDI is  
different  from  the question of whether the manufacturing  change constitutes  
chemical  alteration,  and different  standards apply.  The chemically  altered 
standard in section 413(a)(1)  of the FD&C Act  (21 U.S.C.  350b(a)(1))  governs only 
the manufacturing of  dietary ingredients  that have been  present  in the food supply  
as articles  used for food  (i.e., conventional  foods and their  ingredients)19  and is 
applied to determine  whether an NDI  notification  is  required for a  conventional   food 
ingredient   that was  not  marketed as a  dietary ingredient   before October 15,  1994.  In 
general,  a  broader  range of manufacturing changes  would create an  NDI by  
                                                                                                                                                       
Including Food Ingredients that are Color Additives; June 2014 Available at: 
http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/ucm300661.htm.  
18  FDA, 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; June 2014 Available at: 
http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/ucm300661.htm.  
19  See question  IV.B.1.  
21   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
changing the identity of  a dietary  ingredient  than would  chemically  alter an article 
of food present  in the food supply.  For example,  solution  in water  or tincture  may 
change the composition  of a pre-DSHEA dietary ingredient   enough to make it  an 
NDI for  which a notification   is required.  However, solution  in water  or tincture  
would  not  constitute  a chemical alteration of  a  conventional  food ingredient  (see  
questions  IV.B.4  and IV.B.5), and therefore, no NDI notification  would be  needed 
when a tincture  or solution  in water  made with a  conventional  food ingredient  is  
used as  a dietary ingredient.  
It should also be  noted that some manufacturing changes may alter the  identity of  
the ingredient   to the point  that it  no longer  meets the definition  of a  dietary 
ingredient   (see question IV.D.5).  Firms  planning  a manufacturing change are  
encouraged to consult  with FDA on any questions  as  to  whether such a  change  
would create an  NDI  or an ingredient   that does not  meet the definition  of  a  dietary 
ingredient.20  
13. Should I submit  a  new NDI notification if I  change the manufacturing  
process for an  NDI that  is the subject of a notification for  which I have  
received an acknowledgment without  objection from  FDA?  
That depends  on the nature of the  change to the manufacturing process.  If  the  
manufacturing change does  not  alter  the  chemical  or molecular  composition  or  
structure  of the  dietary ingredient   or the specifications  needed to describe the  
ingredient,   it is not necessary to submit  a  second NDI  notification.   On the other  
hand, a  manufacturing process  change  intended to produce  an ingredient   with 
particles  in the  1 nm to 100 nm (approximate)  nanoscale range may  alter the  
chemical  or molecular  composition  or structure  of the  NDI.  In that case, the  
previously  submitted notification  for a related substance manufactured without  using 
nanotechnology  would not  cover the  ingredient  made  with the new manufacturing 
process,  and a separate NDI  notification   with safety information  taking  into account  
the smaller  particle size of the resulting  new  ingredient  would then be required.   
If you are  planning  a manufacturing change,  we  encourage  you to consult with FDA  
on  whether  such  a change would  create a different NDI  or a  substance that  is no 
longer a  dietary ingredient.21   (See questions  IV.A.12  for  additional  discussion  on 
manufacturing  changes  that  affect the identity   of an ingredient.)      
                                              
20  Contact information for the Office of Dietary Supplement Programs can be found on the title page.  
21  Contact information for the Office of Dietary Supplement Programs can be found on the title page.  
22   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
B.   Exception to Notification Requirement for Certain NDIs with  a 
History of Use in Conventional Food  
1.   When is  a notification  not  required for  an  NDI?  
A notification  is  not  required when the  NDI and all  other  dietary ingredients  in the  
dietary supplement  have been present in the food supply as  articles  used for  food in 
a  form in which the  food has not  been chemically  altered.   See questions  IV.B.4  and 
IV.B.5  for FDAs  current  thinking  on when a  dietary ingredient   has been 
chemically  altered  from  the  form in which it is used in the food supply.  
FDA interprets  the phrase  present  in the food supply  to refer  to the conventional  
food supply.   Accordingly,   we interpret  a dietary  ingredient  that has been present  in 
the food supply as  an article  used for food  to mean a conventional  food or  
conventional  food ingredient.    We  do not consider prior use  in dietary supplements  
to  constitute  presence in the food supply.  Interpreting food supply  to include  
dietary supplements  for  purposes of this exemption  from  the NDI notification 
requirement would expand the  exception to the  point  that  it  would risk swallowing 
the  rule,  as  prior  use  in even one dietary supplement  manufactured in small  
quantities  and distributed  over a  small  area  would exempt all  dietary supplements  
containing  the NDI from the  notification  requirement,  even if  the intake  level  and 
conditions   of use were  much different.  Moreover,  such an interpretation would not  
make sense  in light  of the purpose  of the NDI  notification  requirement,  which is to 
ensure that dietary ingredients  that have not  been widely consumed receive a safety 
evaluation  before reaching  the marketplace.  Because dietary  supplements  are 
generally consumed by a  narrower  segment of  the  population  than conventional  
foods  and typically  have a  shorter  history of use than conventional  food ingredients,  
prior  use  in a  supplement  or supplements  typically  provides  less  information  about a  
substances safety than prior  use in conventional  food.  In addition,   substances  
added to  conventional  foods must  meet the  safety standards  for conventional   food  
ingredients,  which are  more demanding  than those  that apply to dietary ingredients  
used in dietary supplements.      
2.   Am I required to  submit  an  NDI  notification for  a dietary ingredient  that is  
an NDI, but has been (a) listed or affirmed  by FDA  as generally recognized  
as safe (GRAS)  for direct  addition to food  or (b) approved as a  direct food 
additive in the  U.S.?  
No,  as long as  the following  conditions   are  met. The  direct food additive  or GRAS  
substance  (1) has been used in the food supply  (i.e.,  in conventional  foods) and  (2) is  
to be used as  a  dietary ingredient  without  chemical  alteration.   (See questions  IV.B.4  
and IV.B.5  for further discussion on chemical  alteration.)      
 
If the  NDI  has been  legally  marketed in the U.S.  as  an ingredient   for use in 
conventional  food  and has  been introduced into the  food supply as  a  result of such 
23   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
marketing,  it would be  exempt from  the notification  requirement  under  section 
413(a)(1)  of  the FD&C  Act (21 U.S.C. 350b(a)(1))  because it  has been present in  the 
food supply as  an article used for  food in a  form in which the  food is not chemically 
altered.  Similarly,   ingredients   marketed in conventional  foods  outside  the U.S. are  
exempt from the  NDI  notification  requirement  if they are not chemically  altered.  
However, as discussed in the following  question,  the NDI  adulteration  standard still  
applies,  and voluntary  NDI notification  may be advisable.     
3.   Does the adulteration standard in  21 U.S.C. 342(f)(1)(B) apply  to  an  NDI  
that  has been listed or affirmed by FDA as GRAS  for  direct addition  to food  
or approved as  a direct  food additive in the  U.S.?  
Yes.  The  adulteration standard in section 402(f)(1)(B)  of  the  FD&C Act (21  U.S.C.  
342(f)(1)(B)) applies  to all  NDIs, including  NDIs  for which a notification  is not  
required.   In other  words, if  an  ingredient   was not  marketed as a  dietary ingredient   in 
the U.S. before October 15,  1994 (see questions  IV.A.4, IV.A.7  and  IV.A.10), it is  
an  NDI  and the adulteration standard for NDIs  applies.   That standard provides  that  
a dietary supplement  containing  the  NDI  is adulterated unless  there  is adequate 
information  to provide  reasonable assurance  that  the ingredient  does  not  present a  
significant   or unreasonable  risk of  illness  or injury.    
If the intake  level  of the NDI resulting from  its  use under  the conditions  
recommended or suggested in the labeling  of  the dietary supplement  is  the same  as  
or  lower than the  intake level  approved in a  food additive  regulation or specified in a  
GRAS regulation and overall  cumulative   intake of  the  NDI  from dietary sources  is  
the same as  or lower  than  the acceptable  daily intake (see question VI.C.8),  FDA is 
likely  to conclude  that there is  adequate information  to provide  reasonable assurance  
of safety,  assuming that other  conditions   of use remain unchanged.  However, the  
same is not  necessarily true if  the intake  level  of the NDI in the dietary supplement  
is  higher  than that  resulting from  conventional  food use of the NDI.  For  example,  if  
an ingredient  generally used in microgram  quantities  to flavor  food is placed in a  
capsule with a  serving level  of hundreds of milligrams,   a  safety analysis  would be  
necessary to determine  the safety of the much higher  intake  level  in the dietary 
supplement.   In the absence  of adequate information  to provide  reasonable  assurance  
that the higher  intake level  of the NDI  in the  dietary supplement  is  safe, the dietary 
supplement  would be adulterated.    
 
Although an NDI  notification  is not  required for a dietary supplement  that contains  
an NDI  that  has  been present in the food supply as  an article used  for food without  
chemical alteration,  even if  the dietary supplement  contains  more  of the NDI  than is  
used in conventional  foods,  FDA recommends  that you consult  with  us  about  your  
basis  for concluding  that  there  is  adequate information  to provide  reasonable  
assurance  that the use of the NDI in the dietary supplement  will  not  present a  
24   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
significant   or unreasonable  risk of  illness  or injury.22    As  with any new dietary 
supplement  you intend to market, you should assure  yourself  that  the  product  is safe  
under its  labeled conditions   of use before  distributing  it.  To that end,  it  may be  
advisable to submit a  NDI  notification  voluntarily  when a dietary supplement  
contains  a  significantly  higher  level  of an NDI  than is  used in conventional   foods.   
FDA has reviewed and intends to continue  reviewing voluntarily  submitted 
notifications   for NDIs  that are exempt from  the notification  requirement  under 21 
U.S.C.  350b(a)(1)  because  they have  been present  in the food supply as  articles used 
for  food in a  form in which the  food has not  been chemically  altered.   
Like  higher  daily intake  levels, combining   an NDI  with other dietary ingredients  
could  also  present safety risks,  as discussed in question IV.C.2  below.  
4.   What  are examples of processes that chemically alter an  article of food  
present in the food supply?  
Below  are some  examples  of processes  that FDA would likely consider  to involve  
chemical alteration.   These processes  would also be  likely   to affect the safety profile 
of a dietary ingredient.   The examples  below are intended only for the purpose  of  
illustration   and are not  a comprehensive list  of processes that result  in  chemical  
alteration.  See question IV.B.5  for  further discussion  on chemical  alteration.  
   A process that  makes or breaks chemical  bonds,  unless  the bonds  created 
by the process are  reversed when the ingredient   is  dissolved in water  
(e.g.,  creation  of a soluble  salt)  or during ingestion.   Example:  
hydrolysis.  
   Removal of  some  components of  a  tincture or  solution  in water, which 
changes the  chemical  or molecular  composition  or structure  of the  
mixture.   Examples:  chromatography,  distillation,   and  filtration.  
   Use  of  solvents  other than water  or aqueous ethanol to make  an extract  or  
tincture.   The official  legislative   history of DSHEA  specifies that  
solution  in water  and tincture (solution  in aqueous ethanol) are  not  
processes  that chemically  alter a food.23   However, other solvents  
typically   alter the  composition   of the extract  in significantly  different 
ways,  usually by extracting different types of  constituents  than are  
extracted using water  and aqueous  ethanol.  
   High temperature baking or cooking of an ingredient   that has not  
previously  been baked or cooked,  unless  the process  causes  only  minor  
                                              
22  Contact information for the Office of Dietary Supplement Programs can be found on the title page.  
23  Statement of Agreement, 140 Cong. Rec. S14801  (daily ed. Oct. 7,  1994).  
25   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
loss of  volatile  components  with  no other  changes to the  chemical or  
molecular  composition  or structure  of the ingredient.  
   Changing the manufacturing method for an ingredient   such that the  
chemical  or molecular  composition  or structure  is significantly  different.   
Examples:  changes that alter  the composition  of materials  used to make  
the ingredient,   use of a different  solvent,  or  use of a chromatographic  
matrix  instead  of a passive filter.  
   Application  of nanotechnology   that  results  in  new or altered chemical  
properties  of the ingredient.  
   Changing agricultural  or fermentation conditions   to alter  the  chemical or  
molecular  composition  or structure  of the ingredient.   Examples: 
sprouting  garlic  or fermenting  yeast  using a medium containing  large  
amounts  of sodium  selenite  to create  large amounts  of organic  selenium  
compounds.  
   Fermentation using a  fermentation medium  different from the  one  used to 
make conventional  foods  in the food supply.  Example:  use of a  defined 
commercial  growth medium  to produce  a microorganism   previously 
made  by fermenting milk into dairy products like yogurt or  cheese.  
   Use of a botanical  ingredient  that is  at a different  life stage than  the life  
stage of the botanical  ingredient  used as  a conventional  food.  Examples: 
making an extract from  unripe  instead of ripe apples or  using  the  
mycelium   instead of the fruiting  body of a  fungus.  
5.   What  processes for manufacturing  a dietary ingredient from  an article  of  
food present in the food supply  do not  result in  chemical alteration?   
As set  forth  in the Congressional  Statement  of Agreement between the House and  
Senate sponsors  of DSHEA, [T]he term  chemically altered  does not  include  the  
following  physical  modifications:    minor loss  of  volatile   components, dehydration,  
lyoph[i]lization,  milling,   tincture  or solution  in water,  slurry,  a powder,  or solid in 
suspension.24   FDA considers  this list  to represent  examples  of manufacturing 
processes  that  do not involve   chemical  alteration,  but not necessarily a  complete list  
of such processes.    
FDA views chemical alteration specifically  within  the context  of  section 413(a)(1)  
of the FD&C Act, which creates  an exemption from  the NDI  notification 
requirement  for  NDIs  that  have been present in the  food supply  as article[s]  used  
for  food in a  form in which the  food  has not  been chemically  altered.  Because this  
                                              
24  Statement of Agreement, 140 Cong. Rec. S14801  (daily ed. Oct. 7,  1994).  
26   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
exemption is for  articles  that are used for  food and  present in the food supply  
(conventional  foods and their ingredients),  it  applies to  ingredients  that  meet  the  
safety standards for conventional  foods  and have  a history of  safe use  as food.  
These safeguards  provide  some confidence  that  such ingredients   are  likely  to be safe  
when used in dietary supplements  at comparable  levels,  as long as  they are not  
chemically  altered from their form in conventional  food.    
A  process that  chemically  alters an ingredient   found in the  food supply can  
introduce  contaminants,  solvents,  or  impurities  whose safety is  unknown.25   Such a  
process  may result  in an ingredient  that not only differs  from  the source ingredient  
but  also  has an unknown safety profile.   See question  IV.B.4  for further  discussion 
on chemical alteration.   A  well-characterized starting material  may result in  no 
change to the identity of  the  material after  processing, in which  case an  NDI  
notification  would  not be  required.   However, dietary supplements  and dietary 
ingredients  that  are  complex mixtures introduce  more  variability  into the  processing.   
Therefore, their identity is more likely  to change  during processing.  
In general, FDA  considers a  process  that  does not result in chemical  alteration to 
mean a process  that:  (1) involves  an ingredient  composed of one single  raw  material,  
or derived from  a single raw  material using a  manufacturing process that involves  
only physical  steps (e.g.,  water  extraction  and  condensation);  and (2) does not  
involve  attempts to  selectively  increase the concentration  of particular  active 
ingredients or  cause a chemical  reaction (other than esterification)  that would 
modify the  covalent  bonds of any  substance  in the original  material.   This  type of  
process is unlikely  to affect  the safety profile  of the ingredient   in question or  of  
dietary supplements  containing  the ingredient.  
Some  of the processes  characterized as  physical  modifications  in the 
Congressional  Statement of  Agreement  (milling,   slurry,  powder,  or solid in 
suspension)  do not  alter  the chemical  or molecular  composition  or  structure of the  
ingredient.  FDA views  such changes as  unlikely  to create  a  change  in the safety 
profile  of an ingredient  being used in conventional  food.  Dehydration,  
lyophilization,  or making a tincture,  solution  in water, or  slurry  can be  said to 
change the composition  of the  ingredient,  but only by changing the  amount of water  
(or ethanol,  in the case  of a tincture).  FDA regards such a minor  change  in 
composition  as  extremely unlikely  to change the  safety profile  of an ingredient   used 
in conventional   food.   Similarly,   a  minor  loss of  volatile   components  during 
processing is  unlikely  to change the safety profile  of  an ingredient  used in 
conventional  food.  In a typical  extraction,  however,  the first  step is solution  in 
water or  another  solvent,  followed by filtration  to remove undissolved  material.   
                                              
25  FDA, 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; June 2014.  Available at: 
http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/ucm300661.htm  
27   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
This  is  a much larger change  in the composition  of the ingredient.    FDA generally 
regards extraction that includes  a  filtration  step or that  involves  the use of a solvent  
other  than water or  alcohol  (aqueous ethanol)  as a process  that  chemically alters  the  
source  ingredient  and therefore triggers  the NDI notification  requirement  for the  
resulting dietary ingredient.  
As industry develops new technologies   and processes  other  than those  described as 
physical  modifications   in the Congressional  Statement  of Agreement,  we encourage 
you  to consult  with us  when considering  whether  a notification  is needed in a  
particular situation,   as well  as  before  submitting  an NDI notification.26    We intend to  
evaluate any  new technology  or process  based on our  guidance  on chemical  
alteration  as set forth  in this  document.   We  also  intend to consider  whether  or not  
the technology or  process  would  affect  the safety profile  of the dietary ingredient  
and the dietary supplement  in which  it is  used.   
We are  willing  to consider  arguments  supported  by science demonstrating  that  
particular manufacturing processes do  not  actually  result in a chemical  alteration  or  
have any effect  on the safety profile  of  the ingredient.   In such cases,  we encourage 
manufacturers  and distributors   to arrange a pre-notification  meeting  with  FDA to  
discuss their basis for  this  belief.   
C.   Other Questions About When an NDI Notification Is Necessary 
1.   May I submit  a single NDI notification that contains  safety data for  a range  
of conditions of  use and covers multiple products?  
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
You may also submit  a  confidential  NDI master  file  to FDA  which contains  the  
manufacturing,  specifications  and other  identity  information  needed to completely 
                                              
26  Contact information for the Office of Dietary Supplement Programs can be found on the title page.  
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient Notification 
Procedures and Timeframes: Guidance for Industry." 
28   Contains Nonbinding Recommendations  
Draft-Not for Implementation  
 
describe  the ingredient.  You may incorporate  by reference  the  contents  of the  
master file  into an NDI notification.    You may also authorize  other firms  to 
reference the contents of  the master  file  in notifications   describing  the ingredient  
they obtain from you.   FDA expects that most  submitters  will  identify  the contents  
of NDI master  files  and ingredient  specifications  as  trade secrets  (see question 
V.A.16)  and will  only discuss them with the  firm  which submitted them.   
If you are  a  dietary supplement  manufacturer or  distributor   and either  you or the  
manufacturer  or distributor   of the  NDI  have submitted an NDI  notification  that  
covers the conditions   under  which the NDI  will  be used in your  supplement,   you 
need not  submit  a  new notification  for the use of the NDI  in that supplement.   
However,   if you are planning  to market a  product that exceeds  the  highest  daily 
intake level  or single-serving  dose  for which safety information  was submitted in  the  
previous  NDI notification,   you should submit  a  new  notification  because  the  
previous  NDI notification  does not  cover the higher  single-serving  or  daily intake  
level.   Similarly,   if  the  NDI  is not identical  to the NDI  evaluated in the  previous NDI  
notification,   the dietary ingredients   to be combined with the NDI in your  product  
differ  from  those in the product  that  was  the subject  of the previous  notification,   or  
any other  conditions   under  which the NDI  will  be used in  the  new product  were not  
evaluated in the original  notification,   a new  notification  should be submitted.  See 
questions  IV.C.2  and  IV.C.3.  
2.   If  I submit  an  NDI notification  for  a dietary supplement that I  manufacture  
or distribute  and then decide to manufacture  or  distribute a  different  
supplement  that contains  the same NDI, should  I submit another  NDI  
notification?   
The answer  depends  on what was  covered in your  previous  NDI notification,   on how  
FDA responded,  and on the extent  to which the NDIs proposed conditions   of use in 
your new  dietary supplement  differ from those evaluated in the  notification.    If you 
have already submitted an  NDI  notification  for a dietary supplement  containing  an  
NDI, you need not  submit a  separate  notification  for a different  dietary supplement  
containing  the same NDI  if  the following   criteria  are met:   
   The  single-serving  dose and daily   intake level of  the NDI specified  in the  
labeling  of the new supplement  are less  than  or  equal to the  highest single-
serving dose  and daily intake level evaluated  in your  original  NDI  
notification;  
   The new supplement  does not  combine  the NDI with other dietary 
ingredients  that  were not  included  in your  original  NDI notification;    
   The target populations   for the new supplement  are the same  as,  or  a subset  
of,  the target populations   specified in your  original   notification;    
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   All  other conditions   of use are  the same  as or more restrictive  (e.g.,  lower  
dose  and daily intake,  shorter duration of use) than the conditions   of use  
described in your prior  NDI  notification;   and  
   FDA did not  express  safety or other  regulatory concerns in response to your  
prior  NDI notification.  
As discussed in question  IV.C.1, you may  submit a  NDI  notification  that contains  
safety information  about  a range of daily intake  levels  and/or  other  conditions   of use  
for dietary supplements containing  the  NDI.  Once you have submitted a  notification  
for an NDI that covers  multiple   conditions   of use,  you may market as  many dietary 
supplements containing  that  NDI  as  you wish without  submitting  another  
notification,   as long as the  bulleted criteria  above are met.   Put another  way, if  the  
conditions   of use for the  dietary  supplement  you plan to market  are within the  
conditions   of use  evaluated in your original   notification   and FDA did not object  to 
that notification,   you may market the supplement  without submitting  another  
notification.      
However, if  any of  the  bulleted criteria  above  are not  met, you should submit  
another  NDI notification.    For example,  suppose  you want to market a dietary 
supplement  with a higher  daily intake  level  of the NDI than the level  evaluated in 
your original   notification.    In general,  the risk from  a substance is likely  to  increase 
as  intake increases  above levels  safely consumed  in  the past.   A  higher intake level  
of some  substances  could present toxicity risks  to consumers.   If you have  not  
evaluated  safety information  for  the  higher daily intake level,  you do not  have an 
adequate  basis on which to  conclude  that  a  dietary supplement  containing  the NDI at  
that higher  level  will reasonably be expected to be safe.         
The same principle   applies  for other  changes in conditions   of  use, such as combining 
the  NDI with dietary ingredients   other than those  that  were in  the  dietary supplement  
evaluated in the original  NDI notification.   When dietary ingredients  are combined,  
they can  interact.  In  some cases, these interactions  can  present risks  to consumers.  
For  example,  adverse effectssuch as low  blood pressure,  low  heart rate,  
gastrointestinal  distress,  and  in  severe cases, irregular  heartbeatmay occur when a  
new  dietary ingredient   with cholinesterase-inhibiting  properties  (such as huperzine  
A or galantamine)  is  combined with another  dietary ingredient   that is  a  cholinergic  
agonist  (e.g.,  yohimbe  bark extract).  To have a basis  to  conclude  that  a dietary  
supplement  that combines  an NDI with one  or more  pre-DSHEA dietary ingredients  
will  reasonably  be expected to be safe,  it is necessary  to consider whether  the  
addition  of the other  dietary ingredients   will  affect  the safety of the  NDI  or the  
resulting dietary supplement.    
The same analysis  applies  to other  conditions   of use that are  outside  the scope of the  
original  notification.     If the  information  in your  original  notification  is insufficient  
to provide  a  basis to conclude that your new  dietary supplement  will  reasonably be  
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expected to be safe, then the statutory requirement  for  the manufacturer  or  
distributor   of  the dietary ingredient   or dietary supplement  to provide  FDA with 
information  . .  . which is  the basis  on which the manufacturer  or distributor   has  
concluded that a  dietary supplement  containing  such dietary ingredient   will  
reasonably be expected to be safe  (21 U.S.C.  350b(a)(2))  has not  been met.   It is  
your responsibility  to meet it  by conducting  a  safety evaluation and submitting   a 
notification  with data  about  the safety of the NDI  under  the conditions   of use in your  
proposed dietary supplement.     
3.   If a  dietary supplement manufacturer  or  distributor  has submitted an NDI  
notification  prior to  marketing  a dietary  supplement  with  the  NDI, and I  
intend  to market a dietary supplement containing the same NDI, should I  
also submit  an  NDI  notification?  
Yes.   Section 413(a)(2)  of  the  FD&C  Act (21 U.S.C. 350b(a)(2))  states  that a dietary  
supplement  that contains  an  NDI  is  deemed adulterated  unless,  among other things,  
the manufacturer  or distributor   of  the dietary ingredient   or the dietary supplement  
submits  an  NDI  notification  at least  75 days  before introducing  it into interstate  
commerce.   Note that,  in situations  where the NDI  manufacturer  or distributor   has  
not  submitted a notification,  the statute  deems a  dietary supplement  that contains  the  
NDI  to be  adulterated unless  the manufacturer  or distributor   of  the dietary  
supplement  (that  particular dietary supplement),  not a  dietary supplement  (some  
other  dietary supplement  containing  the NDI)  has  submitted a notification.   
Accordingly,  if  the NDI manufacturer  or distributor   has  not  submitted a notification 
covering  the conditions   of the NDIs use,  each  manufacturer  or distributor   of  a  
supplement  containing  the NDI  must  submit  an NDI notification  with information,  
including  any citation to published  articles,  which is the  basis on which the  
manufacturer or  distributor   has  concluded that a  dietary supplement  containing  such 
dietary ingredient   will  reasonably be expected to be safe  (21 U.S.C. 350b(a)(2)).  
The supplement  manufacturer  or distributor   may meet the requirement  to provide  
safety information  either by conducting its own safety evaluation or  relying  on a  
safety evaluation conducted by another entity,  such as  a previously  submitted NDI  
notification   (see question IV.C.4).   Once the  manufacturer or distributor   of  the  
supplement  has submitted an NDI notification  to FDA,  that firm  need not  submit  
further  notifications   for  other supplements  containing  the same NDI  if  the conditions  
of use of the other  supplements  are  within the conditions   of use evaluated in the  
firms original  notification   (see question  IV.C.2).  
4.   When I submit an  NDI notification,  may I  rely on  data from another  NDI 
notification  or master file?  
Yes, if  one of the following  applies:  
   you submitted the previous notification   or master file,  
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   the previous  notification  (or  portion of  a  previous notification)   on which you 
wish to rely is  public,   or   
-
   the person who submitted the previous  notification   or master file  gives you 
written permission  to rely on  non-public   information  from that notification.    
If  you are relying on non-public   information  from  another  firms  NDI  master  
file  or  from  another  notification,   you should provide  FDA  with 
documentation  (such as  a signed letter from  the other  notifier)  showing that  
you are  authorized to use the information,   and the duration of that  
authorization.    If the authorization  does not  extend to the  entire master  file  or  
notification,   the authorization  from  the previous  notifier  should specify the  
part(s) of the notification  you are authorized to use.    
Manufacturing processes  and specifications needed to establish the  identity of  an 
NDI  are  usually  trade  secrets  that are  not  available  in the NDI docket.  It should be  
noted that the original   notifier  is under  no obligation  to share with other  
manufacturers  and distributors   any trade secrets  or confidential  commercial  
information  that were  part of the basis  for a  safety conclusion  for the original  
notifiers product.   A written authorization  to reference a notification  or  master  file  
in NDI notifications   does not  include  the right  to see  or copy the notification  or  
master  file unless  the submitter  otherwise specifies.   Note that while  one  firm  may 
authorize  another  to reference confidential  safety information   in a subsequent  
notification,   that subsequent  notification  must  demonstrate  that the submitting  firm  
understands enough about that safety information  to have  a basis to conclude  that  
consumption  of  the NDI  in the  new product  will  reasonably be  expected  to be safe 
under  the conditions   of use described in its  notification.  
5.   Can  FDA provide  examples  with an  explanation to  help distinguish 
situations in which separate notifications are required for  dietary  
supplements containing the same NDI from  situations in which the same  
NDI notification covers multiple dietary  supplements?    
Two important  factors  you should  consider when deciding whether  to submit  a  
notification   for  a dietary supplement  containing   an  NDI  that was the subject  of a 
previous notification   are:  
1)   Are the NDIs conditions   of use in the second product  within the conditions  
of use evaluated in the  previous  notification?  
 
If not,  you should submit  a separate notification  for  the  second product  
because  the safety evaluation in the previous  notification  did not  include any 
consideration  of the new  conditions   of use  in the  second dietary supplement  
and therefore cannot  provide  a  basis  to conclude  that  the NDI  will reasonably  
be expected to be safe  under  those conditions   of use.  
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2)    Who was  the  previous  notifier  and what  is that  entitys relationship  (e.g.,  
same firm,  supplier,   or competitor)  to the manufacturer  or distributor   who 
intends  to market  the  second product?  
 
See questions  IV.C.2  and IV.C.3  and the  examples below  for more about  
how  the answer  to this  question affects  whether an NDI  notification  for  the  
second product  is  necessary.  
In each  of  the scenarios below,  assume that  FDA  has  acknowledged the filing  of  the  
first NDI  notification  and has  not raised any safety or regulatory concerns  in 
response to that  notification.    
Scenario  1:  Ingredient  Supplier   A submits  a notification  for NDI-A1  and a master  
file  describing its  manufacturing process.  Supplement   Manufacturer X  intends to 
market  a  single-ingredient  dietary supplement containing  a  dietary ingredient   (NDI-
B1)  that purports  to be  the same as  NDI-A1,  but  is  made by  a  different  dietary 
ingredient  manufacturer,  Ingredient  Supplier  B.  
Analysis:  Manufacturer X  should  submit  an NDI notification   for the use of NDI-B1  
in its single-ingredient   dietary supplement  because Supplier   B  has submitted no NDI  
notification  for NDI-B1  (see question IV.C.3).  However, if Manufacturer  X can  
establish  that NDI-B1 is the same as NDI-A1 and Supplier   As  prior  notification 
covers the conditions   of use of  NDI-A1 in Manufacturer Xs single-ingredient  
dietary supplement,   then the  NDI  notification  for the new supplement  made with 
NDI-B1 could  simply  consist of  data showing  that NDI-B1 is identical  to NDI-A1, a  
reference to  the safety evaluation in Supplier   As notification,   and a signed  
authorization   from  Supplier  A for Manufacturer X  to  use  any non-public   safety data 
from  As  notification   and the manufacturing master file.   On the other  hand, if  
Manufacturer  X cannot  establish that NDI-B1 is the same  as NDI-A1, Xs  
notification  will  have to contain safety information  specific to  NDI-B1  because a 
different  NDI requires  its  own safety evaluation.28     
Scenario  2:  Ingredient  Supplier   A submits  a notification  for  NDI-A2.  Supplier   As 
notification  includes  safety information  for  a dietary supplement  tablet containing 
NDI-A2  as  the  sole dietary ingredient   in a formulation  with  several  non-dietary 
ingredients  used as binders  and fillers.  Supplement   Manufacturer X  wants to use  the  
same level  of  NDI-A2  in a  dietary supplement  tablet with NDI-A2 as  the sole  
dietary ingredient,  but  in a formulation  with  different  non-dietary ingredients  used as  
binders  and fillers.  
Analysis:  Manufacturer X  does not  need to  submit  an NDI  notification   because the 
only difference  between Manufacturer Xs product  and the  formulation  described in 
                                              
28  See  21 U.S.C. 350b(a)(2).  
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Supplier   As notification  is  a change  in non-dietary ingredients (i.e.,  inactive  
ingredients).   However, Manufacturer  X  should evaluate  whether  the change  affects  
the safety of the dietary supplement  and document  the  basis  for its conclusion  before  
marketing the product.  
Scenario  3:  Ingredient  Supplier   A submits  a notification  for  NDI-A3  that includes  
safety information  for single-ingredient   dietary supplement formulations   containing 
up to 500 mg/day of the NDI.   Supplement   Manufacturer  X is using NDI-A3  in a  
single-ingredient   dietary supplement  at a level  of  250 mg/day but  wants to increase 
the amount  of NDI-A3  to 500 mg/day.    
Analysis:  Because Supplier  As  initial  notification  included  safety information  for 
NDI-A3  up to 500 mg/day,  Manufacturer X  does not  need to submit  a  notification  
for either  the 250 mg/day or 500 mg/day formulation,   assuming all  other conditions  
of use are the same as  those evaluated in Supplier   As notification.  
Scenario  4:   Ingredient  Supplier   A submits a notification  for  NDI-A4.  Supplier   As 
notification   includes  safety information  for  a dietary supplement  containing  NDI-A4  
in combination  with vitamin A,  vitamin  C,  sodium, calcium,  and iron.  Supplement  
Manufacturer X  intends to use  NDI-A4  in a  dietary supplement  at recommended  
doses and daily intake  levels  that  do not  exceed the high end of the range evaluated 
in Supplier   As  notification.   Manufacturer Xs  supplement  will  also  contain  some, 
but not all,  of the  vitamins  and minerals  included in Supplier As  notification.    All 
other  conditions   of use will  be the same  as those evaluated in As  notification.      
Analysis: Manufacturer  X  does  not  need to submit  another notification   because 
Supplier   As notification   covers  all  the conditions   of NDI-A4s  use in Manufacturer  
Xs new product.  
Scenario 5:  Company Q  wants  to market  a supercritical fluid extract  of  Convallaria 
majalis  L.   The  plant  is on an industry  list  of pre-DSHEA  dietary ingredients.    
Analysis:    Company Q  must  submit  an NDI  notification.    Even though this  
botanical  appears on  an  industry list of  old dietary ingredients,   it  has  historically 
been used only as an herbal  drug,  so a history of use in food has  not  been 
established.  In addition,   supercritical  fluid extraction was not commonly  used prior  
to 1994,  and there is  no evidence  of extracts  like  this  having being marketed as  food 
prior to 1994.    
Scenario 6:   Company Q  received an acknowledgment  letter without  objection  in  
response to  its NDI  notification  for the  Convallaria majalis  L.  supplement  described 
in  Scenario 5.   Now Company Q  wants  to market  the ingredient  in combination  with 
another  dietary ingredient,   an  extract from  Nerium oleander  L., which has been the  
subject of  an  NDI notification  from  one of Company Qs competitors,  Company Y.   
Company Y  received an acknowledgment  letter  without objection   in response to its  
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notification.   Both  notifications   discussed the safety of the extracts in depth and 
described manufacturing procedures  and specifications   for cardiac glycosides.   The  
notifications   also included results from clinical  testing or  testing in a  non-rodent  
species appropriate  for the evaluation  of cardiac risk.   
Analysis:  Company Q must  submit  a  new notification  for  the combination.   A 
combination  of two NDIs  is  itself  an NDI.  Although the  notifications  included  in-
depth discussions  of the safety of the extracts,  each of the plants  is known to contain 
glycosides with potent  cardiotoxic activity and it  is  difficult   to predict  the toxicity of  
the combination.    The new  notification  should include a  discussion of  the  safety of  
the  combination,   which is  likely  to be an in-depth discussion because  both 
ingredients  affect  the same organ system.  Given the overlapping  toxicological  
endpoint  and the severity of the potential  toxicity,   we  would recommend that  the  
new notification  include  results from  safety testing of the combination.    However, in 
a notification  for  a combination  of  two NDIs with no  specific safety  problems  where 
each of the  NDIs  had been the subject  of a  prior  notification  to FDA that was  
acknowledged without  objection,   the section of the  new notification  discussing the  
safety of the  combination  could be brief.  
6.   Should I notify  FDA about  a  microbial  ingredient in my  dietary  
supplement?    
Yes,  if it is  an  NDI  that has not  been present in the food supply as an article  used for  
food in a  form in which the  food has  not been chemically altered (21 U.S.C.  
350b(a)(1)).    
However,  not  all bacterial microorganisms   are dietary ingredients,   and a  
microorganism   that is  not a dietary ingredient   cannot  be  an  NDI.  For  example,  
pathogenic species of bacteria,  such as  Salmonella species  or  Escherichia  coli, are 
not  dietary ingredients   even though they may have been inadvertently  present in 
foods  as  contaminants.  Bacteria  that  have never been consumed as food are  unlikely 
to be dietary ingredients.    
A bacterial  microorganism   is a dietary  ingredient  if  it  is a dietary  substance (an  
intentional   constituent  of food) or  otherwise falls  within one  of the  dietary ingredient  
categories listed in 21 U.S.C.  321(ff)(1).   For  example,  bacteria that  are used to  
produce fermented foods that  are  eaten without  a  cooking or pasteurization  step 
(e.g., lactic acid  bacteria used  to produce  cheese  or yogurt)  could be dietary 
substances for use by man to supplement  the diet  by increasing the total  dietary 
intake, which are  defined as  dietary ingredients  in section 201(ff)(1)(E) of  the  
FD&C  Act (21 U.S.C. 321(ff)(1)(E)).  FDA  does  not  have  a separate regulatory  
category or  definition  for dietary ingredients   consisting of  live  or viable  
microorganisms.  
7.   If  I want  to market a  dietary  supplement containing  several  pre-DSHEA 
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ingredients  that havent previously been marketed together, do I have to 
submit  an NDI notification?  
No.  The NDI  notification  requirement  applies only  to dietary supplements that  
contain at least  one NDI.  If  each of the dietary ingredients  in a dietary supplement  
was marketed  in the United States  before October 15,  1994,  marketing these  
ingredients  together for the  first time in the  same  dietary supplement  does not  create  
an NDI  or  trigger  the NDI notification  requirement.      
8.   Can FDA provide visual aids  to help me decide whether I should submit  an  
NDI  notification?  
Yes.   The following  table  illustrates  when an  NDI  notification  is  required and when  
the  NDI adulteration  standard  applies.  In addition,   Section VIII. Appendix: 
Decision Tree for NDI Notification  has  a decision tree to  walk you through the  
steps of deciding whether  to submit  an  NDI  notification.  
 
 
Table 1: Definition of New Dietary Ingredient (NDI), Requirement for NDI 
Notification and Applicability  of NDI  Adulteration Standard  
  NDI  
New Dietary   NDI  
adulteration 
Ingredient   notification 
standard29  
(NDI)   required?  
applies?  
A dietary ingredient   that was  marketed 
No   No   No  
in the U.S. before October 15,  1994  
A dietary ingredient   that was  NOT  
marketed in the  U.S.  before October  15,  
1994,  AND was present  in the  food   Yes   See a) or b)   Yes  
supply as  an article used for food which 
has  
a)  not been chemically altered  
Yes   No   Yes  
b)    been chemically  altered   Yes   Yes   Yes  
A dietary ingredient   that was  NOT  
marketed in the  U.S.  before October  15,  
Yes   Yes   Yes  
1994,  AND was NOT present  in the  
food supply as  an article used for  food.  
 
                                              
29 The NDI adulteration standard in 21 U.S.C.  342(f)(1)(B) provides that a dietary supplement containing an NDI is  
adulterated unless there is adequate information to provide reasonable assurance that  the NDI does not present a  
significant or unreasonable risk of illness or injury.  
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D.   Additional Issues to Consider Before Submitting an NDI  
Notification  
1.   What  is  a dietary ingredient?   
The definition  of  dietary supplement  describes  a dietary ingredient  in 21 U.S.C.         
321(ff)(1)  as:  
(A)  A  vitamin;  
(B) A  mineral;  
(C) An herb or other  botanical;  
(D) An amino acid;  
(E) A  dietary substance for use by man to supplement  the  diet by increasing the  total  
dietary intake;  or  
(F) A  concentrate, metabolite,  constituent,  extract,  or combination  of any ingredient  
described  in  (A), (B), (C),  (D), or (E).  
2.   May a contaminant  that is  found in  the food supply be  a dietary ingredient?  
No.  Although most  constituents  of conventional  foods in the  food supply would be  
dietary  substances that  could be used as  dietary ingredients  under  section 
201(ff)(1)(E)  of the  FD&C  Act  (21  U.S.C. 321(ff)(1)(E)),  contaminants  are different  
from  other food constituents.  A contaminant  of  food (like  Salmonella  or  lead) is not  
a dietary substance  that qualifies   for  use as  a dietary ingredient  in a dietary 
supplement  product  even if it  is not  harmful  to health  (e.g.,  sterilized   Salmonella)  
because  contaminants  are not  intended for ingestion,   nor are  they considered to be  
food or part  of the food supply.   Contaminants  are consumed unintentionally  and are  
not  dietary substance[s]  for  use  by man to supplement  the diet by increasing the  
total dietary  intake (21 U.S.C.  321(ff)(1)(E)).    
3.    Under what  circumstances does FDA consider synthetically produced 
substances to be  dietary ingredients  under the FD&C Act?  
Whether a synthetically  produced substance qualifies  as  a dietary ingredient   depends  
on  whether the substance fits  into one of  the categories of dietary ingredients  that are 
defined  in  section  201(ff)(1)  of the FD&C Act (21 U.S.C. 321(ff)(1)).   In some  
cases,  description  of the category in the  FD&C Act  encompasses  synthetically 
produced substances;  in others, it does not.   The  six  dietary ingredient  categories  are 
discussed in the  bullets  below.    
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   Vitamins, Minerals,  and Amino  Acids (21 U.S.C. 321(ff)(1)(A), (B), (D))  
Synthetic  vitamins,   minerals,  and amino acids  qualify  as dietary ingredients  because 
vitamins,  minerals,  and amino  acids, regardless of  source, are specifically  designated  
as dietary ingredients  under  sections  201(ff)(1)(A),  201(ff)(1)(B),  and 201(ff)(1)(D)  
of the FD&C Act, respectively.  Synthetic vitamins,  minerals,  and amino  acids  are 
recognized as dietary ingredients   because a vitamin,   mineral,  or  amino acid is  
defined by its  nutritional   function  (its  ability  to provide  nutrients  to the human 
body),  not by its state  of matter  like  a  botanical.  
 
   Herb or other botanical  (21 U.S.C. 321(ff)(1)(C))  
Under a plain reading of the FD&C Act, a  synthetic  copy of  an herb or  other  
botanical  does  not  qualify as a  dietary ingredient   under section 201(ff)(1)(C)  of the  
FD&C Act.  As defined in the  glossary, an herb or botanical  includes  only plants, 
algae, fungi,  their exudates  (secretions,  such as  sap or  resin), and their physical  
parts.   A substance that has been synthesized in a laboratory or factory  has never  
been  part of an herb or other  botanical  and,  therefore,  is not a  dietary ingredient  
under  section 201(ff)(1)(C) of the FD&C Act.30    
   Dietary substance for use by man to  supplement the diet by increasing the  
total dietary intake  (21 U.S.C. 321(ff)(1)(E))  
For purposes of  section 201(ff)(1)(E)  of the FD&C Act, we  interpret   dietary 
substance  in accordance with  its  common,  usual meaning  because the term  is not  
defined in the  FD&C  Act  or by regulation.   According to Websters II New 
Riverside University Dictionary  (1994),  dietary  means  of  or relating to diet  and  
diet  means  an organisms  usual food and drink.   In conjunction  with for  use by 
man,  we interpret  dietary substance,  as used in section 201(ff)(1)(E),  to mean a 
substance commonly   used as  human food or drink.   The  rest  of the definition,  which 
specifies  that the substance  be  for use  to supplement  the diet by increasing  the  total  
dietary intake,31  is  further evidence  that dietary substance  is intended to mean  
foods  and food components  that humans  eat  as  part of their  usual  diet.  One cannot  
increase the total dietary intake  of  something that is  not  part of the human diet  in  
the first  place.   
Because the dietary  substance category is  defined  in  part by history of use, a  
synthetic  copy of  a botanical  ingredient   may qualify  as a dietary ingredient  under  
section 201(ff)(1)(E) if the  synthetic copy has been used as  a lawfully  marketed  
                                              
30  Note, however, that if the synthetic copy  has itself been used as a lawfully marketed ingredient in the conventional  
food supply, it may be a  dietary substance[s] for use by man to supplement the diet by increasing the total dietary  
intake  and therefore qualify as a dietary ingredient under 21 U.S.C.  321(ff)(1)(E)  (see next bullet in text),  even though  
it  is  not an herbal or botanical dietary ingredient under 21 U.S.C.  321(ff)(1)(C).      
31 21 U.S.C.  321(ff)(1)(E) (emphasis added).    
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ingredient   in the conventional  food supply.  For example,  a  synthetic copy of a  
botanical  ingredient  would be  a  dietary ingredient   under section 201(ff)(1)(E)  if  the  
synthetic copy  has been used as  an ingredient   in the conventional  food supply.   Two 
common examples are  vanillin  and cinnamic acid, botanical  constituents that, for 
economic  reasons, are  usually produced synthetically  for  use  as  flavorings  in food.    
   Concentrate, metabolite, constituent, extract, or combination of another  
dietary  ingredient described in clause (A), (B), (C), (D), or (E) (21 U.S.C.  
321(ff)(1)(F))  
A constituent is  an article that  is a physical  part  of a whole and can be isolated  
from  the whole.  A  synthetic  copy of  a constituent  of  a botanical  was never  part  of  
the botanical.   Therefore, the  synthetic  copy is  not a constituent  of the botanical  
and does not qualify  as  a  dietary ingredient  under  section 201(ff)(1)(F) of  the  FD&C  
Act (21  U.S.C. 321(ff)(1)(F)),  even if  the synthetic  copy is  chemically identical  to a  
constituent  of  a plant.32    
By the same principle,   an extract  made from  a  synthetic  copy of  one or more  
constituents  of  a botanical  is  not an extract of  the  botanical  under section 
201(ff)(1)(F) of the FD&C Act  because the constituents  were  never part of the  
botanical  and therefore could not  be extracted from  the botanical.   Similarly,   a  
synthetic copy  of a botanical  concentrate is  not  a concentrate of a botanical  because, 
by definition,   a  concentrate is  an article  that has been reduced in volume or  bulk 
by removal  of liquid.   To make  a concentrate of a botanical,  one must start  by 
extracting the desired constituents  from  the botanical  with a solvent  and then 
concentrate  the constituents  by reducing  the amount  of  solvent  (e.g., by  boiling   the  
extract).   If synthetic material  that was  never actually in the botanical  is used as the 
starting point  for  a  concentrate,  the final  product  will  be  a concentrate of the  
synthetic material,  not a concentrate of the botanical.     
For more than a decade,  FDA has consistently interpreted section 201(ff)(1)(F)  of  
the FD&C Act as not including   synthetic  copies  of  botanical constituents, extracts,  
or  concentrates.  33  Such a substance  may in some cases, however,  qualify as  a 
                                              
32  See, e.g., Final  Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They  
Present an Unreasonable Risk, 69 FR  6788, 6793 (Feb. 11, 2004).  
33  This interpretation dates back to at least 2001,  and the dietary supplement industry has been aware of it since that  
time.   See Letter from Dennis E.  Baker, Associate Director for Regulatory Affairs, FDA, to Laura M. Nagel, Deputy  
Assistant Administrator, Office of Diversion Control, DEA (June 21, 2001)  Available at: 
http://odspracticum.od.nih.gov/2011/readinglists/dea_ephedrine_letter.pdf; Final Rule Declaring Dietary Supplements  
Containing Ephedrine Alkaloids Adulterated,  supra  note 32; Natural Products Insider, Consumer Group Asks FDA to  
Seize Synthetic Ephedrine 'Supplements' (Feb. 1, 2002)  Available at:  
http://www.naturalproductsinsider.com/news/2002/02/consumer-group-asks-fda-to-seize-synthetic-ephedri.aspx;  
Citizen Petition 2004P-0169 from Coalition to Preserve DSHEA (Apr. 8, 2004),  Docket No. 2004P-0169  (asking FDA  
to reconsider position that botanical dietary ingredient category excludes synthetic equivalents) Available at:  
http://www.fda.gov/ohrms/dockets/dailys/04/apr04/040804/04p-0169-cp00001-vol1.pdf; Letter from Michael M.  
 
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dietary ingredient   under another provision  of  section 201(ff)(1).   For example,  there 
are  synthetically  produced substances in the food supply that are  dietary ingredients  
under section 201(ff)(1)(E)  because they  are  dietary substance[s]  for use by man to 
supplement  the  diet by increasing the  total  dietary intake  (see discussion in 
preceding bullet).    A  synthetic  copy of  a botanical  constituent  (e.g., vanillin 
synthesized from  lignins)   or an extract made from  a  synthetic  copy of  a  botanical  
constituent (e.g.,  artificial vanilla   extract)  would qualify as  a  dietary ingredient  
under  section 201(ff)(1)(E)  if used  as a food ingredient.    
A  metabolite that has been synthesized from another dietary ingredient   would be a 
dietary ingredient   under section  201(ff)(1)(F) and could be  used  as a dietary  
ingredient   in a dietary supplement.  Although  the definition  of a  metabolite34  
requires human ingestion of  the dietary ingredient   to increase  the  production  or flux  
of the metabolite  in the human body, it does  not require the  metabolism   to actually 
take place in a  human being  during the manufacture  of a  dietary ingredient.    A 
metabolite  may be synthetically  produced,  provided that the  starting material  is a  
dietary ingredient   and the production  process mimics  the metabolic  process in the  
body following  ingestion.  
4.   Are food contact substances and other indirect food additives dietary  
ingredients?   What about  secondary direct food additives?  
These substances  generally do not qualify as  dietary ingredients  by virtue of their  
use  as food additives.  Although  food contact substances35  and  other indirect  food 
additives36  may be  present  in the food supply because they migrate into certain 
foods from packaging or other  articles that  contact  the food, their presence in these 
foods is merely incidental.    A  substance  that migrates into a  food during 
manufacturing or storage  is not  a dietary substance for use by man to supplement  
the  diet by increasing the total dietary intake (21 U.S.C.  321(ff)(1)(E))  because it  is  
not  consumed as a  component  of the diet,  but  merely  as a  byproduct  of  its  use in 
articles  that contact food.   However, if  such a  substance  falls  under  one of the other  
                                                                                                                                                       
Landa, Acting Director, Center for Food Safety  and Applied Nutrition, FDA, to Marc Ullman, Ullman,  Shapiro &  
Ullman,  LLP,  responding to Citizen Petition FDA-2009-P-0298 from OVOS  Natural Health Inc. (Feb. 23, 2011)   
Available at: https://www.regulations.gov/document?D=FDA-2009-P-0298-0008. 
34  See section VII, Metabolite.  
35  A food contact substance is a substance intended for use as a component of materials used in manufacturing, packing,  
packaging, transporting, or holding food if that use is not intended to have any technical effect in the food.   21 U.S.C.  
348(h)(6).  
36  Indirect food additives come into contact with food as part of packaging, holding, or processing, but they are not  
intended to be added directly to, become a component of, or have a technical effect in or on the food.   Before the FDA  
Modernization Act of 1997, indirect food additives were approved by regulation.   Now, additional indirect food  
additives are authorized through the food contact substance notification program.   In addition, indirect food additives  
may be authorized through the threshold of regulation exemption process in 21 CFR 170.39.   See FDA, Food  
Ingredients and  Packaging Terms. Available at:  
http://www.fda.gov/Food/IngredientsPackagingLabeling/Definitions/default.htm (accessed April 22,  2015).  
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dietary ingredient   categories listed in section 201(ff)(1)  of  the  FD&C  Act, it  could 
be  a dietary ingredient.     
 
For similar  reasons,  secondary direct food additives  generally do not  qualify  as  
dietary ingredients   through their use  in food manufacturing.  Secondary direct food 
additives  are  added  during the  manufacturing of  a food  to  achieve a technical  effect  
(e.g., controlling  the growth of microbes), but  they have  no technical  effect  in the  
finished food.   Generally,  secondary direct food additives are used as  processing 
aids, and often they  also meet the definition  of a food contact substance.37   Although 
they may remain in the  food after  processing,  they are  generally present  in the  
finished food only  at trace levels,  if  at all.  Like indirect additives,  secondary direct  
food additives  are not  consumed as components  of  the diet, but are  only incidentally 
present, if at  all,  in the  finished food as  byproducts  of processing.   Accordingly,   they 
are not  dietary substances  for use by man to supplement  the  diet by increasing the  
total dietary  intake.  However, as  with  indirect additives,   a  secondary direct  food 
additive  could be  a  dietary ingredient  if  it  belongs to  one  of the other  dietary 
ingredient   categories  listed in section 201(ff)(1) of  the  FD&C Act.  
5.   If I alter the chemical structure of a dietary ingredient, is the new substance  
still a  dietary  ingredient?  
It depends.  Altering  the chemical  structure of a dietary  ingredient  (e.g.,  creation of  
new stereoisomers,  addition  of new chemical  groups as in  esterification) creates a  
new substance  that is  different  from  the original   dietary ingredient.  The new  
substance  is  not considered to be a  dietary ingredient  merely  because it  has been 
altered  from a substance that  is a  dietary ingredient  and,  therefore,  is in some way 
related to  the dietary ingredient.    
In some  cases,  however,  the new substance  may independently  qualify for  one of the  
dietary ingredient   categories listed in section 201(ff)(1)  of  the  FD&C Act.   For  
example,  taurine  is the  end product  of the metabolism   of the amino acid cysteine.   It  
is  thus  a metabolite of an amino  acid  and fits one  of the definitions   of a dietary 
ingredient   (see 21 U.S.C. 321(ff)(1)(D), (F)).  The  enzymatic  or synthetic  processing 
of cysteine  or any other dietary  ingredient  would be  an appropriate  method for the  
manufacture of  a  metabolite  of a  dietary ingredient   like  taurine  for  use  in a  dietary 
supplement.   See questions  IV.B.4  and IV.B.5  for additional   discussion on chemical  
alteration.     
6.   In  what forms may a dietary supplement  containing  my NDI  be  sold?  
The FD&C  Act specifically   provides for  dietary supplements  to be in  tablet,  capsule,  
powder, softgel,  gelcap, or liquid  form  (21  U.S.C. 321(ff)(2)(A)(i),  350(c)(1)(B)(i)).  
                                              
37  See FDA,  Food Ingredients and Packaging Terms. Available at: 
http://www.fda.gov/Food/IngredientsPackagingLabeling/Definitions/default.htm (accessed April 22,  2015).  
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In addition,   the statute permits  dietary supplements  in other forms  as long as  the  
product  is intended for ingestion,  is  not  represented as conventional  food,  and is not   
represented for use as  a sole item  of a meal  or  of the diet  (21 U.S.C. 321(ff)(2), 
350(c)(1)(B)(ii)).  
7.   When FDA reviews  an NDI notification, does the agency consider whether  
the prohibition in section 301(ll) of the FD&C Act applies to the use of the  
NDI  in a dietary supplement?  
No.   Section 301(ll)   of the  FD&C  Act (21 U.S.C.  331(ll))  prohibits  the  introduction 
or delivery for introduction  into interstate commerce of  any food that  contains  a  
drug approved under 21 U.S.C.  355,  a  biological   product licensed under 42 U.S.C.  
262,  or a drug or a biological  product  for which substantial clinical investigations  
have been instituted  and their  existence  made public,   unless  one  of the exemptions  
in section 301(ll)(1)-(4)   applies.  When reviewing NDI notifications,   FDAs current  
practice is  not  to consider  whether section 301(ll)   or  any of its exemptions  apply to 
the  NDI.   Accordingly,   a  no objection   response  to an  NDI  notification   should not  
be construed to be a statement that a dietary supplement containing the  NDI, if  
introduced or delivered for introduction  into interstate  commerce, would not violate  
section 301(ll)   of the FD&C Act.  
8.   May an ingredient that has  not been marketed as a food or as  a dietary 
supplement, but has  been approved as a new drug  or licensed as a biologic,  
be used as  an NDI  in a dietary  supplement?  
No, unless  FDA issues a regulation,  after notice and  comment,  finding  that the  
ingredient,   when used as or  in a dietary supplement,  would be lawful  under the  
FD&C  Act.  A  regulation  of this  type  may be requested by filing  a  citizen petition 
under 21 CFR  10.30,  but none has  been issued to date.   Absent such a  regulation,   an 
ingredient  that  has been approved as  a new drug or licensed as  a biologic   can be a 
dietary ingredient   for  use  in a  dietary supplement  if,  and only if, prior  to such 
approval  or licensing,   the ingredient  was marketed  as  a dietary  supplement  or  as a 
food.    
9.   May  I  use  an ingredient  in a dietary supplement  if it has been clinically  
tested as a drug but has not been approved as a drug  in the U.S.?  
It depends  on whether the  ingredient was  authorized for  investigation   in clinical 
trials  under  an investigational   new  drug application  (IND), whether the date the IND  
went into  effect  was  before or after  the date the ingredient  was  first  marketed as a 
food or as a  dietary supplement,  whether the  clinical  trials  were substantial  clinical  
investigations,   and whether their  existence was  made public.   The general rule is  
that an article that was authorized for investigation  as  a new drug or  as a biologic  
before being marketed as  a food or  as a dietary supplement  cannot be  marketed as  a 
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dietary supplement  if substantial  clinical  investigations   of the article have  begun and 
the existence  of such investigations   has been made public.    
FDA  can create an  exception  to this  prohibition  by regulation,   but only if the  agency  
finds  that the use of the article  in dietary supplements  would be lawful.  To date,  no 
such regulations   have been issued.   The appropriate  mechanism  to request such a  
regulation   is to  file  a citizen  petition  under 21 CFR  10.30.  
10. Howdo I determine  whether a dietary ingredient is an article that is  
approved  or authorized for  investigation as a new drug?   
Either an entire product  or  a component  of  the  product,  such as  an active ingredient,  
may be an article that is approved as  a  new drug  or an article  authorized  for 
investigation  as  a new drug  within the meaning of section 201(ff)(3)(B)  of  the  
FD&C Act (21 U.S.C. 321(ff)(3)(B)).38   For example,  assume that Substance A,  
which is  a constituent  of a plant  and has never been marketed as an article  of food  or  
as  a dietary supplement,   is a  botanical  dietary ingredient   under section  201(ff)(1)(C) 
of the  FD&C  Act.  A  drug company is studying  a  salt  of Substance A, Substance A  
hydrochloride,   as  an investigational   new drug  under an IND.  In this  situation,  the  
relevant article for purposes of  whether  Substance A can be used in a dietary 
supplement  is not  Substance A  hydrochloride,  but  Substance A itself,  because 
Substance A  is the  active moiety39  that is  being studied for its  possible  therapeutic 
action.   Any compound  that delivers  Substance A  is excluded from being used in a  
dietary  supplement.40  
11. May a dietary ingredient that was  authorized for investigation as a new 
drug  in the past be  used as  an NDI in a dietary  supplement if the IND was  
withdrawn  or the ingredient is no longer being investigated as a new drug?  
It depends  on the facts  of  the  particular  situation  (see answer to IV.D.9  above),  but  
withdrawal  of the  IND  and cessation of clinical  trials  of the ingredients  use as a  
new drug  make  no difference in whether the ingredient   may be used in a  dietary  
supplement.  The dietary supplement  category  does  not include  an article authorized 
for investigation  as a  new drug or biologic   for  which substantial  clinical  
investigations   have been instituted  and for which the existence of  such 
investigations   has been made public,   which was  not  before such authorization 
marketed as a dietary supplement  or  as a food,  unless  FDA  has issued a regulation 
                                              
38  Pharmanex v. Shalala, 221 F.3d  1151,  1154-1160  (10th Cir.  2000).  
39 Under 21 CFR 316.3(b)(2),  active moiety means "the molecule or ion, excluding those appended portions of the 
molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other  
noncovalent derivative (such  as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or  
pharmacological action of the drug substance."   See also 21 CFR 314.108(a).  
40  Letter from  Michael A. Chappell, Acting Associate Commissioner of Regulatory Affairs, FDA, to Kathleen M.  
Sanzo, Morgan, Lewis & Bockius LLP,  responding to Citizen Petition 2005P-0259  from Biostratum, Inc (Jan. 12,  
2009).   Docket No.   FDA-2005-P-0259   [Document ID: FDA-2005-P-0259-0004].    
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finding  that the article  would be lawful  under  the  FD&C  Act (21  U.S.C. 
321(ff)((3)(B)(ii)).    Authorized for investigation  means that the article is the  
subject  of an IND  that has gone  into effect  (see 21  CFR 312.40).  
12. May I manufacture  and sell a dietary supplement containing a  dietary 
ingredient that  was  marketed as a  food or  dietary  supplement before it was  
approved as a drug,  licensed as a biologic, or authorized  for investigation  
under  an IND?   
Yes,  in this  situation  the dietary ingredient  may be used  in dietary supplements.  In 
considering  whether a  substance  has been marketed  as a dietary  supplement  or as a 
food, FDA  looks  for evidence  of one  of the following:    
1.   Evidence that the substance itself  was  sold  or offered for sale in  the U.S.  as  a 
dietary supplement,   dietary ingredient   for use in dietary supplements,  or  
conventional  food.   For example,  a catalog listing  a product  identified  as a  
Substance  A supplement  would establish the marketing of Substance A as  
a  dietary supplement.  Similarly,   business  records documenting  that a  
substance was sold or  offered for wholesale or retail  sale for use as an  
ingredient   in  a conventional   food would establish the marketing of the  
substance as  a food.   
2.   Evidence that  the substance was  a  component  of a  food or dietary 
supplement  that was  sold or offered for  sale in the U.S., and that  a 
manufacturer  or distributor   of the  food or dietary supplement  marketed  it  for 
the content  of the  substance  by, for  example, making claims about  the  
substance or otherwise  highlighting  its  presence in the product.41   For  
example, in Pharmanex  v. Shalala, the firm  marketed  lovastatin,  a 
component  of its red yeast rice product  Cholestin,   by promoting  the  
lovastatin content  of Cholestin.42    Merely showing that the  substance  was 
present  as a  component  in a  marketed  food  would not  be  enough  to show  that  
the substance was  marketed, however.  
V.   NDI Notification Procedures and Timeframes   
A.   Procedure for  Submitting an NDI notification 
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
                                              
41  See  Pharmanex v. Shalala, 2001 WL 741419,  at *4 & n.5 (D.  Utah March 30, 2001).  
42  Id.  at *3.  
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RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
 
Notification Procedures and Timeframes: Guidance for Industry." 
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RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
 
Notification Procedures and Timeframes: Guidance for Industry." 
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RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
47   Contains Nonbinding Recommendations  
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 RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
48   Contains Nonbinding Recommendations  
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 RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
                                              
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient Notification 
Procedures and Timeframes: Guidance for Industry." 
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 RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
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RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
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RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
                                              
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient Notification 
Procedures and Timeframes: Guidance for Industry." 
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RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
B.   What Happens After  an NDI Notification  Is Submitted?  
RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
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 RESERVED  See the final guidance "Dietary Supplements: New Dietary Ingredient 
Notification Procedures and Timeframes: Guidance for Industry." 
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VI.   What  to Include   in an  NDI  Notification   
A.   Identity Information About the NDI and the Dietary Supplement  
1.   What  is the purpose of including  information about the identity of the NDI  
and the dietary  supplement containing the NDI in my  notification?  
The  purpose of including  identity  information  in an NDI  notification  is to establish 
what the NDI  is,  including  the category of  dietary ingredient   in section 201(ff)(1) of  
the  FD&C  Act (21  U.S.C. 321(ff)(1)) to which it  belongs;  to identify the other  
ingredients and components  of the dietary supplement;  and to provide  the basis  for  
FDA to evaluate  the qualitative   and quantitative   relationship  between the  NDI  and 
the substances that are the subject  of  the history of  use  or  other evidence  of safety in 
your notification   (see questions  VI.A.5  and VI.C.2).  Without  complete and accurate 
identity  information,   FDA cannot evaluate  whether there is  a  history of  use  or  other  
evidence  establishing  that  the dietary supplement  containing  the NDI will  
reasonably be expected to be safe  under  your  proposed conditions   of use.  
2.   What types of identity information should I include in my NDI notification?  
We recommend  including   the following  in the identity  section of your  NDI  
notification:  
    The  name of the  NDI, as  given in the  cover  letter (see  question V.A.2), its  
trade name (if  different),  and any other names by which the NDI  is  known;  
   A  description  of the  physical  properties  of the  NDI, a description of the  
chemical  or molecular  composition  or structure  of the  NDI, or both;   
   Controls  and/or  acceptable ranges  for batch-to-batch variability,   where 
applicable;  
   The identity  and level  of any impurities   and contaminants  that  may be in the  
NDI  or dietary supplement;  
   Additional   information  specific  to the type  of dietary ingredient,   as  
recommended in question  VI.A.6  (vitamins,  minerals, amino acids, 
constituents,  metabolites,  and other  discrete chemical  entities), VI.A.7  
(salts),  VI.A.8  (enzymes),  VI.A.9  (covalently modified  derivatives of  a  
dietary ingredient),    VI.A.11(mixtures),  VI.A.12  and VI.A.13  (botanicals),  
VI.A.15  (extracts and  concentrates),  VI.A.16  (ingredients  produced using 
fermentation), and VI.A.17  (live  microbial  dietary ingredients);   and  
   A description of the identity  of the other  dietary ingredients   and the other  
ingredients in the  dietary supplement product.  
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FDA recommends  that you establish identity specifications   for the NDI  and for  
those components  of the NDI  and  dietary supplement  that  are  relevant to 
establishing  the basis  for the  safety of the dietary supplement.  Your notification  
should provide  a detailed description  of  the identity specifications  in table form, as  
recommended in question  VI.A.5.     
In addition,   for a manufactured NDI, you should describe  the manufacturing process  
and provide  detailed information  about  the aspects  of the manufacturing  process  that  
are  relevant  to safety and identity,   as  recommended in question VI.A.3  below.  
3.   How much detail should my  description of the  manufacturing  process 
contain?  
The description should have sufficient  detail  to enable  FDA to understand the  
overall  process used to make the NDI  and the dietary supplement.  You should 
identify  any points in the  process  that you know to be  relevant to the  safety of the  
dietary supplement.  Detailed descriptions   of manufacturing can be limited  to those  
portions  relevant  to safety  and identity,   if  they can be identified.    For  example,  you 
might  establish a specification  to limit   mold contamination  of a  component  used to 
make your  NDI (e.g., aflatoxin in corn).   You might  also use  a specification  for  the  
temperature of  a key extraction  step  to prevent  formation of a toxic  byproduct  and/or  
a specification  for  that byproduct  in an analysis  of an interim  material  or  of the  final 
product.  You may describe  the entire  process and all  specifications  or select only 
those that  are  relevant  to the identity  and safety information  that  provides  the basis  
for the safety of your  NDI.  
4.   What  is a  specification?  
A specification  is  a set of standards developed by the manufacturer  or distributor   of  
a material  (e.g.,  an NDI  or a  dietary supplement).  The specification  includes  
standards for  each of the components  of  the material  and for the material  as  a whole.   
For the  purpose of  an  NDI  notification,   the specifications  should include critical  
safety attributes  and may omit  attributes  not  relevant  to safety or identity.  The  
specification  sheet should  provide a list  of tests, the acceptance criteria for each  test,  
and analytical  methods  used to support  the acceptance criteria.   Acceptance criteria 
are numerical  limits,  ranges,  or other  criteria for the tests described.  They are used  
to determine  whether to accept  or reject the ingredient   or product  being analyzed.   
Acceptance criteria should  be specific,  rather than vague.    
 
The description of  the analytical  methods  should include a  detailed set  of  directions  
that must  be followed exactly for the  results to be accepted for the stated purpose.   
The directions  should cover all  steps,  from preparing  the test sample  to reporting the  
results  of the analysis.   The description of  the method should be complete,  whether  it  
is  proprietary or included  as  a  publication.   Details  of  the method,  such as a  
description of  the  chromatographic column,  solvent elution conditions,   and the  
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source and authenticity  of any reference  standards, are  integral  to understanding  how  
a method is  used to identify the analyte.  
 
A vague acceptance  criterion is  rarely useful.  For example,  it  is not  informative   to 
say that a  chromatogram  or  a spectrum  matches  the reference sample unless every 
peak matches (both height  and location)  or there is  a  description  of  which peak or  
peaks match and how they match (e.g.,  description  of the acceptable variation in 
peak retention time  and peak height  or area  under  curve).  The use  of  fingerprint  
analysis  of complex spectra  or chromatography of mixtures  containing  many 
ingredients  does  not  require  knowledge  of  the identity of all  or even any of the  
peaks, but does  require  matching  sufficient numbers  of  peaks across  the entire 
spectrum  or chromatogram  to ensure the validity  of the test result.   Components that  
are  known to be toxic  can be identified  by a single  acceptance  criterion (e.g.,  less 
than), but  acceptance criteria for  other components  should be  expressed as  a range.   
The source and authenticity  of analytical  standards  should also be documented.  
5.   What  specifications for my process and ingredients  should I include in the  
notification?  
Manufacturers  and  distributors   of dietary supplements  must  establish  specifications  
for the components  of  their  products  (see 21 CFR 111.70(b)).   The required types of  
component specifications   include:  
   An identity  specification  for each component;  
   Component specifications  necessary  to ensure that  specifications  for the  
purity, strength,  and composition  of dietary supplements  manufactured 
using the  components  are met;  and  
   Limits  on the  types of contamination  that may adulterate  or may lead to 
adulteration of  the  finished product.  
Your notification   should list  and explain the role  of  those specifications   that are 
relevant  to the  identity of the NDI and to the  safe consumption  of  the  dietary 
supplement  containing  the NDI,  including  how you arrived at  the criteria  for  
acceptance or rejection  based on  the results  of each  test in  the specification.  This  
might include  specifications for  starting materials  used to make your  NDI, process  
controls during manufacturing,   and/or interim  or  final  product specifications  for the  
NDI  or the  dietary supplement.   For ease of reference, we recommend listing  the  
specifications  in  table form  (see example in Table 2).   You should describe the 
controls  in place to  maintain  the  strength,  composition,   and purity  of the NDI  
throughout   the  shelf life of the  product.    
If  you rely on history of  use or other  evidence  of safety for  materials  other than your  
NDI, you should explain,  based on the  manufacturing method and specifications  of  
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your  NDI,  the  qualitative   and quantitative   relationship  between your  NDI and  the  
materials  used to demonstrate safety.  For example,  if  your  NDI  is  a  mixture  of  
polyphenolic   compounds  extracted from  grapes, you might  use information  such as  
quantitative   high performance liquid  chromatography (HPLC)  analysis  to  relate the 
quantity of  those  compounds in a  serving of  your  ingredient  to the  quantity in a  
serving of unprocessed grapes or grape juice.   
Table  2.  An Example of a Specification Sheet or Table  for  a Dietary Ingredient  
Analytical Method  
Test   Acceptance  Criteria   (Referenced Method or  
InHouse Method Name)  
Appearance:  Color/physical 
White to off white/powder   Visual, R-015451  
state  
Dietary ingredient identity   Matches reference standard   HPLC, R-020301  
Dietary ingredient assay   a  b  mg/capsule   HPLC, R-020301  
 
Related substances:   No more  than (NMT) 0.5% of 
Total related substances   total peak area of the dietary   HPLC, R-020301  
  ingredient  
 
Microbial limits,  if  applicable:  
NMT 100  CFU/g  
Total Aerobic Microbial Count  
Absent   USP <61>  
Staphylococcus aureus  
Absent  
Pseudomonas aeruginosa  
Apparent pH, 25 C  (if  
4.5  to 5.5   USP  <791>  or  in house method  
applicable)  
Residual solvent, e.g.,   ethanol, 
NMT specified limit  in  ppm   GC, R-019011  
acetone, hexane2  
Heavy metals   NMT 20 ppm   USP 30<231>  Method II  
1  In-house analytical methods, which  should  be described in sufficient detail in the NDI  notification  
for FDA to evaluate them.   Use of a method published by an authoritative source (such as AOAC  
International or the United  States Pharmacopeia (USP)) or described in  a peer-reviewed journal (such  
as  Journal  of Chromatography)  is also  appropriate, as long  as a reprint or copy of the publication is  
provided. 
2 Solvents that were used  in the manufacturing process.  
6.   What  additional  information should I submit if my  NDI  is a  discrete  
chemical entity (e.g., a vitamin,  mineral,  amino  acid,  or a constituent or a  
metabolite of another dietary  ingredient)?  
You should provide  sufficient  information  to uniquely  characterize your  NDI  as a 
discrete molecular  entity (or mixture  of discrete molecular  entities).  Information 
that uniquely  characterizes  a single molecular  entity  should  include  the common or  
usual  name  of  the  molecular  entity, the  molecular  formula and formula weight, the  
structural  formula  (as  noted, for  example, in ChemIDPlusAdvanced, PubChem, or  
International Union of  Pure  and Applied  Chemistry  (IUPAC)) and, if available,  the  
Chemical  Abstracts Service (CAS) registry  number.  For  example,  if  the substance 
exists  as  a configurational   isomer  (stereoisomer),  such as  an enantiomer  or  a  
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geometric isomer, the  isomer in question should be specified  and  characterized.  For  
an enantiomer,  the notification   should include the  correct  stereoisomeric  structure  
and the correct chemical  name with the appropriate  R  or  S designations.    
Other systems of nomenclature  (such as  D or L for amino acids)  are also  appropriate  
as long as the  name  unambiguously  identifies   which isomer(s)  are present.  For  a  
geometric isomer,  the correct cis (Z) or trans (E) stereoisomeric structure and  the 
correct  chemical  name should be provided.  In addition,   if  the notification  asserts  
that the  NDI  is a metabolite,   you should document  the basis for  this  assertion.  For  
example,  the notification  should cite evidence  showing that the level  of  the  NDI  in  
the human body increases with intake  of a precursor constituent  of food.   (See 
definition  of metabolite   in section VII.)  
 
Other relevant  information  might  include:  
   Specifications  for  your raw  materials  (e.g.,  food grade),  and evidence that  
your  raw  materials  conform  to the specifications.  
   A detailed description of each step of the production  process, including:    
  Reaction conditions   in the synthesis  and purification  process.   
o 
  The process and quality  controls  used in the manufacturing 
o 
process;  for  example, temperature, time, pH,  shielding  gas, etc.  
  Flow diagrams  of  the manufacturing process.  
o 
  Composition:   Provide  the  identity and quantity (including  units  
o 
and any ranges) for each component.  
  A description of how  undesirable  byproducts  of manufacturing 
o 
are removed.   Examples  of undesirable  byproducts include  
unreacted chemical  reagents, reaction byproducts,   and solvents  
like  methanol  or hexane.  
7.   What  additional  chemistry information should I  submit if  my NDI is a salt?  
You should describe the  extent to which the  salt will  dissociate  following  ingestion,  
particularly  if the  history of use  or other  evidence of  safety describes forms  of the  
ingredient   other than the salt that  is the subject  of the notification.    Specific  
discussion of whether  different salt forms  have  different  toxic properties  also should 
be included.  
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8.   What  additional  chemistry information should I  submit if  my NDI is an  
enzyme?  
If your  NDI  is  an enzyme,  you should describe the  following   in the specifications  
portion of the identity  section of your  notification:  
   The  analytical  method used to determine enzyme  activity;  
   The  specifications  for enzyme activity in the  NDI;  and  
   The  acceptance  criteria for  enzyme activity and for  the  number of units  
of activity per serving of the NDI in the dietary supplement.  
9.   What  additional chemistry information should I  submit if  my NDI is a 
covalently modified  derivative of a  dietary ingredient?  
Covalent modification  chemically  alters  the ingredient   and changes  its  identity.   
Examples  include  covalent bonding  of one  dietary ingredient   to another or  
exchanging a functional  group (e.g.,  an alcohol)  for another  (e.g.,  an acid or  an 
ester).   The chemical  structure of the new ingredient  should be described explicitly 
and clearly.   Before submitting  an  NDI  notification  for the new ingredient,   you 
should consider whether  it qualifies   as  a  dietary ingredient  under one of  the  
categories in section 201(ff)(1)(A)-(F) of the  FD&C  Act  (21  U.S.C. 321(ff)(1)(A)-
(F))  (see question IV.D.5).  If  not,  the new ingredient  cannot  be  an  NDI  because it  is  
not  a dietary ingredient.    
10. What  information should I submit if  my notification  relies  on history of use  
or other evidence of safety for a substance or product that  is similar to, but  
not  exactly the same as, my NDI or dietary supplement?  
You should use chemical,  microbiological,   and  botanical characterizations,  as  
appropriate,  to explain how  the substance or product  is similar   to your  NDI or  
dietary supplement  and to provide  a  rationale  for  how the safety information  that  is  
presented for the  similar  substance or product  is  relevant  to the safety of your  NDI  
or dietary supplement.   Note that developing  such a  rationale  requires  knowledge  of  
the identity  (e.g.,  composition  and strength)  of  the related substances that were 
studied or that  have a  history of  safe  use.  The discussion in the notification  should 
include  the scientific  rationale  that supports  extrapolating  conclusions  from  a safety 
evaluation of the  related substance or product  to your  NDI  or dietary supplement.   
Otherwise,  such evidence  of safety may not provide  a  basis  to conclude  that  your  
NDI  or  product  will  reasonably be expected to be safe.    
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11.  What  additional identity  information should I  submit  if my product  
contains  a mixture of ingredients?  
You should state the identity and level  of each ingredient   in the dietary supplement,  
including  both dietary ingredients   and other ingredients,   such as  those  used for a  
technical  or functional  effect  in the product  (e.g., binders,  fillers,   and color  
additives).   You should also describe  how the  ingredient   combination  in the mixture  
relates to the history of safe  use or other  evidence  of safety of  the dietary 
supplement  in which the NDI  will  be used.   The dietary supplement  safety narrative 
should address  bioavailability  of the ingredients   as  formulated,  including  use of  any 
binders  or fillers  that affect  bioavailability  of  any of the dietary ingredients  in the  
dietary supplement.  
12.  What  additional  identity information should I  submit if  my NDI is a 
botanical  or is  derived  from a botanical?  
You must  provide  the Latin binomial   name,  including  the author  citation,   for any 
ingredient   that is  a  botanical  or derived from  a  botanical  (21 CFR  190.6(b)(2);  see  
also 21 CFR  101.4(h)).   We  recommend that you also specify  the part of the plant  
from which the  ingredient   is derived.   You may, in addition,   provide  a common or  
usual name for  your  botanical  ingredient.  The  Latin binomial  name should be  in 
accordance with internationally  accepted rules  on nomenclature,  such as those  found 
in the  International  Code of  Nomenclature  for algae,  fungi,  and plants  (ICN)  
(formerly known as  the  International  Code of Botanical  Nomenclature).   FDA 
recommends using  the  most  recent edition of  ICN.45  We also  recommend  providing  
the following   to help us evaluate  whether your  botanical  ingredient   is the same as  or  
similar to botanical ingredients described in  the history of use or other  safety 
evidence in your  notification:  
   Description of specific  tests or examinations   you use to ensure correct  
taxonomic identity,   including  identification  of any authenticated 
botanical reference materials  or  authoritative  botanical descriptions used;  
   Conditions   of propagation,   if  they involve   deliberate  manipulation  of  
propagation in a  manner that  is significantly  different than common plant  
propagation and breeding practices;  
   Conditions   of cultivation  (e.g., wild harvest,  field,  or greenhouse)  and 
geographical  origin  of  plant material, if  necessary  to accurately identify 
the NDI  or  relevant  to your  conclusion   that  the ingredient  is reasonably 
expected to  be safe;  
                                              
45 McNeill, J.; Barrie, F.R.; Buck, W.R. et al., editors.  International Code of Nomenclature for algae, fungi, and plants  
(Melbourne Code)  2012  (electronic ed.).  Available at: http://www.iapt-taxon.org/nomen/main.php  
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   Periods  during which the  botanical  is cultivated and  harvested (season or  
month(s)  and year,  age  of plant,  or both)  and the stage of maturity of  the  
harvested plant  part;  
   The part of the plant  from  which the ingredient  is  derived;  
   Whether  the botanical  is  used in a  fresh or dehydrated state;  
   The form  in which the  botanical  is  used (e.g.,  whole,  chopped, cut-and-
sifted,  or  powdered);  
   A properly  prepared and curated voucher  of the botanical  source  
material; and  
   The full  Latin binomial   name (with author) of  any known adulterant  
species that must  be excluded from  use in production  of the NDI, and a  
description of how  its  use is  excluded.   
13.  Should I describe the production methods for  my  botanical  NDI?  
Yes.  You should describe  the production methods  for your  botanical  NDI to the  
extent  necessary to  demonstrate that the  NDI  is the same as  or  similar  to the 
botanical  materials  described in information  submitted as  evidence  of the safety of  
the NDI.  Thus,  cultivation  of  plants, algae,  or  fungi in wild or  standard conditions  
might  not require extensive explanation.    However,  unusual  production  conditions  
should be  explained.   For instance, if you culture  Saccharomyces cerevisiae  in a  
medium  with unusually  large amounts  of  selenium,   you should describe  the  
fermentation process,  as  well  as  the levels  and types  of selenium  compounds  in your  
final  product.   If you use traditional  or  molecular  methods  to produce  a variety with 
novel  properties,  you should describe the variety in sufficient  detail  to demonstrate  
that  the  ingredient   you derive from it is reasonably likely  to be  safe  under the  
conditions   of use of the  dietary supplement  to which the NDI  will  be added.  
14. How should the identity section of my NDI notification deal with toxins in 
related  plants or microorganisms?   
You should identify  the toxins  or classes of toxins  or other deleterious  constituents  
or properties  (e.g., antibiotic   resistance  genes in microorganisms   or toxigenic  
properties  for which the toxin is  unidentified)   known to be present in the same  
species or in a  family or genus  that is  phylogenetically  related to the NDI.  You 
should also document  the absence  (or the amount,  if  present)  of those toxins  or other  
deleterious  constituents  or properties  in the NDI,  as  well  as in the substances that are 
the subject  of  the history of use or other  evidence  of safety presented in the  
notification.    Identification  below  the species level  (e.g.,  plant  variety or strain 
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designation)   can be relevant  to the safety determination  when some varieties  or  
strains of  a species are  known to contain toxins.    
15. How should I describe an extract or concentrate of a botanical  or a dietary  
substance?  
You should include  the following  in the  description of your extract  or concentrate:   
 
   Overview  of the manufacturing process,  including  a general  description 
of each step (e.g.,  a  flowchart),  followed by a  description  of the method 
of manufacturing in sufficient  detail  to make clear the identity  of the final  
product  (the  finished extract  or concentrate)  and how  it is similar   to and  
different from the  starting  material.  
 
   Description and amount,  expressed as  a  percentage or range of  
percentages,  of all added ingredients,   including  all  solvents  used, along 
with  specifications   for residual  solvents  other  than water  in the finished 
NDI  or dietary supplement.  
   Concentration or dilution  ratio,  or  range of concentration  or dilution  
ratios,  of the finished extract or concentrate relative  to the original  
starting  material.  If the concentration  or dilution  ratio is based on the  
weight  of fresh herb,  rather than dried,  this  fact should be  disclosed.  
   Content,  minimum   content,  or range of content  of any marker substances,  
expressed  as a percentage of  the finished  extract or  concentrate,  
accompanied by (1) a  description  of whether the marker is  a  marker of 
effectiveness, toxicity,  or a surrogate marker,  and (2) a  calculation  or  
estimate of the relative level  of each  marker in  the NDI  compared to the  
original  starting material.    
   The names and specifications  for any marker  substances deemed relevant  
to the identity  of the NDI (e.g., markers whose presence  or  absence  is  
relevant  to the  identity of the botanical  or that  must  occur in a  particular  
ratio to each other  to confirm  identity).  
   How the extract or concentrate is standardized from  batch to batch.  
   Measures taken to remove  adulterants  (e.g., nonfood solvents)  that may  
be  present due to production  methods  or  to reduce  such adulterants  to 
within  acceptable limits.  
   Measures taken to control  adulterants  (e.g.,  pesticides, heavy  metals, and  
filth)  that may be  present in raw  materials  from which  the  NDI is 
derived.   
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   Quantitative  limits   on contaminants  that  must  be controlled  to ensure the  
NDIs  safety,  if any  are present in  the source material  or  may result  from  
the manufacturing process.  
   If  reagents used during processing are  likely to make covalent  changes to 
components  in the  mixture  during processing, you should determine  
whether the new  material is  still a dietary ingredient.   For example,  use  
of a large amount  of an  oxidizing   acid like  sulfuric  acid  to process a  
botanical  mixture may  create a new semi-synthetic   mixture that  is  no 
longer  a  mixture  of components  that  were  present in the original  plant.   
Therefore, the mixture  would  no longer  be  a dietary ingredient.  
16.  What  additional  information should I  include if  my  NDI  is produced using  
fermentation?  
The notification  should include  information  about  the organism(s)  and fermentation 
process used to culture  the microorganism   that  produces  the NDI.  The safety of the  
fermenting organism  for use in food production  should be discussed.  Poorly defined 
microbiological   mixtures  are  acceptable if  there is a long history of use in 
production  of food (e.g.,  mixtures  used to make dairy products like  kefir or  cheese)  
and the fermentation substrate is  consistent  with that history of use.   The notification 
should describe the  history of use of the  fermenting organism(s)  to produce food or,  
in the absence of such history,  should thoroughly  explain how the manufacturing 
process excludes  toxins  and other undesirable  byproducts  of fermentation from  the  
finished NDI.     
The information  about  the fermentation process should describe the complete  media  
formulation,   the fermentation vessel(s),  the fermentation conditions,   the  methods  
used to harvest the NDI  from  the fermentation mixture, and any specifications for  
the production  organism  in the finished NDI, particularly  if  the production  organism  
is  not  inactivated  or  removed.    
You should also address methods  used to ensure the integrity  of the production 
organism,  such as how  you guard against contamination  and genetic change.   FDA  
is  particularly  concerned about  contamination  when fermentation occurs outside  of a  
sterile production  vessel (e.g.,  production of algae  in ponds).    
Note that the use of a major  food allergen in the fermentation medium  may require a 
separate  notification  or petition  to the FDA  if  the presence of the allergen  is  not  
declared on the product  label.   See section 403(w)  of the  FD&C  Act (21  U.S.C. 
343(w)).   
If your  ingredient   is an enzyme,  the  specifications   portion of the identity  section  of  
your notification  should describe the  analytical  method used to determine  enzyme  
activity,  the specifications  for enzyme activity  in  the NDI, and the acceptance 
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criteria for enzyme activity  and for the number  of units  of activity per serving of the  
NDI in the  dietary supplement.   Post-fermentation harvest and processing should be  
described, including  filtration,   washing,  and preservation methods.  
17.  What  additional  information should I  include  if my NDI is  a  live microbial  
dietary ingredient?   
You should include  a complete  description  of the organism,  including:  
   The strain;  
   Methods  used to establish the identity  of the strain,  such as  identification 
by internationally  recognized third-party repositories   (e.g.,  the American 
Type Culture Collection);   and  
   The relationship  of the strain to the  strain(s) of  the same  species used to 
establish the history of use or other  evidence  of safety for  the  NDI.  
The use of scientific names  (Latin binomial  name with author citation)  is required  
for botanical  ingredients  (21 CFR 190.6(b)(2))  and is  recommended for bacteria.   
For bacteria, FDA  recommends  using the  Bacteriological  Code  (1990 Revision),46  
validated lists  of names in the  International  Journal  of Systematic  and Evolutionary 
Microbiology,   and public   lists  of prokaryotic  nomenclature  (e.g.,  Prokaryotic  
Nomenclature Up-to-Date47  or  the  List  of Prokaryotic  Names with Standing in 
Nomenclature48).   FDA  will  pay particularly  close attention to the proper  
identification  of organisms  from  genera or species that  do not  have a long history of  
food use  and to those  from genera, like  Bacillus  and Streptococcus,  which contain  
both species  with long histories  of  food use  and species  known to contain human 
pathogens.    
FDA regards all  members  of a species that contains  human pathogens  as  potentially 
harmful  to human health  and,  therefore,  inappropriate   for use as  dietary ingredients,  
because of the absence of a consensus  that there are valid  scientific ways to  
distinguish  between pathogenic  and non-pathogenic   members  of a single  species or  
to prevent horizontal   transfer  of genes  for pathogenic  traits between members  of the  
                                              
46 Lapage, S. P.;  Sneath, P. H. A.; Lessel, E. F.; Skerman, V. B. D.;  Seeliger, H. P. R.;  Clark, W. A., editors.  
International Code of Nomenclature of Bacteria (Bacteriological Code), 1990 Revision.   Washington (DC):   American  
Society for Microbiology Press; 1992.  
47  Leibniz Institute DSMZ-German Collection of Microorganisms  and Cell Cultures,   
Prokaryotic  Nomenclature Up-to-Date. Available at: http://www.dsmz.de/bacterial-diversity/prokaryotic-nomenclature-
up-to-date/prokariotic-nomenclature-up-to-date.html [Note that content on  this website is updated frequently. Use the  
search function in the embedded  link to retrieve the current validated name of a bacterial organism.] 
48 Parte, A.C., editor.  List of Prokaryotic Names with Standing in Nomenclature (LPSN) Database. Available at:  
http://www.bacterio.net/.   [Note that content on this website is updated frequently. Use the search function in the  
embedded link to retrieve the current validated name of a bacterial organism.]  
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same bacterial  species.  Examples  of  species that should  not  be used  in  dietary 
supplements  include  Escherichia coli, Enterococcus faecalis, and Enterococcus  
faecium.  
FDA  considers each  strain of a bacterial or yeast  species  to be a separate ingredient.   
You should explain how your strain was  obtained and how it varies  from other  
members  of the same species.  If your  strain  was  genetically  modified  using either  
random  mutagenesis or bioengineering,   you should describe the  process  used and 
how you characterized the  properties of the  new  strain.   
FDA also considers  the manufacturing process,  including  the fermentation,  as an 
intrinsic  part of the identity  of an ingredient   that is  viable  at the time  of ingestion.  
We  recommend that the fermentation and other  parts of the manufacturing process  
relevant  to safety and identity  be  described in detail  in your notification,   as  
recommended in questions  VI.A.3  and VI.A.16.  
 
FDA will  pay particular  attention to the viability  of microorganisms   in the NDI.   
The per-serving level  of a viable  microorganism   depends  on both the mass (in 
grams) and the viability  (e.g., number  of  colony-forming  units) of  the  organism in 
the final  product.   The composition  of  the growth medium  and the fermentation 
conditions   of  the organism  are  also relevant to the  safety of  the product,  particularly 
when they alter the  form  of the  organism  (e.g., spore vs.  vegetative)  or the  
composition  of the ingredient   (e.g., when the ingredient   includes  both the organism  
and the growth medium).  The notification  should explain the relevance of safety 
information  presented about  other  strains  from  the same species.  
18.  What  information should I  provide in  my notification  if  the labeling of  the  
NDI or  dietary  supplement containing the NDI will  include  an expiration 
date  or  use by date?  
The expiration  or  use by  date  should be based on appropriate supportive  stability  
data  showing  that (1) no new degradants  will  form during the  labeled shelf life  of  
the product  under  the  conditions   of storage  specified in the notification,  if any, or  
under  normal  storage conditions;  and (2)  the  NDI  or dietary supplement  will 
continue  to meet the critical  safety attributes  of  identity,   strength,  and purity through 
its  labeled expiration  or use by  date.   You should provide these  supportive  data in 
the notification.  
19. What information  should I submit to describe  the conditions of use that I  
intend to recommend or suggest in the labeling of my dietary  supplement?  
Your notification  must  describe the  conditions   of use  that will  be  recommended or  
suggested in the  labeling  of your dietary supplement  or, if no conditions   of use  will 
be  recommended or  suggested in the  supplement  labeling,   the ordinary conditions   of  
use of the supplement  (21 CFR 190.6(b)(2)(ii)).    Conditions   of use include  the dose  
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(serving size),  serving form  (e.g., capsule or  powder)),  frequency of use (e.g.,  
number of  servings per  day  and interval  between servings),  duration of use,  
instructions   for use, target population,   other dietary ingredients  in the  dietary 
supplement,  and any restrictions  on use, such as excluded populations.    
 
For purposes of  review, daily lifetime  use  by all  age  groups  and other  populations   at 
the  highest recommended serving size  will  be  assumed  unless the notification 
specifies  that the  labeling  will  contain restrictions  on conditions   of use (e.g.,  
excluded populations   or frequency and duration of intake).  Population  restrictions  
could include  exclusion of  children,   pregnant  or  lactating women, or  sensitive  
individuals   who should not consume the  product.   Allergen warnings  are  an example  
of a population  restriction on conditions   of use.  The conditions   of use  to be  
recommended or  suggested in the  labeling  of the  dietary supplement(s)  containing 
the NDI  should be described prominently  in the administrative   section  near the 
beginning  of the notification  (see  question  V.A.2).  
B.   History of Use or  Other  Evidence of Safety  
1.   What  safety information is required to support  an NDI notification?  
You must  provide  the information  that forms  the basis  on which you have concluded 
that a dietary supplement containing  the NDI will  reasonably be expected to be safe  
under  the supplements  labeled conditions   of use (21 U.S.C. 350b(a)(2)).  In general,  
this  information  should include  an adequate history of  safe use,  safety studies,  or  
both.  
For dietary supplements  that contain dietary ingredients   or other components  in 
addition  to the NDI,  the notification  should include  safety information  for  the  
finished product  as  well  as for the NDI  because it  is not  possible  to conclude  that the  
dietary supplement  containing  the NDI will  reasonably be expected to be safe  
without  considering the safety of these other components.  As discussed in section 
VI.C, FDA recommends  including  a  comprehensive  safety profile  for the NDI and a  
safety narrative  for the dietary supplement  in NDI notifications   (see questions  
VI.C.1  through VI.C.3).   
2.   Should I submit both a history of safe  use  and safety testing data for the  
NDI?  
It depends.   A notification  should provide  evidence  of  a history of safe  use; other  
evidence of  safety, including  clinical  testing,  animal testing,  or both; or some  
combination  of history of  use  and other evidence  of  safety.  The submitted data  
should provide  the basis  for a conclusion  that there is a reasonable expectation of  
safety under the  proposed conditions   of use of the dietary supplement  containing  the  
NDI.    
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FDA expects  that  when history of  use  evidence  alone  is  adequate to support  the  
safety of the NDI  in the supplement,  notifiers  will prefer to use  that route.   
Compared to the cost and time  needed to conduct  clinical  or animal  toxicology 
studies,  it  is  generally less expensive  and faster  to gather  historical  information  and 
to conduct  chemistry studies  to establish the identity of  the historically  used 
materials.    
Submitting  clinical  studies,  animal studies,  or both,  in addition  to history of use data,  
would be appropriate  when the  history of use  evidence  contains  gaps or when the  
proposed conditions   of use for the NDI differ  from  the historical  conditions   of use.  
3.   What  data  and information should I  submit  to substantiate  an  NDIs  
history of safe  use?  
A history of safe  use can be substantiated by providing  evidence  that  the substance  
was  safely consumed as  a food or dietary supplement  or as  a component  of a more  
complex mixture  (e.g.,  calcium in milk or  beta-glucan  in oatmeal) at  levels  equal to  
or  higher  than those  that would be  consumed by someone taking the  NDI-containing 
supplement  under  the proposed conditions   of use.   This  history of use  could be  from  
the United States  or another  country,  as long as the  substance  was consumed as a  
food,  dietary supplement,   or, in the case  of  foreign history of  use,  category of  
product  comparable to a  dietary supplement  in the U.S.  
Elements  that FDA recommends  to substantiate that an  NDI  has a  history of  safe use  
include:  (1) a characterization and comparison of  the identity of  the NDI  and the  
historically  consumed article;  and (2) an explanation of  how the compositions   of the  
two  are related.   That is, the  composition  and other  identifying   characteristics  of the  
NDI  and the historically  consumed article  should be characterized in sufficient  detail  
to demonstrate  that  safe  use  of  the historically  consumed article  is relevant  to the  
safety of the NDI  and provides  a basis to conclude  that the supplement  in which the  
NDI  will  be marketed will  reasonably be expected to be safe  under  the proposed 
conditions   of use.  If  the  NDIs  history of use was  as a  component  of  a  more  
complex mixture,   you should demonstrate  how the NDI  is qualitatively  and 
quantitatively  related to the historically  consumed component.  If the NDI  is  itself  a  
mixture  of dietary ingredients,   you should demonstrate how the  component  dietary 
ingredients  in the  NDI are related to historically  consumed ingredients  or  
components.  
In addition,   (a)  the dose  (per-serving  intake)  and total  daily intake;  (b) duration of  
use;  (c) frequency of  intake;  and (d)  any additional   information  that  describes the  
conditions   of use of the  historically  consumed material  should be  provided.   For  
example, if  consumption  is not uniform  within the  population,   you should provide  
information  about  the mean and high (e.g., 90th  percentile) exposure levels.   Finally,  
the size  and relevant  characteristics of the consuming  population  (e.g.,  everyone vs.  
limitations   based on age, gender,  or health status)  should be discussed.  
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For  these data  to demonstrate  a history of safe  use, the  intake  level  for the  
historically  consumed article  should be the same  as or higher  than the  anticipated  
intake level  of the  NDI  in the dietary supplement,   based  on the conditions   of use  
described in the  NDI notification.   For example,  information  showing that a  steroid 
hormone  is present  in nanogram  amounts  in a  serving of milk or  beeffoods that  
have  a long history of  safe use  would not  support  the safety of a  highly 
concentrated bovine  extract  that contains the steroid hormone in milligram   amounts.   
In contrast,  consumption  of  cows  milk  could be used to support  the safety of a  
specific  protein purified from  milk at  a  serving level equal  to or lower  than the  
amount  of the protein found in an 8 ounce serving of milk.  
 
As another  example,  if your  NDI  is  an oil  made  from a plant  or fish and you can 
show that  the oil  consists  only of a mixture  of fatty acids,  each of  which  you can 
identify and demonstrate to be  widely consumed at  higher  levels  in conventional  
foods,  you may be able to conclude  that the dietary supplement  containing  the NDI  
will reasonably  be  expected to be safe  based on compositional  information  alone.  
The safety assessment  should describe  and discuss  situations  in which the conditions  
of use and composition  of  the NDI  differ  from  the documented conditions   of  use  and 
composition  of the historically  consumed substance (e.g., when the  NDI  is  derived 
from a  plant  variety bred to produce  an additional   constituent  or to remove  a  toxic  
constituent).  When the historical  usage differs  substantially  from  the proposed use  
of the  NDI, additional   supportive  data may be needed.  Examples  of differences  in 
an  NDIs proposed use that might  necessitate  further  supportive  data include:  
   Higher dosage;   
   Different route  of administration   (e.g., an article that has  a history of safe  use  
in sublingual   form  and is  now intended for ingestion  as  an  NDI);   
   Longer  duration of use;   
   Other changes that increase exposure to potential  toxic effects;  and  
   Any  other difference that raises new safety  issues, such as  a change in target  
population   (see definition  in section VII).  
4.   What documentation of an  NDIs history of use should I submit?  
Documentation of  an  NDIs history of safe  use in food could include published  data  
and information,   such  as peer-reviewed scientific literature,  reports from  
authoritative   bodies,  survey data on food or nutrient  composition  and consumption,  
advertisements  or other  published  promotional   material  describing the composition 
of products,  published  agricultural  or  food production  data, or cookbooks  or other  
published  recipes documenting  the use of an ingredient   to prepare conventional  
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foods.  Documentation of history of  use  could  also include trade secret  or  
confidential  commercial  information,   such as proprietary survey or consumption 
data, product  sales data, and compositional   analyses.  
5.   Am I required to submit a comprehensive survey of every historical use of  
the NDI?  
No,  only the data and information  on which your  reasonable  expectation of safety is  
based are  required.  For  example,  if  you have documentation  that soybeans  have a  
history of  safe use in a large  population  in Asia, data  describing lower historical  
consumption  in the  U.S.  or  Europe is not necessary to support  the safety of  an  NDI  
that  is  a constituent  of  soybeans.  
6.   How do I determine whether historical use was daily chronic or  
intermittent?  
Daily  chronic  use  of the historically  consumed material  refers  to ingestion  at  least  
once a  day,  every day,  for  at least  three  months  in a row.   Daily chronic use  includes  
long-term use.   Intermittent use, for purposes  of this  guidance,  means less than  daily  
chronic  use  and  can be either  daily and finite in duration or  non-daily   and lifetime  in  
duration.   An example  of intermittent   use is the use of seasonal  fruit  for less than 90 
days.  
7.   Should I estimate  the intake of historically consumed materials  related to  
my NDI if I am relying on those  related materials  to establish a history of  
safe use,  and should this  estimate  be included in my  NDI notification?  
Yes  to both questions.  If your  conclusion  that the dietary supplement  containing 
your  NDI will  reasonably be expected to be safe  is based on a  history of safe  use  of  
materials  other than  the NDI  itself, you should estimate  the  historical intake  of  the  
materials  that you determine  to be relevant  (see  question  VI.A.10) and include  this  
information  in your  NDI notification.   In developing  these  estimates,  you should 
take into account the complete  pattern of  intake,  including  dose,  duration,   and 
frequency of  intake,  as  well  as  the  size of the  population  known to have  consumed 
the substance.  The  distribution  of intake  within the population  (e.g., the  mean and 
90th  percentile amounts  consumed)  is also important.  
8.   Where may I find information on how to estimate consumer intake?  
For references  and information  on methods of  estimating  consumer intake  of food 
ingredients,   including  dietary ingredients  in dietary supplements,   refer  to 
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Estimating  Dietary Intake  of Substances  in Food49;  section III.G, Intake  
Estimate,  in Recommendations   for Submission  of Chemical  and Technological  
Data  for  Direct Food Additive  Petitions50; and  Principles   and Methods  for the  
Risk Assessment of Chemicals  in Food.51    FDA  is also aware of  the existence of  
extensive analyses of  consumption  of specific conventional  foods,  especially in the  
U.S.,  in proprietary databases.   Because  these  proprietary databases  contain food 
categories much narrower  than those  described in public  databases,  they may be  
helpful in estimating consumer intake of  a food constituent  that becomes  an  NDI  for 
use in a dietary supplement.   
9.   How is the reliability of history of  use data evaluated?  
One  important  component  of reliability  is the length of an ingredients  history of  
use.   A  description  of the  population  consuming  the ingredient   and the ways in 
which they use  it is also important.   Finally,   the number  of consumers  who used  the  
ingredient   and the frequency of consumption  are at least as  important  as the number  
of years over which the  ingredient  has been used.   FDA considers  25 years of  
widespread use to be the minimum   to establish a  history of safe  use.52   Because 
there  is  little   scientific literature addressing this topic,  we  cannot make  more  specific 
recommendations  at this  time.  
10. Should I cite the history of use of an  NDI in traditional medicine?  
It  depends on how  much information  is available  about  the  use  of the  NDI  in 
traditional  medicine  and how  similar  the  traditional  medicine  use is  to the proposed 
use in a dietary supplement.   The  history of use of  an  NDI  in traditional  medicine  
can help to establish a  reasonable  expectation of safety for the NDIs  use in a  dietary 
supplement.  However, because differences in composition,   conditions   of use,  and 
target population  often limit   the  relevance of a  safe  history of use in traditional  
                                              
49 FDA, Center for Food Safety and Applied Nutrition, Office of Food Additive Safety.   Guidance for Industry:   
Estimating Dietary Intake of Substances in Food;  August 2006. Available at:  
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRAS 
Packaging/ucm074725.htm 
50 FDA, Center for Food Safety and Applied Nutrition, Office of Food Additive Safety.   Guidance for Industry:   
Recommendations for Submission of Chemical and Technological Data for Direct Food Additive Petitions; March  
2006;  revised March 2009. Available at:  
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/IngredientsAdditivesGRAS 
Packaging/ucm124917.htm  
51 Principles and Methods for the Risk Assessment of Chemicals in Food.   Environmental Health Criteria 240.   A joint  
publication of the Food and Agriculture Organization of the United Nations and the World Health Organization.   2009.  
Available at: http://whqlibdoc.who.int/ehc/WHO_EHC_240_4_eng_Chapter1.pdf  
52  See, e.g., the definition proposed in the European Union: "[H]istory of safe food use in a third country means that  
the safety of the food in question is confirmed with compositional data and from experience of use and continued use  
for  at least 25  years in the customary diet of a large part of the population of a country."   Official Journal of the  
European Union  C 122  E  (May 11,  2010);  p. 38-57.  
 
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medicine  to the safety of  an  NDI  in a  dietary supplement, additional   safety 
information  is almost  always needed.   
As  previously  described,  it  is important  to document  the size  and characteristics  of  
the population  that consumed the NDI  in or as  a traditional  medicine,  as well  as  
conditions   of use,  such as dose,  duration,  and frequency (see  questions  VI.B.3  and  
VI.B.7).   In addition,   if  the medicinal  product was  consumed under the  supervision 
of a trained practitioner  of traditional   medicine,  it is important  to document safety-
related restrictions  on use  within  the  written or  oral tradition.   Often, traditional  
medicinal  products  are  chemically  and compositionally  very different  from the NDI  
that  is the  subject of the  NDI  notification.    Therefore, it is important  to document  
and explain how  any information  about  a  substances history of safe  use in 
traditional  medicine  is  qualitatively  and quantitatively  related  to the NDI that is  the  
subject of  the notification   and its  proposed conditions   of use.  
11.  Does FDA recommend submitting  additional animal  and human studies  to  
supplement evidence of a history of safe use by humans?  
It depends  on the situation.  Data  on history of use in humans  should be the first  
evidence  considered in evaluating the safety of  an  NDI.   
When the NDI  has been previously  consumed by humans,  additional   animal  or  
human  safety data are seldom  needed if  (1) the proposed use level  is  similar  to  or  
less than the levels  safely consumed by humans  in the past;  and (2) the population 
expected to consume  the NDI  is  the same  as, or  a  subset of,  the population  that  
safely consumed the substance in the past.  In many cases,  no additional   animal  or  
human safety  data are needed because the NDI is  reasonably  expected to  be safe 
based on a  large  margin of safety between the level  shown to cause  no observed 
adverse  effects  in humans and the  intake level  that  would result from the  proposed 
use of the NDI  in the  dietary supplement,   or  based on longstanding  and widespread 
use of the ingredient   as  a  constituent  of conventional  food at  or below  the intake  
level  that would result  from  the proposed use of the NDI in the dietary supplement.   
 
When the historical  use differs  significantly  from the  proposed use of the NDI in a  
dietary supplement,   however,  additional   supportive  data are  usually needed.   
Examples  of  differences in proposed use  that  would ordinarily  necessitate  further 
supportive  data include  higher  dosage than the  historical  use, different route of  
administration,   longer duration of  use, other  changes  that increase  exposure to 
potential  toxic  effects,  and any other differences  that  raise new  safety concerns (e.g.,  
a  different  target population).   These examples are based  on the general principle 
that the risk  of a substance is  likely  to increase as  intake increases above levels  
safely consumed in the  past.   When historical  use of  an  NDI  differs significantly  
from the  proposed dietary supplement  use,  FDA encourages you to submit  
additional  animal studies,  human studies,  or both.   Such studies should be  designed 
to address gaps in the history of  use  evidence.  
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12.  What factors  are  helpful in evaluating  whether  to submit  animal  or human  
safety studies in addition to history of use  data?  
Generally,   the best way to determine  whether history of use data provides  a basis for  
a  reasonable  expectation that a dietary supplement  containing  an  NDI  will be  safe is  
to compare  the conditions   of use proposed in the NDI notification   with the  
documented historical  conditions   of  safe use.  The  following  are examples  of  
situations  where FDA  would typically  recommend that  history of use data be  
supplemented with additional   animal or  human safety studies:  
   Higher proposed per-serving intake level  or total daily intake level.  
   Longer proposed duration of  consumption  than historically  reported (e.g.,  
notification  states  that NDI will  be marketed with labeling  that  
recommends  or  implies   continuous daily use  for  improved digestive  
function, but  the history of safe  use involves  only infrequent,  short-term  
use for indigestion).  
   Different proposed route of  administration  (e.g.,  data  about historical  use  
of a substance as  a  poultice  or  by injection  ordinarily  would not  be  
sufficient to support the  safety of  an  NDI  for use in a dietary supplement,  
which by definition  is intended for ingestion).  
   A change from  historical  use that might  increase potential  toxic effects  
(e.g., the NDI will  be sold as capsules of a ground leaf,  but  the form  
historically  used was a tea made from  the plants  roots).  
   A change in the  target population  (e.g., history of safe  use has  been 
established in adults,  but NDI  will  be  used in a  dietary supplement  
marketed  for use by  young children).  
13. Should  I use toxicology or clinical studies published by others, or 
unpublished studies I have performed, if those studies used test articles that 
are  similar  but  not identical  to the NDI or  the  dietary supplement  
containing  the NDI?  
FDA  generally recommends that  the  test  article  used in safety  studies  be identical  to 
the NDI  or the  dietary supplement  that  is the  subject of your notification.    However,  
in the absence of safety data  on the NDI  or supplement  itself,  it may be  useful to 
provide  data  on the safety of a  related substance  or product.   
For  example,  if  the NDI  is  a  component  of another  substance for which safety 
studies  are  available,   it  may be helpful  to submit  data from  those studies,  
accompanied by an explanation of  why the data on the related substance support  the  
safety of your  NDI.   Data from  a study involving  the  oral  administration  of  the  dried 
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ground root  of a plant  could be relevant  to the safety of  an  NDI  that is  an 
isopropanol   extract  of the same root  if  you document  that the components  of the  
isopropanol   extract were present  at the same  or  lower levels  in the ground root  fed to 
the study  subjects.  The safety of an ester  ingredient  can be inferred if  you can 
provide  data  to demonstrate  that the ingredient   is rapidly  hydrolyzed  in the stomach 
or intestine  into an acid and an alcohol,   and that the acid and the alcohol  each have a  
long history of safe  use in food.    
The more  different  the composition  of the  test  article in a  study is from that  of  the  
NDI, however,  the more  difficult   it  will  be to argue that the study is  relevant.  
14.   Are there scenarios in which FDA considers  additional safety data 
unnecessary if the proposed use of the NDI leads to intake levels that are the  
same as or less than the levels consumed historically?   
Yes.  When the proposed use of the NDI  leads  to intake levels  that are the same as  
or less than the levels  for which there  is  a  documented history of safe  use,  additional  
safety  data are not  needed if  the  dietary supplement  containing  the  NDI is  intended 
for (1) daily chronic  use, and the documented historical  use data  support  safe daily 
chronic use  in the same population  or  a  broader  population;   (2) intermittent   use, and 
the documented historical  use data  support  safe intermittent   use  in  the same 
population  or a broader population;   or  (3) intermittent  use, and the documented 
historical  use  data  support safe  daily chronic use  in the same population  or a broader  
population.   In other  circumstances,  we  recommend submitting  additional   safety 
data  as  shown in Table  3 and discussed in the  following  six questions.   (See Table  3:   
Safety Testing Recommendations  Matrix.)  
15. What  types of data does FDA recommend to assess safety if the dietary 
supplement containing the NDI is intended for  daily  chronic  use, the NDI  
has a  documented history of safe  intermittent use, and the proposed use of  
the NDI leads to intake levels that are the same as or less than the levels  
consumed historically?   
(1) A three-study genetic toxicity  (genetox) battery (bacterial mutagenesis,  in vitro  
cytogenetics, and in vivo  mammalian test)  that includes  a  test for gene mutations  in 
bacteria, either an  in vitro  mouse lymphoma   thymidine   kinase+/- gene mutation 
assay  (preferred) or another  suitable  in vitro  test  with cytogenetic evaluation of  
chromosomal  damage using  mammalian  cells,  and an in vivo  test for  chromosomal  
damage using mammalian hematopoietic  cells;  
(2) A  14-day range-finding  oral study to establish a  maximum   tolerated dose  (MTD)  
in an appropriate  animal  model;  
(3) A  90-day subchronic  oral study (see questions  VI.B.6  and VI.B.28-30)  in  the  
same species as  the range-finding  study  to establish  an MTD and  a No Observed 
Adverse Effect  Level  (NOAEL) for use in  calculating  the margin of safety;   
(4) A  multi-generation  rodent reproductive  study (minimum   of two generations)  (see 
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note at  end of  list); and  
(5) A  teratology study (rodent  or  non-rodent)  (see  note at end of list).  
Note:  The rodent  reproductive  study and the teratology study  are  not needed if the  
product  is labeled as not  for use by women of childbearing  age, pregnant  or lactating 
women,  or  children  13 and  younger.  (See Table  3:   Safety Testing 
Recommendations Matrix.)   
16. What  types of data  does FDA recommend to assess safety if the dietary 
supplement containing the NDI is intended for  daily  chronic  use, the NDI  
has a  documented history of safe daily  chronic  use, and the proposed use of  
the NDI leads to intake levels that are greater than  the levels consumed  
historically?  
(1) A two-study genetox battery (bacterial  mutagenesis and in vitro  cytogenetics)  
that includes  a test for gene mutations  in  bacteria,  either an  in vitro  mouse  
lymphoma  thymidine  kinase+/- gene mutation assay (preferred)  or  another suitable  
in vitro  test with cytogenetic  evaluation  of chromosomal  damage using mammalian 
cells;  
(2) A  14-day range-finding  oral  study to establish an MTD  in an appropriate  animal  
model;   
(3) A  90-day subchronic  oral study (same species as  the range-finding  study)  to 
establish an MTD and a  NOAEL for use in calculating  the margin of safety;   
(4) A  repeat-dose tolerability  study in humans  (30-90 day duration);  
(5) A  one-year chronic  toxicity study in an appropriate  animal  model  or  a two-year  
carcinogenesis study  in rodents;   
(6) A  one-generation rodent reproductive  study  (see note  at end of  list); and  
(7) A  teratology study (rodent  or  non-rodent)  (see  note at end of list).   
 
Note:  The rodent  reproductive  study and the teratology study  are not  needed if the  
product  is labeled as not  for use by women of childbearing  age, pregnant  or lactating 
women,  or  children 13 and  younger.  (See Table  3:   Safety Testing 
Recommendations Matrix.)   
17. What  types of data does FDA recommend to assess safety if the dietary 
supplement containing the NDI is intended for  daily  chronic  use, the NDI  
has a  documented history of safe intermittent use, and the proposed use of  
the NDI leads to intake levels that are greater than the levels consumed 
historically?  
(1) A three-study genetox battery as  described in question VI.B.15;  
(2) 14-day range-finding  oral  studies  to establish an MTD  in  at least two  appropriate  
species,  at  least  one of which is non-rodent;  
(3) Two 90-day subchronic oral  studies (one for each  species  for  which there is  a  
range-finding  study)  to establish an MTD and a  NOAEL for use in calculating  the  
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margin of safety;  
(4) A  one-year chronic  toxicity study in an appropriate animal  model  or  a two-year  
carcinogenesis study  in rodents;  
(5) A repeat-dose tolerability  study in humans  (30-90 day duration);   
(6) A multi-generation  rodent reproductive  study (minimum   of two generations)  (see 
note at  end of  list); and  
(7) A teratology study (rodent  or  non-rodent)  (see note at end of list).   
 
Note:  The rodent  reproductive  study and the teratology study  are generally not  
needed if  the product  is  labeled as  not  for use by women of  childbearing  age,  
pregnant  or lactating women,  or  children 13 and  younger.  (See Table  3:  Safety  
Testing Recommendations  Matrix.)   
18. What  types of data does FDA recommend to assess safety if the dietary 
supplement containing the NDI is intended for  intermittent  use, the NDI has  
a documented history of safe intermittent use, and the  proposed use of the  
NDI leads to intake levels that are greater than  the  levels consumed 
historically?   
(1) A two-study genetox battery (bacterial  mutagenesis and in vitro  cytogenetics) as  
described in question VI.B.16;  
(2) A  14-day range-finding  oral study to establish an MTD  in an appropriate  animal  
model  
(3)  A  90-day subchronic   oral study (same species as  the range-finding  study)  to 
establish an MTD and a  NOAEL for use in calculating  the margin of safety  
(4)  A  single-dose or  repeat-dose tolerability  study in humans  and/or  an absorption,  
distribution,   metabolism,   and excretion (ADME)  study in animals,  humans,  or both;   
(5) A one-generation rodent reproductive  study  (see note  at end of  list);  
(6)  A teratology study (rodent  or  non-rodent)  (see  note at end of list).  
 
Note:  The rodent  reproductive  study and the teratology study  are  not needed if the  
product  is labeled as not  for use by women of childbearing  age, pregnant  or lactating 
women,  or  children 13 and  younger.  (See Table  3:   Safety Testing 
Recommendations Matrix.)  
19. What  types of data does FDA recommend to assess safety if the dietary 
supplement containing the NDI is intended for  intermittent  use, the NDI has  
a documented history of safe daily  chronic  use, and the proposed use of the  
NDI leads to intake levels that are greater than the levels consumed 
historically?    
(1) A two-study genetox battery as  described in question VI.B.16;  
(2)  A  14-day range-finding  oral study to establish an MTD  in an appropriate  animal  
model;  
(3) A  90-day subchronic   oral study (same species as  the range-finding  study) to 
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establish  an MTD and a  NOAEL for use in calculating  the margin of safety;   
(4) A single-dose  or repeat-dose tolerability  study in humans  and/or  an ADME study 
in animals,  humans,  or both; and  
(5) A  teratology study (rodent  or  non-rodent)  (see  note at end of list).  
 
Note:  The  teratology study is not needed if the  product is labeled as  not for use  by 
women of childbearing  age, pregnant or lactating women,  or  children 13 and  
younger.  (See Table  3:   Safety Testing Recommendations  Matrix.)    
20. What  types of data does FDA recommend to assess safety if there is no  
history of use of the NDI that  can be relied on to provide evidence of safe  
use in dietary  supplements?  
(1) A three-study genetox battery as  described in question VI.B.15;  
(2) 14-day range-finding  oral  studies  to establish an MTD  in at least  two appropriate 
species,  at least  one of which is  non-rodent;  
(3) Two 90-day subchronic oral studies  (one for  each  species for which  there is a  
range-finding  study)  to establish an MTD and a  NOAEL for use in calculating  the  
margin of safety (see  footnote   in Table  3:   Safety Testing Recommendations  
Matrix);  
(4) A  repeat-dose tolerability  study in humans and/or  an ADME study in animals, 
humans,  or both (30-90 day duration);  
(5) A  one-year chronic  toxicity study or  a two-year carcinogenesis  study  in  at least  
two animal species,  if the  proposed use  is either intermittent  or daily chronic;  
(6) A  multi-generation  rodent reproductive  study (minimum   of two generations)  (see 
note at  end of  list); and  
(7) A  teratology study (rodent  or  non-rodent)  (see  note at end of list).   
Note:   The  rodent reproductive  study and the  teratology study are  not needed  if the  
product  is labeled as not  for use by women of childbearing  age, pregnant  or lactating 
women,  or  children 13 and  younger.    
Based on the nature of  the NDI  and the results  of other testing,  special  studies  (e.g.,  
carcinogenicity,  ADME)  may be needed to provide  a  reasonable  expectation of  
safety.   Other nonclinical  studies  to assess  immunotoxicity  and neurotoxicity  should 
be  conducted on a  case-by-case basis,  as  appropriate.   (See Table  3:  Safety Testing 
Recommendations Matrix.)  
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Table  3:   Safety Testing Recommendations Matrix   
Single-
Dose  Repeat-Dose 
One-Year  
Tw o- Three- 14-Day  90-Day  One- Multi- Tolerability   Tolerability  
Chronic Toxicity  
Documented   Study   Study   Range- Subchronic   Generation   Generation   Teratology   and/or   and/or ADME  
Proposed Use   or Tw o-Year  
Historical  Genetic   Genetic   Finding   Oral Study  Rodent   Rodent   Study in   ADME   Study in  
of the NDI   Carcinogenesis  
Use   Toxicity  Toxicity  Oral Study  in   Reproductive    Reproductive    Animals[2]   Study in   Animals  
Study in  
Battery[1]   Battery[1]   in Anim als   Animals[3]   Study  [2]   Study[2]   Anim als   and/or  
Animals*  
and/or   Humans*  
Humans*  
Intermittent:  
Less Than  
Daily  Chronic   Historical Use   Documented  history of  use should be sufficient as  evidence of safety.  
(see question 
VI.B.14)  
Intermittent:  
Greater Than  
Daily  Chronic   Historical Use   X      X   X         X      X     
(see question 
VI.B.19)  
Daily  Chronic:  
Less Than  
Daily  Chronic   Historical Use   Documented  history of  use should be sufficient as  evidence of safety.  
(see question 
VI.B.14)  
Daily Chronic:  
Greater Than  
Daily  Chronic   Historical Use   X   X   X   X   X   X   X   X  
   
(see question 
VI.B.16)  
Intermittent:   
Less Than  
Intermittent   Historical Use   Documented  history of  use should be sufficient as  evidence of safety.  
(see question 
VI.B.14)  
Intermittent:   
Greater Than  
Intermittent   Historical Use   X   X   X   X   X   X  
       
(see question 
VI.B.18)  
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Single-
Dose  Repeat-Dose 
One-Year  
Tw o- Three- 14-Day  90-Day  One- Multi- Tolerability   Tolerability  
Chronic Toxicity  
Documented   Study   Study   Range- Subchronic   Generation   Generation   Teratology   and/or   and/or ADME  
Proposed Use   or Tw o-Year  
Historical  Genetic   Genetic   Finding   Oral Study  Rodent   Rodent   Study in   ADME   Study in  
of the NDI   Carcinogenesis  
Use   Toxicity  Toxicity  Oral Study  in   Reproductive    Reproductive    Animals[2]   Study in   Animals  
Study in  
Battery[1]   Battery[1]   in Anim als   Animals[3]   Study  [2]   Study[2]   Anim als   and/or 
Animals*  
and/or   Humans*  
Humans*  
Daily  Chronic:  
Less Than  
Intermittent   Historical Use      X   X   X      X   X           
(see 
questionVI.B.15)  
Daily Chronic:  
Greater Than  
Intermittent   Historical Use      X   X   X  [3]      X   X   X  [3]      X  
(see question 
VI.B.17)  
Daily  Chronic  
No History   (see question     X   X   X  [3]      X   X   X  [3]      X  
VI.B.20)  
Intermittent  (see  
No History      X   X   X  [3]      X   X   X  [3]      X  
question VI.B.20)  
 
1   Genetic  toxicity batteries are described in questions VI.B.15  and VI.B.16.  
2   Reproductive  and teratology testing is not needed if the product is labeled  as not for use by  women  of childbearing age,  pregnant or lactating women, and children  13 and younger.  
3   In general, if there is no history of use, two species should be  used for 90-day subchronic  studies.   In addition,  the one-year chronic toxicity study or two-year carcinogenesis study should be  done in two 
species.  However, the one-year chronic toxicity study, two-year carcinogenesis study,  or second subchronic study  may not be necessary in  some cases  based  on the amount and type of historical use data or  
the duration of use  of the NDI, if  significantly shorter than lifetime daily use.   For example, if the proposed use of the NDI is for 30 days or less,  then a 28-day animal study  might be  sufficient under  certain  
circumstances (e.g.,  live microbial NDI).    
*Special  studies  (such as one-year chronic toxicity studies in animals;  two-year carcinogenicity  studies in animals; and ADME, bioavailability,  and tolerability  studies  in  animals, humans,  or both)  
should be conducted on a case-by-case basis,  as appropriate, if the toxicology data or the identity of the NDI raises a  special safety concern.  
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21. Am I  required to use only FDA-published safety test protocols?  
No.  You  should use your  own judgment   in selecting among FDAs protocols  and other  
internationally  recognized safety testing protocols  and testing batteries developed for other  types  
of products  when you choose  safety testing protocols  for your NDI  or the  dietary supplement  to 
which your  NDI  will  be added.  Regardless  of the protocols  used,  you should cite the source for  
each protocol  and why the protocol  or the battery of  protocols  you chose is  appropriate  for  the  
safety endpoints  that are  being investigated.  
The NDI  safety standard is different  than the standard for food additives,   drugs,  and other  FDA-
regulated products.   Recommendations   in guidance  documents  that are  tailored to the safety 
assessment  needs of  other FDA-regulated products  may not  always be appropriate  for dietary 
ingredients  or  dietary supplements.   You should compile  scientific  evidence that provides  a  basis  
to conclude  that the  NDI  that  is the  subject of your notification   will  reasonably be expected to be  
safe  when used under  the conditions   recommended or  suggested in the labeling  of the dietary 
supplement  described in the notification.      
22. What  are some sources of safety testing protocols that can be used in testing NDIs  and 
dietary supplements?  
Useful  guidelines   for safety testing include:  
   OECD  Guidelines   for the  Testing of Chemicals,  Section 4:   Health Effects,  published 
by the Organization  for Economic  Co-operation and Development53;   
   Harmonized Test  Guidelines,   published  by the Office of Chemical  Safety and 
Pollution  Prevention of the U.S.  Environmental   Protection Agency (EPA)54;  and  
   Principles  and Methods  for  the Risk Assessment of Chemicals  in  Food,   published 
jointly  by  the Food and Agriculture  Organization  of the United Nations  and the  
World Health Organization.55  
23. What  is the  appropriate  highest dose of an NDI to  use in animal  and human  safety 
studies?  
To maximize  the chance that toxicity  associated with  the test article can be detected, the highest  
dose (commonly  referred to as  the top dose) in animal  studies  should be the maximum  
                                              
53 Organisation for Economic Co-operation and Development (OECD).   OECD Guidelines for the Testing of Chemicals, Section 4:   
Health Effects.   Available at: http://www.oecd.org/chemicalsafety/testing/oecdguidelinesforthetestingofchemicals.htm.  
54 U.S.  Environmental Protection Agency (EPA), Office of Chemical Safety and Pollution Prevention (OCSPP).   OCSPP Harmonized  
Test Guidelines; September 2015. Available at:  https://www.epa.gov/test-guidelines-pesticides-and-toxic-substances.  
55 Principles and Methods for the Risk Assessment of Chemicals in Food. Environmental Health Criteria 240.   A joint publication of  
the Food and Agriculture Organization of the United Nations and  the World Health Organization. 2009. Available at: 
http://whqlibdoc.who.int/ehc/WHO_EHC_240_4_eng_Chapter1.pdf.  
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tolerated dose (MTD)  (see definition  in section VII).  Lower doses are  used to establish the dose-
response relationship  and the no-effect dose (see question VI.C.4  for  information  on  the latter  ).   
Shorter-term  studies  are  needed to estimate the MTD for  longer  studies;  for  example,  the results  
of a 14-day study must  be known before the dose for a 90-day study can be determined.    
Considering  a  broad range  of biological  information  is essential to pick the  correct  top dose  or  
MTD.  For example,  data concerning changes in body and organ weight  and clinically  significant  
alterations in hematological,   urinary,  neurological,   and clinical  chemistry parameters,  in 
combination  with more definitive   toxic,  gross,  or  histopathologic   endpoints,   can be  used to 
estimate the MTD.   FDA intends  to  consider  whether the test article was  tested at the MTD as  a 
major  factor  in evaluating the adequacy of studies  submitted in  an  NDI  notification.   The  studies  
should include  a  description of  the process used to select the MTD for the  study,  if it  is not  
readily apparent.    
Please  note  that it  is  not  scientifically  valid to select doses for tests based on information  
unrelated to the toxicity  of the test article.  For  example,  the highest  dose  should not  be selected 
so as  to provide  a pre-determined margin of  safety over  the maximum  expected human 
consumption  of the  test  article,  assuming that the results  of testing at  that  dose will  be negative.    
FDA recognizes  that there may be limitations   on using a  top dose.  For  example,  limits   on top 
doses can be based on animal  handling  considerations,   such as the amount  that  can be safely 
administered by gavage  or  the amount in feed that  still  permits proper  nutrition.    The  top dose in 
clinical  studies  should be governed by safety considerations,   as  determined by an Institutional  
Review  Board.  However,  within  the limits   of safety, the  top dose  in clinical  studies  should be as  
high as feasible.  At  a minimum,   the top dose or total  daily intake  level  in a  clinical  trial  of  an  
NDI  should be as  high as  the top dose or total  daily intake  level  of the NDI under  the conditions  
of use proposed in the notification.   Preferably,  the  highest  total daily  intake level in  the trial 
should be higher  than the  highest  total  daily intake  level  of the NDI  proposed in the notification.  
24. What  should I do to justify  the use of a particular  protocol?  
You should cite  an authoritative  source for the protocol  and explain how  information   generated  
by the study using the protocol  supports  the safety of  the dietary supplement  in which the NDI  
will  be used.  If  you decide  to deviate  from  a  standard or published  protocol,   you should explain 
why you altered the protocol  and how the alteration affects  the relevance of  the study results to  
the safety of your  product.    
25. How will Iidentify  a potential hazard using a standard genetic toxicity test, and what  
should I do after  identifying  a potential genetic toxicity hazard?  
A positive  finding  in one  or more  of the standard genetic  toxicity  tests  constitutes  a clear but  
non-quantitative   identification  of a  potential  hazard.  Positive  results  in genetic  toxicity  tests  may 
necessitate additional  safety testing,  such as  an evaluation of carcinogenicity  from two-year or  
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lifetime  chronic  toxicity  assays.   General  guidance  on following  up positive  results in genetic  
toxicity  testing can be found in the scientific  literature  on this  topic.56  
26. Should the NDI notification discuss the history of use or other evidence of safety that  
forms  the basis for my  conclusion that  a genotoxic dietary ingredient can reasonably be  
expected to be safe?  
Yes, your  NDI notification  should discuss  this  history of use or other  evidence  of safety.   You 
should conduct a  risk assessment  to determine  whether the genetic  toxicity  of the NDI prevents  
the  dietary supplement  from being reasonably expected to be  safe  under the  proposed conditions  
of use.    
27. Where can I find good examples of genotoxicity protocols that can be used in 
conducting  animal and human studies  on NDIs?  
The sources cited in the answer  to question VI.B.22  contain test  guidelines   and testing batteries  
for evaluating genetic  toxicity.     
28. What  is the purpose of a subchronic  oral toxicity study?  
When properly conducted (e.g., with doses selected based on shorter term  repeat-dose studies),  
subchronic  oral  toxicity studies  are  used to identify  the maximum  tolerated dose (MTD) of a  
substance,  as  well  as  the substances No Observed Adverse Effect  Level  (NOAEL).   Toxicity  
data and the NOAEL identified  by the subchronic  oral  study are  used (1) to predict  the organ 
toxicity  or other types  of toxicity  that are  likely  to be associated with human or animal  
consumption  of unsafe quantities  of  the test  article;  (2) to determine  the need for  and design of  
additional   animal  studies,  such as  specialized toxicity  studies and chronic toxicity  studies;  and 
(3) to assess  the  safety of short-term repeat-dose exposure  to the test article,  either  for consumers  
or for participants  in clinical  trials.   
29.  What  is  the  appropriate  duration for  a subchronic oral toxicity study?  
Subchronic  oral toxicity  studies are  generally conducted for  90 days  (3 months).   Protocols  
described as lasting 12 or  13 weeks are considered equivalent.   Subchronic  toxicity studies  
provide  information  on the possible  health hazards  likely  to arise from  repeated exposure  to a  
substance over a  three-month period.  
30. Where can I find more information and examples of a subchronic  oral toxicity study?  
We recommend referring to  the  OECD Guidelines   for the Testing of Chemicals.  Protocols  for  
rodent studies  are in  OECD  Guideline   408,  Repeated Dose 90-day Oral Toxicity  Study in 
                                              
56 Dearfield KL,  Thybaud V, Cimino  MC, Custer L, Czich A, Harvey JS, et al.  Follow-up actions from positive results  of in vitro  
genetic toxicity testing.   Environ Mol Mutagen. 2011 Apr; 52(3):177-204.  
 
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Rodents.57   Protocols  for non-rodent  studies  are in OECD Guideline   409,  Repeated Dose 90-
Day Oral Toxicity  Study in Non-Rodents.58   The appropriate  animal  species  and study design 
may vary depending on the safety questions  associated with the NDI  being studied.    
31. What  is the purpose of reproductive toxicity and teratology studies?   
The purpose of reproductive  toxicity  studies is to provide  information  regarding the  effects  of  a  
dietary ingredient   on all aspects  of  reproduction,   including  sexual behavior,  spermatogenic and 
estrus cycles,  gonadal  function,  fertility,   parturition   (giving  birth), lactation, and prenatal  
development.  The purpose  of teratology studies  is  to provide  information  on whether the test  
article  causes  congenital  malformations   in the offspring of a  test animal.  The purpose  of  multi-
generation reproductive  studies is to provide growth and reproductive function data regarding the  
effects  of the test article on  male and  female offspring  of test animals  and on the  growth and 
reproductive  function of their offspring in the  subsequent generation(s).      
32. Should I include a discussion of the reproductive and teratology studies in my NDI  
notification?  
Yes.  FDA  recommends  that you provide  a  summary and a detailed discussion of the results  of  
each reproductive  and teratology study in the  comprehensive  safety profile  for the  NDI (see  
question  VI.C.2).    
33. Should I identify the  No Observed Adverse Effect Level  (NOAEL) for all test 
substance-related changes in both reproductive and teratology test endpoints?  
Yes.   You should identify the NOAEL for parental  animals  and their  offspring in each generation 
in reproductive  studies,  including  teratology studies.   In addition  to information  about  
reproductive  success,  data from  the study should also be used to provide  information  on 
development  (i.e., growth and function of the  offspring)  and teratogenesis (i.e., birth defects,  
both structural  and functional).     
34. Where can I find sample protocols for reproductive and teratology studies?  
We recommend that you refer  to the  OECD Guidelines   for  the Testing of Chemicals,  Guidelines  
415 (One-Generation Reproduction  Toxicity Study),59  416 (Two-Generation  Reproduction 
                                              
57 Organisation for Economic Co-operation and Development.   OECD Guidelines for the Testing of Chemicals, Guideline 408:  
Repeated Dose 90-day Oral Toxicity Study in Rodents.   Paris:  OECD Publishing; May 1981; revised September 1998.   Available at:  
http://www.oecd-ilibrary.org/environment/test-no-408-repeated-dose-90-day-oral-toxicity-study-in-rodents_9789264070707-en. 
58 Organisation for Economic Co-operation and Development.   OECD Guidelines for the Testing of Chemicals, Guideline 409:  
Repeated Dose 90-day Oral Toxicity Study in Non-Rodents.   Paris:   OECD Publishing; May 1981; revised September 1998.  Available  
at:  http://www.oecd-ilibrary.org/environment/test-no-409-repeated-dose-90-day-oral-toxicity-study-in-non-rodents_9789264070721-
en.  
 
59 Organisation for Economic Co-operation and Development.   OECD Guidelines for the Testing of Chemicals, Guideline 415:  One-
Generation Reproduction Toxicity Study.   Paris:  OECD Publishing; May 1983. Available at:  
http://www.oecd.org/chemicalsafety/risk-assessment/1948458.pdf  
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Toxicity   Study),60  421 (Reproduction/Developmental   Toxicity  Screening Test),61  and 422 
(Combined  Repeated Dose Toxicity  Study with the Reproduction/Developmental  Toxicity  
Screening Test)62  to find protocols for  conducting reproductive toxicity  and teratology studies.   
You may also wish to consider  how data  from these  studies are  assembled and used for other  
regulatory programs  (e.g., for pesticides, see EPAs Harmonized Test Guidelines,63   and for  
medicinal  products,  see ICHs Safety  Guidelines64).  In particular,  Detection of Toxicity to 
Reproduction for  Medicinal  Products & Toxicity to Male Fertility65   contains  useful guidelines  
for detecting reproductive  toxicity.  
35. What  is the purpose of repeat-dose toxicity testing?  
In general,  the purpose  of repeat-dose toxicity  testing is to define  toxic effects  on body systems  
and target organs  based on repeated and/or  cumulative   exposure  to the test substance or to 
constituents  and/or  metabolites  of  the test  substance.  Repeat-dose testing defines  the nature of 
the  tissue or  organ damage, particularly  in relation to dose and duration of exposure.  Repeat-
dose testing is  also used to identify  dosages associated with toxic  and biological   responses and to 
define  a  NOAEL.    
The route  of administration  in repeat-dose testing for a  dietary supplement  containing  an  NDI  
should always be oral,  and the study should include  a range of doses at and above  the proposed 
dose  of the  NDI  in the dietary supplement.   An oral study, as  described in this  guidance,  can 
include  administration  in feed or  drinking  water (with the feed or water consumption  measured 
to confirm  actual intake)  or via  gavage,  which involves   introduction  of the test article  through a  
tube passed through the mouth into the stomach.   Ideally, the  test  article used in these studies  
should have  the  same composition  and form  as the  dietary supplement  described in the  
notification   since the  other ingredients   can affect  the safety of the NDI  as used in the product.  
                                              
60 Organisation for Economic Co-operation and Development.   OECD Guidelines for the Testing of Chemicals, Guideline 416:   Two-
Generation Reproduction Toxicity Study.   Paris:   OECD Publishing; May 1983; revised January 2001. Available at:  
http://www.oecd.org/chemicalsafety/risk-assessment/1948466.pdf 
61 Organisation for Economic Co-operation and Development.   OECD Guidelines for the Testing of Chemicals, Guideline 421:   
Reproduction/Developmental Toxicity Screening Test.   Paris:  OECD Publishing; July 2015.  Available at: http://www.oecd-
ilibrary.org/environment/test-no-421-reproduction-developmental-toxicity-screening-test_9789264242692-en  
62 Organisation for Economic Co-operation and Development.   OECD Guidelines for the Testing of Chemicals, Guideline 422:   
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test.   Paris:  OECD Publishing; 
March 1996.   Available at: http://www.oecd-ilibrary.org/environment/test-no-422-combined-repeated-dose-toxicity-study-with-the-
reproduction-developmental-toxicity-screening-test_9789264070981-en 
63 U.S.  Environmental Protection Agency (EPA), Office  of Chemical Safety and Pollution Prevention (OCSPP). OCSPP Harmonized  
Test Guidelines; September 2015. Available at: https://www.epa.gov/test-guidelines-pesticides-and-toxic-substances. 
64  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).   
Safety Guidelines. Available at: http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html Accessed August 28,  
2015.   
65  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).   
Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2);   June 1993;  addendum dated  
November 2000  incorporated November 2005.  Available at:  
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S5/Step4/S5_R2__Guideline.pdf.  
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36. AmI required to conduct human clinical studies  to assess the safety of my NDI or the  
dietary  supplement containing my  NDI?  
The  FD&C  Act  contains  no explicit  requirement  for  a  manufacturer or  distributor   to conduct  
human clinical  studies before  submitting  an  NDI  notification.   However, there may be  
circumstances in which you find it necessary to perform such studies because  the  existing  history 
of use data, safety data,  and data on population  exposure  do not  provide  a sufficient  basis  for you 
to conclude  that  the dietary supplement  containing  the NDI  will  reasonably be expected to be  
safe under  its proposed conditions   of  use.66   
37. What  kinds  of human clinical studies  are  useful to assess the safety of an NDI or dietary  
supplement containing an NDI?  
The  most useful studies  are  usually short-term tolerability  studies and absorption, distribution,  
metabolism,   and excretion (ADME)  studies.   The test article  used in these  studies  should have  
the same identity and composition   (including   ingredients  used in combination  with the  NDI) and 
forms  as described in  the dietary supplement  composition   section of your  notification.   When 
human ADME  studies  are  done in conjunction  with ADME  studies  conducted in the  animal  
species used for  toxicological   testing,  the relevance of the animal data to humans  can be  
demonstrated  and the safety factors  used to  calculate the margin  of safety can be reduced  (see 
question VI.C.5).  
 
Tolerability  studies  identify acute toxicity,   such as that associated with toxins  or  with  
indigestible   nutrients at  very high serving levels of  ingredients   like fats  and oils.   Human repeat-
dose studies  are  more rarely used to directly demonstrate  the safety of the test article in  humans.   
They can be used to allay specific  safety concerns raised by animal  studies  or history of use  
information,   or  to establish a margin of safety for  an  NDI  when the  proposed conditions   of use  
would result  in doses that cannot  be humanely administered to animals.   
38. What  is the purpose of  repeat-dose human studies, and how are  such studies  
classified?  
Human studies can be  used alone or in conjunction  with animal studies.   If animal toxicity  
studies  or  history of use data do not document  an adequate margin of safety between the NOAEL  
for your  NDI and the expected intake  of the NDI from its  proposed dietary supplement  use,  we  
recommend a human clinical  trial  consisting  of a repeat-dose study.   Clinical  trials  should 
include  male  and female  subjects,  as  well  as an adequate sample size and duration.  Sample size 
is  a  very important  consideration,   as  the study should be sufficiently  powered to show  
differences  in your data.   If  a  clinical  trial  is not powered by a  large enough sample size,  results  
showing  no adverse effects  cannot be relied  on  as  evidence of safety because the absence of  
                                              
66 Human clinical studies must comply with FDAs regulations for the protection of human subjects (21 CFR Parts 50 and 56).  A  
clinical  study intended to evaluate the safety of a dietary ingredient or dietary supplement generally does not require an investigational 
new drug application (IND), but if the study also evaluates the use of the product to treat or mitigate a disease (i.e., a use of the  
product as a drug), it would require an IND. See FDA, Guidance for Clinical Investigators, Sponsors, and IRBs:   Investigational New 
Drug Applications (INDs)    Determining Whether Human Research Studies Can Be Conducted  Without an IND; September 2013.   
Available at: http://www.fda.gov/downloads/Drugs/Guidances/UCM229175.pdf.  
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adverse effects  from intake  of the NDI  could be due  to chance.  Duration  of the clinical  trial is  
also an important  factor  in your study design  and depends on the  proposed conditions   of  use.  
Clinical  trials  may be  grouped by their  purpose  and objective.  Phase  I trials  are the first  stage  of  
testing in humans.   They are  designed to assess  absorption,  distribution,  metabolism,  and 
excretion (ADME),  safety,  tolerability,   pharmacokinetics,   and pharmacodynamics.  Phase I  
studies  are generally single-dose studies,  followed by dose-range  or dose escalation studies,  and 
finally  short-term repeat-dose studies to evaluate pharmacokinetic parameters  and  tolerance (see 
Table 3:   Safety Testing Recommendations  Matrix).   Single-dose   and repeat-dose studies  are  
elements of  Phase  I  studies to assess  human pharmacology.   Phase II studies  (designed to assess  
dosing requirements  and efficacy)  and Phase III studies  (randomized,   controlled multicenter  
studies  involving  large sample  sizes  to evaluate effectiveness of a treatment)  focus on  efficacy  
and are generally not  useful  to establish the safety of a  dietary supplement.  A  clinical  trial of  less 
than 90 days  is considered subchronic  and cannot,  by itself,  support  safety of chronic  use.   The  
endpoints  of  any  clinical  study  should be clearly defined.    
39. Where  can I find more information and examples of clinical protocols that can be used 
in conducting human studies for NDIs and dietary  supplements?  
FDA  recommends consulting  Principles   and Methods  for  the Risk Assessment of Chemicals  in 
Food67  for a good general  discussion of  this  topic.  This  reference, which  recognizes  the value  
of  the  experience gained from pharmaceutical  safety studies in designing  food safety studies,  
also includes  a  discussion of  the similarities   and differences  between clinical  studies  conducted 
for  foods  and those for pharmaceuticals.  Guidance  for IndustryM3 (R2) Nonclinical   Safety 
Studies  for the Conduct  of Human Clinical  Trials  and Marketing Authorization  for  
Pharmaceuticals68  contains  a useful  discussion of selecting an appropriate  dose  for  subchronic  
oral studies in animals  and clinical  trials in human volunteers  (pp.  1-5).   
40. What  information should I  submit to demonstrate the safety of an  NDI produced by  
fermentation  using microorganisms like bacteria or yeast?  
You should identify  the microorganism   using scientifically  valid nomenclature  for the genus,  
species,  and the name of the strain.   You should also discuss the  history of use  of  the organism  or  
related organisms  as  food or to produce food.   In addition,   you should identify any human 
pathogens  that are  phylogenetically  related to the fermentation microorganism   at  the species or  
genus  level.  You should also identify  any toxins,  classes of toxins,  or other  deleterious  
substances known to be present in the same species as  the  microorganism   or  in a genus  or  
species that is  phylogenetically  related to the microorganism.    Finally,  you should document  the  
absence  (or the  amount,  if  present) of such toxins  or other  deleterious  substances in the  
                                              
67 Principles and Methods for the Risk Assessment of Chemicals in Food. Environmental Health Criteria 240.   A joint publication of  
the Food and Agriculture Organization of the United Nations  and the World Health Organization. 2009. Available at:  
http://whqlibdoc.who.int/ehc/WHO_EHC_240_4_eng_Chapter1.pdf  
68 FDA, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research.   Guidance for Industry:   M3  
(R2)  Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, Revision  
1;  January 2010. Available at:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073246.pdf  
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microorganism.   The absence  of  unsafe  levels  of such deleterious  substances should be  
demonstrated by an appropriate  combination  of specifications  for  the NDI, safety testing in 
humans, and/or  safety testing in an appropriate animal model.  
41. What  information should I  submit to demonstrate the safety of a microbial NDI (live or  
killed)?  
You should identify  any human pathogens that are  phylogenetically  related to the  microbial   NDI  
at the species or genus  level.  You should identify  any toxins,  classes of toxins,  or other  
deleterious  substances  known to be present in  the same species  or in  a phylogenetically  related  
family or genus.   You should also document  the absence  (or the amount,  if  present) of such 
toxins  or  other deleterious  substances in the NDI.  You should document  resistance to any 
clinically   relevant antibiotics,   and if  applicable,  the genetic nature of  the resistance.  If the 
microbial  NDI is resistant  to  any clinically   relevant  antibiotics,   it is  also recommended that you 
perform  an assessment  of  the ability  of the antibiotic   resistance genes to mobilize   and transfer to 
human pathogens under the  conditions   of use  of the  dietary supplement.   
 
If your  notification  cites the history of use of a  live  microorganism   as  evidence  of  safety, FDA  
recommends  a careful assessment of the relative level  of historical  exposure compared to the  
proposed conditions   of use of the NDI, including  a  discussion  of how the form  of  the dietary 
supplement  and any  non-dietary ingredients (e.g.,  binders  and fillers)  used in it  affect delivery of  
the  NDI  to various points in the  human gastrointestinal   tract.    
If history of use data  are  inadequate  to support  the safety of  the microbial  NDI, you should 
include  safety studies in humans or  appropriate animal  models in your  notification.    FDA  
considers pigs  to be  the most  appropriate  animal  model  for the  human digestive  tract.   Human or  
animal  safety studies  should include  measurements  of the persistence of  the organism  in the body 
after  administration,   the ability  of the organism  to translocate  outside  of the gastrointestinal  tract,  
and tolerance  of the ingredient   using the proposed serving form.   Because this  is a rapidly  
evolving  scientific  discipline,   FDA recommends  that notifiers  be familiar  with the  state  of the  
recent  scientific literature at the time the notification   is  submitted.  
42. What  should I do to demonstrate the safety of an  NDI that  contains nanomaterials  or  
otherwise involves the application of  nanotechnology?  
Because there is  little scientific literature discussing the safety  of  nanomaterials in  dietary  
supplements,  FDA recommends  that notifiers  contact FDA69  prior  to submitting  an  NDI  
notification  for  an  NDI  that contains nanomaterials  or otherwise involves  the  application  of  
nanotechnology.70  
                                              
69  Contact information for the Office of Dietary Supplement Programs can be found on  the title page.  
70  FDA, 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. June 2014.  Available at: 
http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/ucm300661.htm.   See also FDA, Guidance for  
 
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C.   Summary of the Basis for  Your  Conclusion of Safety  
1.   Should my notification  include  separate safety profiles for the NDI and the dietary 
supplement  in which  the NDI  will be used?  
Yes.  FDA  recommends  that the discussion of  history of use and other  evidence  of safety in your  
notification  should include  two separate safety profiles:   first,  a comprehensive  safety profile  
evaluating the safety of the NDI, and second,  a  dietary supplement  safety narrative explaining 
why the information  in the notification   provides  a  basis  to conclude  that the  dietary supplement  
that contains  the NDI  will  reasonably be expected to be safe  when used under  the conditions  
recommended or suggested in the  dietary  supplements  labeling.   Each piece of  data or  
information  in the  notification  should be  cited in the  comprehensive  safety  profile,  the  safety  
narrative,  or both,  so that it is  clear  how each piece  of data  or information  is used to form the  
basis  for the safety of the dietary supplement containing   the NDI.  
 
When a notification  describes  a  dietary supplement  containing  more  than one  NDI, FDA  
recommends including  a  comprehensive  safety profile  for each NDI, with the safety of the  
combination  of NDIs  addressed in the  safety narrative.  However, when there is  history of  use  or  
other evidence of  safety for the  combination  of  NDIs  used in the dietary supplement,   it  may be 
appropriate  to have  a  comprehensive  safety  profile  for that combination  in addition  to a separate 
profile  for each NDI (or instead of separate profiles  for the individual   NDIs when most  or all of  
the safety information  is  for the combination).  
2.   What should I include in my  comprehensive safety profile for  the NDI?  
The NDI  comprehensive  safety profile  should provide  objective summaries of  all available  
human and animal  toxicological   information  (including  both published  and unpublished  safety 
studies) and any other  information  relevant  to the safety assessment of the NDI.  
 
The information  in the NDI  comprehensive  safety  profile  should substantiate  the  safe use of  the  
NDI  in humans under the  proposed conditions   of use  described in the notification.    A history of  
use discussion in the NDI  comprehensive  safety  profile should document  the  identity  and 
historical  uses  of the NDI,  including  the  intake level,  frequency,  and duration of the historical  
uses, as well  as  a description  of the size and characteristics  of the population  that consumed the  
NDI.  To the extent  that test articles  or materials  described in the history of use and other  
evidence  of safety are  not  identical  to the NDI, the similarities   and differences should be  
described,  and the applicability  of the  study to the safety evaluation of the NDI should be  
explained.    
If the NDI  notification  relies  on safety studies,  the NDI  comprehensive  safety  profile should 
qualitatively  and quantitatively  compare  the ingredients  tested in each of the studies  cited with 
the NDI.   If you cite a study on the feeding of a  whole  herb to a test  animal  and the NDI  is an 
                                                                                                                                                                          
Industry:  Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology; June 2014.   Available at: 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm.  
 
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extract of that herb,  the NDI  comprehensive  safety  profile  should qualitatively  and quantitatively 
compare the dose  and total daily intake  of the herb in the  study to the  proposed dose  and total  
daily intake  of the NDI.   Whenever  possible,  the notification  should identify  the effect  and no-
effect doses  in  each human and animal  study,  and the  relationships   between observed adverse  
effects  and other  related observed effects  should be  described.   
The NDI  comprehensive  safety  profile should identify the  NOAEL (see question  VI.C.4) and 
describe the toxicity  data or adverse events that were the basis  for determining  it.   The  
comprehensive safety  profile should also describe the  acceptable daily  intake  (ADI) for the NDI  
and explain how  it was  calculated  (see question VI.C.5). Finally,  the  comprehensive  safety  
profile  should state the basis  for the margin of safety for the NDI  and how  the margin of safety 
was calculated.   
 
The NDI  comprehensive  safety  profile  may need to rely heavily on trade secrets  or  confidential  
commercial information.   Any information  in the NDI  comprehensive  safety  profile  that you 
believe to be a trade secret  or  confidential   commercial information   should be  identified  as such 
(see question V.A.16).   
3.   What  should I include in my dietary supplement safety narrative?  
The  dietary supplement  safety narrative should include  a  concise summary of the  scientific  basis  
for your  conclusion  that the  dietary supplement  containing  the NDI  will  reasonably be expected 
to be safe  when used under  the conditions   recommended or suggested in the supplements  
labeling.   The purpose  of the  dietary supplement  safety narrative is  to explain how  the various  
pieces  of  data  and information  fit together to form  the basis  for your conclusions  about the safety 
of the dietary supplement.    
The  dietary supplement  safety narrative  should be based on the identity  information,   safety 
information,   and analyses in other sections  of  the NDI  notification,   including  the  NDI  
comprehensive  safety  profile.  The  dietary supplement  safety narrative should include a  
summary of  the more detailed  discussion in the  comprehensive  safety  profile of how you 
concluded that  the NDI  in the dietary supplement  will  reasonably be expected to be safe  based on 
the margin  of  safety  between the NDI  intake level  that shows no  adverse effects  (the NOAEL)  
and the  proposed intake  level and other  conditions   of use of the NDI  in the dietary supplement.    
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If the supplement  contains  dietary ingredients  other  than the NDI,  the  dietary supplement  safety  
narrative should identify the NOAEL and ADI for each ingredient   (see  questions  VI.C.4  and 
VI.C.5), describe  the toxicity  data  or  adverse  events that  were  the basis for  determining  the  
NOAEL, state the basis for  the margin of safety for each ingredient,   and discuss  whether there is  
any possible  synergy or interaction among any or  all  ingredients  that could affect  the safety of  
the  dietary supplement.   For each dietary ingredient   other than the NDI, the  dietary supplement  
safety narrative should concisely evaluate known safety concerns and describe  how the notifier  
concluded that the  combination  of ingredients  will  reasonably  be expected to be safe.   If the  
formulation  of the product,  including  other ingredients,   affects  the bioavailability  of dietary 
ingredients,  then the safety narrative  should include  a  discussion  of the effective  per-serving 
intake  level  of the  dietary ingredient(s)  in the  products compared to per-serving intake  levels  or  
dosages  described in the  history of use  or other  evidence of  safety.  
The  safety narrative should also describe  the  function of  each food additive,  color additive,  and 
GRAS  substance (i.e.,  each non-dietary ingredient),   including  the technical effect  and the  
quantity  needed to  achieve that technical  effect.  References  to the  applicable   food additive  
regulation,   color additive  regulation, GRAS  regulation,   or  GRAS notification   are also  
recommended.     
 
The  dietary supplement  safety narrative should estimate the  total daily  human intake  of the  
dietary supplement  containing   the NDI and describe any potential  toxicity or health concerns  
associated with  human consumption  of the dietary supplement,   particularly  if  concerns that may 
result  from  the proposed use of the dietary supplement  by a  vulnerable  population  have been 
identified.   The description of toxicity  and health concerns should include  the effects  of  binders,  
fillers,  formulation  aids,  and other  non-dietary ingredients   present  in the dietary supplement, 
particularly  if  they alter  the safety profile  of one  or more  ingredients,   such as by increasing 
uptake  into the  body after  ingestion.   If any ingredient   in the dietary supplement  is present at a  
level  close to  the ADI,  the  presence  of that  ingredient  from other sources  in the  diet should also 
be addressed.     
Because of  the central  importance of the dietary supplement  safety narrative to the  overall  
conclusion  of safety, the  dietary supplement  safety narrative should be written in such a  way that  
it  will  be comprehensible  after  FDA has redacted  any trade secrets  and confidential  commercial  
information  and placed the notification  in the public   docket.   As  with the  comprehensive safety 
profile,  any information  in the  dietary supplement  safety narrative that  you believe  to  be a trade 
secret or  confidential  commercial  information  should be identified  as such (see  question 
V.A.16).  
4.   What  is the difference between a NOEL and a NOAEL, and which should I  use?  
The No-Observed-Adverse-Effect Level  (NOAEL) is a number  signifying  the highest  dose or  
total daily intake  level that did not elicit  an adverse  effect  in a  properly designed and executed 
toxicological  study.71   The No-Observable-Effect Level (NOEL) is  the  highest  dose at which no 
                                              
71 Adapted from Hayes, A. Wallace, editor.   Principles and Methods of Toxicology.   5th ed.   New York:   Informa Healthcare USA,  
Inc; 2008.  
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effects  of any kind were  observed,  including   beneficial  and neutral  effects  as well  as  adverse 
effects.  Therefore, the  NOAEL, which  is  the threshold for adverse effects,  is  the appropriate  
level  to use in calculating  the margin of  safety for  an  NDI.   
 
FDA expects  that  many dietary ingredients,   because they are  intended to have beneficial  
nutritional   effects  or other  effects  on the structure  or function of the body,  will  cause  changes  in 
parameters that are measured in  animal  and clinical  safety studies.  FDA also  expects  that,  as  
dose  and total intake increase,  effects that  are neutral  or  beneficial  at lower  exposures  may  
become adverse effects  or be supplanted by adverse effects.  Thus,  it  is important  that  the  
notification  contain a  discussion of  the nature of the effects  that are  observed in safety studies.   
This  discussion  should distinguish  between adverse effects and other  effects (neutral  or  
beneficial  effects).    
The  purpose of the  NOAEL,  which is  typically  higher  than the NOEL,  is to  identify  a safe  level 
of a substance (that is,  the level  at which no adverse effects  are observed); therefore,  the NOAEL 
should be used to calculate  the margin of safety in the NDI  notification.    A  comparative 
discussion of  the effects  observed at different  doses of  an  NDI  should appear in the  
comprehensive  safety profile  for the NDI.   FDA also  recommends that  this discussion be  
summarized  in the  dietary supplement  safety narrative because it  is  central to the overall  safety  
evaluation.  
5.   What  safety factors  should be used if only animal  toxicity studies are available?  
It is  important  for the notifier   to determine  the ADI, in addition  to the NOAEL, to conduct  an 
adequate risk assessment of the NDI.  The NOAEL, expressed on a  body weight  basis (e.g.,  
mg/kg/day),   is divided  by a  safety factor (also referred to as  an uncertainty factor)  to derive the  
ADI.  Safety factors  account  for the uncertainty  in extrapolating   from  experimental  data to 
predict  the safety of  a substance in humans.   
If  the  NOAEL  is  derived from  a  chronic toxicity study (one-year duration or longer)  in animals,  
the  combined safety factor  is usually 100.   This number  is calculated using a  factor  of  10 to 
account  for interspecies variation between animals  and humans and another  factor  of  10 to 
account for  the variation in sensitivity  within the human population.     
Extrapolation  from  subchronic  toxicity studies  to chronic  use  of  an  NDI  or dietary supplement  
necessitates an additional   safety factor.  In this  situation,   FDA recommends  using at least two 
subchronic toxicity studies,  at least one  of which was  conducted in a non-rodent  species and the  
other in a  rodent  species,  and introducing  another safety factor of 10 for a  combined safety factor  
of 1,000.   In the  absence  of  supporting  history of  use  data,  using only a  single rodent subchronic  
toxicity  study as a basis  to conclude that  chronic use  of  an  NDI  in humans  will  be safe  is strongly 
discouraged,  but  may be acceptable if  a safety  factor of 2,000 is  used and there is  no toxicity  to 
the rodents  at the  maximum tolerated dose  (MTD).  The additional   safety factor  of  2  is  used in  
this situation   because a complete  animal  toxicology  assessment includes  two subchronic  (90-
day) animal  studies.    
The  safety factors in these  examples  are approximate values,  which can vary with the  specific  
data that  are available.  For  example,  a higher  value  may be appropriate  if toxicity  is  particularly 
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severe  or the variation in human sensitivity  is  expected to be great.  On the other  hand,  a  lower  
value may be  appropriate  if subchronic  studies  in both rodent  and non-rodent  species showed no 
adverse effects.   If human  data from chronic  toxicity  or ADME  (absorption,  distribution,  
metabolism,   and excretion) studies  (typically   one year  in duration)  are available,  a safety  factor  
lower  than 100 may be appropriate.  While  FDA does not  consider  the  ADI to be a  sharp 
dividing  line  between safe  and unsafe levels,  the ADI does provide  a  useful  benchmark for  
protecting the consumer.  
In summary,  safety factors are uncertainty factors used multiplicatively  to arrive  at the  combined 
safety factor  that is  applied  to a  particular  dataset provided in a notification.    This combined 
safety factor  is  used to  calculate the ADI.  
 
ADI =  NOAEL/combined  safety  factor = NOAEL/  (Uf  x  Uf x  Uf )  
intra  extrap   inter
 
   Ufintra: An uncertainty factor to account for  intraspecies  variation is introduced to 
protect  sensitive  members of  the population  when clinical  trials  include  only healthy 
subjects,  since dietary supplements  may be  consumed by anyonethe young,  the  
aged,  the healthy,  and the infirm.  A  value  of 10 is usually used.   The  size of the  
intraspecies  uncertainty factor  should be smaller  when there is  a  long history of food 
use by a large,  diverse  population.   The size  of the  intraspecies  uncertainty factor  
should be larger when toxicity is  severe  or  when a notification  relies on  studies  with  
limited  duration or small  populations.  
 
   Ufinter:   Extrapolation  from animal  to human requires an uncertainty factor  for  
interspecies  variation.  A factor  of  10 is  usually used to capture the uncertainty 
associated with using chronic animal studies to predict the  safety  of chronic  human 
exposure.   A factor of 10 can  also be used to account for the uncertainty of using 
subchronic  animal studies to  predict  the safety of  subchronic (including  intermittent)  
human exposure.  
 
   Ufextrap: Extrapolating   from a  set of  two  subchronic  toxicity  studies  in different  
animal species  to chronic  exposure  in humans  is not  recommended,  but  the associated  
uncertainty may be approximated by an additional  safety  factor of 10  to account for  
the use  of subchronic  data  to predict chronic  use.  If subchronic  toxicity  data are 
available in only a  single animal  species,  an additional  safety factor  should be used.   
Usually,  this  additional  safety factor should be  approximately   2.  
6.   Does FDA recommend including margin of safety discussions in NDI notifications?  
Yes.  To conclude  that a dietary supplement  containing  an  NDI  is  reasonably expected to be safe  
based on animal  or human safety studies,  it  is  necessary  to determine the margin  of safety  
between the level  of the NDI shown to cause no observed adverse  effects (the  NOAEL) in each  
animal  and/or human  study  and the  intake level  that  would result from the  proposed conditions  
of use of the NDI in the dietary supplement.    
The  margin of safety is calculated by dividing  the  NOAEL (not the  NOEL)  in animal  or  human 
studies by the  estimated daily  intake (EDI)  of the  NDI.   If you are calculating a  margin of  safety 
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for a combination  of  ingredients  or for  the finished dietary supplement,   the same  principles  
apply.    
Appropriate safety factors  and margin of safety should be  discussed for each  particular study or  
safety  endpoint and should  also  be  summarized  in the  dietary supplement  safety narrative  
because  of its  importance  to the overall  safety evaluation.  
7.   What  is the difference between a safety factor and a margin of safety?  
Safety factors are  used to account  for uncertainty about  the extent  to which data  gathered in one  
context  can be used to predict  the  safety of a substance in other  contexts.  For  example,  safety 
factors attempt to account for differences  between animals  and humans  and differences in 
sensitivity  among humans.   The  use of safety factors  is  based on the observation that  toxic  
substances usually have thresholds  below  which toxic  effects  cannot be detected.  Safety factors  
are used in  calculating  an acceptable daily  intake (ADI) for various  FDA-regulated products,  
including  color  additives,   food additives,   and new animal  drugs.  Safety factors  can be combined 
multiplicatively  to  predict toxicity in  the human population.     
   ADI =  NOAEL/combined  safety  factors   
   Margin  of safety = NOAEL/EDI  
In contrast,  the margin of safety is  a calculation derived from  the NOAEL  in  a single  study  and 
the  highest  total daily intake level determined from  the  conditions   of  use  in the  NDI  notification, 
the EDI.   A margin of safety is  a  measure  of how  close the EDI is  to the level  that has been 
shown to have no adverse effect  in animal  or human studies  (the NOAEL).  When reviewing 
notifications,   FDA intends  to calculate  the EDI based on the  highest daily intake level  that is  
possible  under the  conditions   of use proposed in the notification   as  well  as cumulative  exposure 
from all  dietary sources.   
The margin of  safety for a dietary ingredient   is calculated by dividing  the NOAEL  in animal  or  
human studies  by the EDI of the dietary ingredient.    So a  margin of safety of  100-fold means the  
doses shown to be without  adverse  effects  in animals  or humans  are  100 times  greater than the  
levels  that would be consumed from  the use  of  the dietary supplement.  Discussions of how ADIs 
and EDIs are  calculated and used in safety evaluations  for  a  variety of  products  can be  found in 
the following  references:    
   Frankos,  V.H., and J.V. Rodricks.   Food additives  and nutrition  supplements.   
Regulatory Toxicology,   2nd Ed., S.C.  Gad, ed.  London:  Taylor and Francis,  2001.  
   World Health Organization.    Principles  for the Safety Assessment of Food Additives  
and Contaminants  in Food.   Environmental   Health Criteria 70.   Geneva, Switzerland:   
1987.   Available at: http://www.inchem.org/documents/ehc/ehc/ehc70.htm.     
   Food and Nutrition  Board,  Institute  of Medicine.  Dietary  Reference Intakes:  A Risk  
Assessment Model  for  Establishing  Upper Intake Levels  for Nutrients.    Washington,  
DC:  National Academy  Press, 1998.  
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Example:  The only safety evidence  available is  a  single subchronic  rat  study during which no 
adverse effects  were noted at the highest  dose, which was  the maximum  tolerated dose of  3,000 
mg/kg body weight.  The top dose was  limited   by the fact that larger volumes  could not  be  
humanely administered to the  animals.   
 
If the proposed conditions   of use for the ingredient   are  1 mg/person per day in adults  daily,  the  
EDI is (1 mg/person)/70 kg average  adult  =  0.014 mg/kg.   The  margin of safety is 3,000/0.014 
=2.1x105.   The safety factors  chosen  are Uf  x  Uf x  Uf =10x20x10  = 2,000.  The ADI is  
intra  extrap   inter  
3,000/2,000  = 1.5  mg/kg.  The EDI/ADI  ratio  is 0.014/1.5 = 0.01.   This  value is  much less  than 
1, which  suggests  that,  if  these safety  factors  are appropriate,  the test  article may reasonably  be 
expected to be safe  at the proposed daily intake  level.   An intake  level of 1  g per day (1,000 
times greater)  would result in an  EDI/ADI  ratio  of close  to 10.   More studies would be  needed to 
justify the  higher serving level.  
8.   When is  the ratio  of  the EDI  to the  ADI  adequate to support  the conclusion that  a  
dietary  supplement containing an NDI  will reasonably be  expected to be safe?  
The  ratio of the  EDI  to the  ADI  should be  less  than or  equal to 1  to support a  conclusion   that the  
proposed use  of  the NDI  in the dietary supplement  will  reasonably be expected to be safe  under  
the conditions   recommended or suggested in the supplements  labeling.   The size  of  the  
EDI/ADI ratio  will  vary in accordance  with the nature  and extent of  data  available  and the  
circumstances  of use of the NDI.   For  example,  a  ratio  of  1,  where  the proposed dose (EDI) is  
equal  to the safe  dose (ADI), could be adequate if  the levels  of historical  chronic  safe use of the 
ingredient   are  the  same  as  the  levels proposed in the dietary supplement.    
 
Stated another  way, the  EDI  of  the NDI  or dietary supplement  must be less  than or equal  to the  
ADI of  the  NDI or  dietary supplement.  
The EDI  for the NDI or for the  dietary supplement  is the  highest  total daily intake level under  the  
proposed conditions   of use described in the notification.   The ADI is calculated as  the ratio of  the  
NOAEL to the combined safety factor, which is  calculated by multiplying  the individual   safety  
factors for each study.  If the ratio of the EDI to the ADI is  greater  than unity (EDI/ADI > 1),  
then the study does not  support  a  reasonable  expectation of safety for the NDI under the  
proposed conditions   of use.  
9.   What  is an example of a common error about  margin  of safety in  NDI notifications that  
have been submitted to FDA for  review?  
Many manufacturers or  distributors   assume that if  the NDI  has a  history of safe  use in humans,  
no further safety discussion is  warranted.  That is  incorrect.  A  margin of  safety for  NDI intake  
should be calculated,  and the method of calculation  explained and justified  in the notification,  
even if  a  history of safe  use is the  basis of  the safety evaluation.  When the  notification  relies  on 
a history of  safe  use,  the  margin of safety should be  calculated based upon the historical  levels  of  
the NDI  that  were  safely consumed and the NDI intake  levels  that would result  from  the  
conditions   of use proposed in the notification.   A  margin of safety  less than or equal to  1   
corresponds to the  argument that  a  history of  safe  use  alone is sufficient  to demonstrate the  safety 
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of the proposed use based on conditions   of use that are  the same or lower  than the  conditions  of  
historical  use (see question VI.B.14).  
10. Are the  recommendations  in section VI requirements  for safety information to include  
in  an  NDI notification?  
No.  The answers  to the questions  in section VI.A,  VI.B,  and VI.C  are guidance  on how  to 
approach the task of describing the basis  for the safety of the dietary supplement  containing  an 
NDI.  These answers are recommendations  and not  requirements.  In many  cases  FDA  has tried  
to provide  detailed recommendations   to illustrate  specific  examples  of situations   which might  
arise.  These details  are specific  to the situation  described.  The amount  of  information  needed to 
identify an ingredient   and provide  a basis  for  a reasonable expectation of  safety will vary  
enormously  from notification  to notification  based on factors such as  the complexity  of the  
ingredient,   history of use, and the presence  or absence of specific  safety concerns.    
 
VII.   Definitions  
The following  definitions   represent FDAs  current  thinking  on the meaning of the terms below  in the context  of  
the new dietary ingredient   provisions   of the  FD&C  Act  and regulations.  The definitions   are  intended for use  
only in that  context and may not be  appropriate  in other contexts.72      
Acceptable  daily intake (ADI):  The daily intake  of  a substance  that,  during the  human lifetime,   appears to  be 
without appreciable risk on the basis  of all known facts  at  the time.73   In the context  of  an NDI notification,   the  
ADI of  an NDI or  dietary supplement  is calculated  as  the ratio  of  the NOAEL  to  the total  safety factor  
(determined from  the studies  submitted in the notification).  
Amino acid:  An alpha-amino carboxylic  acid used as a  constituent  of  proteins  or peptides.74    
Botanical or herbal:  A  plant,  alga, or fungus;  a part  of a plant,  alga,  or  fungus  (e.g.,  bark,  leaves,  stems, roots,  
flowers,  fruits,  seeds, berries,  or parts thereof);  or an exudate (secretion)  of a plant,  alga,  or fungus.   
Botanical  raw material:  Whole  or physically  processed (e.g.,  cleaned,  frozen,  dried,  or sliced)  parts of a single  
species of plant  or a fresh or  processed alga or  fungus.  
Chemically altered: See questions  IV.B.4  and IV.B.5.  
                                              
72  For  example,  FDA recognizes that amino acid can be defined differently in non-nutritional contexts than in the definition in this  
section.  
73 Hayes, A. Wallace, editor.   Principles and Methods of Toxicology.   5th ed.   New York:   Informa Healthcare USA, Inc; 2008.    
74  Letter from  Michael M. Landa, Acting  Director, Center for Food Safety and Applied Nutrition, FDA, to  Marc Ullman, Ullman, 
Shapiro & Ullman,  LLP,  responding to Citizen Petition FDA-2009-P-0298 from OVOS Natural Health Inc. (Feb. 23, 2011).  Docket  
No. FDA-2009-P-0298 [Document ID: FDA-2009-P-0298-0008].  Available at:   
http://www.regulations.gov/#!documentDetail;D=FDA-2009-P-0298-0008  
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Chronic:  Chronic  exposure is exposure for  more than 3 months.   Periods of  daily use  interspersed with periods  
of non-use would be  considered chronic  exposure.   In the context  of toxicology  studies,  the term chronic  
generally refers to studies  with at least  1 year of  repeated dosing.   Repeated exposure is divided into 3 
categories:  subacute, subchronic,  and chronic.  Subacute exposure refers  to repeated exposure to a  substance  for 
1 month or  less,  subchronic  for 1 to 3 months,  and chronic  for  longer  than subchronic.75    
Component:   A substance that is  part  of  a mixture.   Includes  substances that cannot  be isolated  from  the whole, 
as well  as those that  can.  Once  isolated,  a component  of a mixture  is  also a  constituent  (see  definition   below).  
Concentrate:  An article  in which constituents  are  more  concentrated than in  the original.    An herbal  
concentrate  is an extract  from which all  or  most of the  solvent  has  been removed, reducing the  product to a  
solid,  semi-solid,   or  syrupy form.   The  solvent  and the process  by which the concentrate  is made  are  part  of the  
definition  of the concentrate.  
Configurational isomer:   See Stereoisomers.  
Constituent:  An article  that is  a  physical  part of the  whole  and can be isolated from  the whole.   
Dietary ingredient:  A  dietary ingredient  is  (A)  a vitamin,   (B) a  mineral,   (C)  an herb or other botanical,   (D) an 
amino acid,  (E)  a  dietary substance  for use  by man to supplement  the  diet by increasing the  total dietary intake,  
or (F) a concentrate, metabolite,   constituent,  extract,  or combination  of any ingredient   described in (A)  through 
(E).76  
Dietary substance:  A  substance that is  commonly  used as  human food or drink.  
Dietary supplement: See  definition   in  21 U.S.C. 321(ff).   
Enantiomers:  Mirror-image  isomers  (optical isomers)  that generally have similar chemical  and physical  
properties,  but  different  biological  properties  in a  chiral environment.  
Estimated daily intake (EDI):  For  purposes  of an NDI  notification,  the  EDI is  the  highest  possible  total daily  
intake  level (in mg/day  or mg/kg/day) of an NDI,  as determined from  the  proposed conditions   of  use  in the  
notification   and any background exposure from other dietary sources.   It is  the maximum   amount  that  would be  
consumed based on the conditions   of use proposed in the notification,  taking  into account cumulative   exposure  
from  other dietary sources.  The EDI should not  be  higher  than the ADI.  
Extract:  A product  consisting  of a  solvent  (menstruum)  combined with a  dietary substance or botanical  
biomass  by a  process that physically  separates  constituents  from the  dietary substance or botanical  and dissolves  
them  into the solvent.   The  extract  can be further concentrated through drying to a dry powder  or semi-solid  
form.  
                                              
75Curtis D.  Klaassen, ed.   Casarett and Doulls Toxicology: The Basic Science of Poisons. 8th Edition. Chapter 2: General Principles of  
Toxicology. McGraw-Hill Education, 2013.  
76  21 U.S.C.  321(ff)(1).  
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Formulation:   A formula  that  (1) lists  the identity and quantity of each dietary ingredient  and other ingredients  
(formulation  aids) of  a  dietary supplement,  and (2) describes the administered  form  (e.g.,  powder, liquid,  
capsule, etc.).  
Geometric isomers:   Compounds  that have  the  same  molecular  formula,  but differ from each other in the  way 
that the atoms  are oriented  in  space, and therefore have different  chemical,  physical,  and biological  properties  
(unless interconverted in the  gut).  
Ingestion: Taking  an article,  such as  a dietary supplement  or other  food,  into the stomach and gastrointestinal  
tract  by swallowing.       
Live microbial dietary  ingredient:  A  single-celled  prokaryotic  or eukaryotic  microorganism   that is  intended 
to be viable  at  the point  of ingestion.     
Margin of safety: A  measure of  how close  the  estimated daily intake  (EDI)  is to the  level  that  has been shown 
to have no adverse effect  in animal  or human studies  (the NOAEL).  It is  calculated as  the  ratio of the NOAEL  
to the  highest  total daily  intake level (EDI)  of the NDI  or  dietary supplement,   as  determined from the  proposed 
conditions   of use in the NDI  notification,   and is  usually expressed in terms of  fold  change  (e.g.,  a ten-fold 
margin of safety).   
Marketed:  See question IV.A.7.  
Master File: In the dietary supplement  context,  a  master file  is a file  containing  manufacturing  or other  identity 
information  submitted to FDA for use in an NDI  notification  by the submitter  of the master file  or  by a person 
designated by the submitter.    The submitter  may rely on information  from  the master  file  in  an  NDI notification  
by incorporating  it by reference,  or  may  grant written authorization  to other parties to incorporate information 
from  the  master  file  by reference in notifications   covering the use of the NDI in their  own products.  A  written 
authorization  granting a right  of  reference  to  a master  file  in NDI  notifications   does not  include  the right  to see  
or copy  the master file unless  the submitter  of  the master  file otherwise specifies.    
Maximum tolerated dose (MTD): The  highest  dose that causes no more  than a 10  percent  reduction in body 
weight  and does not  produce  mortality,   clinical  signs  of toxicity,   or pathologic   lesions  that  would be predicted 
to shorten the natural  life  span of an experimental  animal  for any reason other  than the induction  of  
neoplasms.77  
Metabolite: A  metabolite  is  a product  of metabolism.    In the dietary supplement  context, a  metabolite of a 
dietary ingredient  is a molecular  intermediate that  incorporates  structural elements of  the ingested  dietary  
ingredient   and whose flux or net production  in the  human body increases on ingestion  of the dietary ingredient.   
A metabolite can  be part of (or  an intermediate of)  the catabolic or  metabolic  pathway of a dietary ingredient.    
                                              
77 Hayes, A. Wallace, editor.   Principles and Methods of Toxicology.   5th ed.   New York:   Informa Healthcare USA, Inc; 2008.  
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FDA  considers  X  to  be  a metabolite  of  Y  if ingestion  of  Y  by humans results in net  production  of/increased flux 
of  X, incorporating  structural elements  of  Y.78   
Mineral:   A substance of defined chemical  composition  which  provides  a  form  or source of inorganic   elements  
to the diet.  An element  is  one of  a  class of  substances  that  cannot be separated into simpler  substances  by 
chemical  means.   Examples:   calcium,  iodine,  and zinc.  
Nanomaterial,  nanotechnology:  FDA  has  not established regulatory definitions   of nanotechnology,  
nanomaterial,  nanoscale, or other  related terms.   In the absence  of a formal  definition,   when considering 
whether an FDA-regulated product, including  dietary ingredients,   contains nanomaterials or  otherwise  involves  
the application  of  nanotechnology,   FDA intends  to 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 1  micrometer  (1,000 nm).79  
New dietary  ingredient:  A dietary ingredient   that was  not  marketed in the  U.S.  before  October 15, 1994.80      
No-Observable-Effect Level (NOEL): The  highest dose  or  total daily intake level  at which  no  effects  
(beneficial,  neutral,  or adverse)  are observed  in a properly designed and executed toxicological  study.  
No-Observed-Adverse-Effect Level (NOAEL): The highest  dose  or  total  daily intake  level that  did not  elicit  
an adverse effect in a properly designed and executed toxicological  study. 81      
Pre-DSHEA dietary  ingredient:  A dietary ingredient   that was  marketed in  the U.S.  before October 15,  1994.  
Safety factor  or  uncertainty factor:  A multiplier   used to account for  uncertainty about  the extent to which 
data gathered in one context  can be used to predict  the safety of a substance in other  contexts.  For  example,  
safety factors  attempt  to account  for differences between animals  and  humans  (uncertainty  factor of interspecies  
variation),   differences  in sensitivity  among humans  (uncertainty factor  of  intraspecies variation),   and 
extrapolation  of subchronic  to chronic  data (uncertainty factor of extrapolated data  from  subchronic  to chronic).   
Safety factors can be combined multiplicatively  to account  for multiple   sources  of  uncertainty.   Safety factors  
are used in  calculating  an acceptable daily  intake  (ADI) for various  FDA-regulated products,  including  color  
additives,   food additives,   and new animal  drugs.   See questions  VI.C.5  and VI.C.7.  
                                              
78  See  Hardy, Constance J. (Executive Secretary, Dietary Supplements Subcommittee of the FDA Food Advisory Committee).   
Summary  Minutes of March 25, 2003  Meeting of the Dietary Supplements Subcommittee; College Park, MD; dated June 3, 2003.  
Available at: http://www.fda.gov/ohrms/dockets/ac/03/minutes/3942m1.pdf.  
79  See  FDA, Office of the Commissioner.   Guidance for Industry:   Considering Whether an FDA-Regulated Product Involves the  
Application of Nanotechnology; June 2014. Available at: www.fda.gov/downloads/regulatoryinformation/guidances/ucm401695.pdf 
80  21 U.S.C.  350b(d).  
81 Adapted from Hayes, A. Wallace, editor.   Principles and Methods of Toxicology. 5th ed.  New York:  Informa Healthcare USA, Inc;  
2008.  
 
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Salt  of a dietary  ingredient:  Salts  are  composed of  cations  (positively  charged ions) bound to anions  
(negatively charged ions).  The salt of  a  dietary ingredient   is  a  neutral  compound that is  formed by the union of  
an acid or a  base with a counter ion and that dissociates  to the starting ingredients  after ingestion.     
Stereoisomers:  Stereoisomers are  molecules  that are  identical  in atomic  composition  and bonding,   but  differ  in 
the three-dimensional   arrangement  of the atoms.  
Subchronic:   Refers to  toxicological  studies  that are  1 to 3 months  in  duration.     
Target Population:  The target population  for a  dietary supplement  means the  population  group  or groups  
(defined by gender, age,  and/or  health status)  that a manufacturer  or  distributor   identifies   (e.g., in product  
labeling,  promotional  materials,  or in  an  NDI  notification)   as those  for whom  the product  is appropriate  or  
recommended.   Examples  of target populations   include  adults,  children 14 and over,  and women going through  
menopause.  
Tincture:  An aqueous alcoholic   solution  (e.g., an aqueous  alcoholic  extract of leaves or other  plant  material).   
A tincture  is  characterized by the ratio of the weight  of the dried botanical  to the volume  or  weight  of the  
finished product.  A 1:5 ratio is  1  part botanical  to 5 parts  solution.    
Uncertainty factor:  See Safety factor.  
Vitamin:  An organic  substance that is  a  minor  component  of  foods,  is essential  for normal  physiological  
functions (e.g.,  maintenance,  growth,  or  development),  is  normally  not  produced endogenously  (within  the  
body) in amounts adequate to meet normal  physiologic   needs,  and which causes,  by its  absence  or  
underutilization,   a  clinically  defined deficiency syndrome  
 
99   VIII.Appendix:  Decision Tree for NDI Notification 
the ingredient marketed as a dietary ingredient in the U.S. before October 15, 1994? (See IV.A) 
Have there been any proposed or implemented changes  New Dietary Ingredient (NOi) 
to the manufacturing process for the dietary ingredient?  Has the NDI been present in the food supply as an 
article used for conventional food?  See IV.B 
Does the new manufacturing process change the 
identity of the ingredient (e.g., different chemical  Has FDA accepted a notification for the same 
structure or composition, use of extraction, use of  manufacturer's ingredient with the same or 
-- a different starting material, such as a different  lower NDI intake level, same composition and 
art of a botanical ? See IV.A.12  same or narrower conditions of use? (See 
IVG 
Was the dietary ingredient, in its revised form, 
marketed as a dietary ingredient in the U.SA  Will there be a manufacturing process 
before October 15, 1994?  which changes the identity of the NDI 
(see IVA 13), a new manufacturer 
of the NDI or supplement, different 
composition, higher intake levels, or 
broader conditions of use?  (See  IVG). 
Pre-OSHEA Dietary Ingredient  The manufacturing change 
No NOi notification required.  may have created an NDI.  NOi 
Adulteration standard in 21 USC  notification may be required. 
342 (fj(1 )(B)) does not apply.  Consult with FDA. 
NDI adulteration standard (21  NOi notification 
USC 342(fj(1)(B)) applies.  required. 
No NOi notification required. 
Has the NOi been chemically altered from its conventional food form'? 
* 
Examples of processes that do not chemically alter an ingredient are minor loss of volatile components, dehydration, 
lyophilization, milling, or formation of tincture, aqueous solution, slurry, powder, or solid in suspension. See IV.B.5. 
Examples of changes that chemically alter an ingredient (see IV.B.4 for more details and additional examples): 
New procaaa  New aolvenla  New nallfacuilg lll8llod  Chaligas in palcla  alaq msl I iJla 
mall8s or lll8all8  (em,pll ncu8 orwalal) or  (e.g_, MW~ or  aiz8 llal alao Illar  (e.g ..   18111 ,pat of a 
daical bonda..  poal-edlacion pn111 f IQ  lalna 111vi condiiona)  llh,licalar  planl)llatdalgelha 
llal dalgea daical  lllll 19licMlly dalgea  daical pniperial  daical canipoaiion 
cx,n..-,n of nilllln..  daical canipoaiion_  o, llioloDical ellac:ls  of lie iigiecilh't. 
The NDI may have been chemically  Is NDI intake level under the intended 
ot Sure 
altered. If so, NOi notification will  conditions of use the same as or lower 
be required. Consult with FDA.  than the intake from conventional food use 
of the NDI? (See IV.B.3.) 
The NDI has probably been chemically altered. 
If so, NOi notification required. 
Regulatory status of the NDI is unchanged.  NDI adulteration standard (21 
NDI adulteration standard  (21 USC  USC 342(fj(1)(B)) applies. 
342(fj(1 )(B)) applies.  NOi notification not 
NOi notification not required.  required, but recommended.  VIII.Appendix:  Decision Tree for NDI Notification 
Text description of the Decision Tree for NDI Notification  to Determine When a Dietary  
Ingredient Requires a New Dietary Ingredient Notification Before Marketing  
1.  Was  the dietary ingredient  marketed in the U.S. before October  15,  1994? (See  IV.A). If 
yes, go to 2. If no,  go to 7. 
2.  Have  there been any proposed or  implemented  changes to the manufacturing process for the 
dietary ingredient?   If  yes, go to 3. If no,  go to 5. 
3.  Does the new  manufacturing  process  change  the identity of the  ingredient  (e.g., different 
chemical  structure or composition,   use of extraction,  use of a different  starting material, 
such as  a different  part of  a botanical)? (See IV.A.12) If yes,  go to 4.  If  no, go to 5. 
4.  Was  the  dietary ingredient,   in its revised form, marketed as  a  dietary ingredient  in the 
U.S.A.  before October 15,  1994?  If yes,  go to 5. If not  sure,  go to 6.  If no,  go to 7. 
5.  Pre-DSHEA Dietary Ingredient. No NDI notification required.  Adulteration  standard in 21 
USC  342 (f)(1)(B)  does not apply. 
6.  The manufacturing change  may have created an NDI.  NDI notification  may be required. 
Consult with FDA. 
7.  New Dietary  Ingredient (NDI). Has the  NDI been present  in the  food supply as an article 
used  for food?  (See  IV.B) If yes, go to11. If  no,  go to 8. 
8.  Has FDA accepted  a notification   for  the same manufacturers  ingredient  with the  same or 
lower  NDI  intake  level,  same composition,   and same or narrower conditions   of use? (See 
IV.C) If yes,  go to 9. If  no,  go to 17. 
9.  Will there be a  manufacturing  process  which changes  the identity  of the NDI  (see IV.A.13), 
a  new manufacturer  of the NDI or supplement,  different  composition,   higher  intake  levels, 
or broader  conditions   of use? (See  IV.C) If yes,  go to17. If  no, go to 10. 
10. NDI adulteration  standard  (21 USC 342(f)(1)(B)) applies.  No NDI notification required. 
11. Has the NDI been chemically altered from  its conventional food form*? 
*Examples  of processes  that  do not chemically alter an ingredient  are  minor  loss of  volatile 
components, dehydration,   lyophilization,   milling,   or formation of tincture,  aqueous  solution, 
slurry, powder, or  solid in suspension. See  IV.B.5. Examples  of changes that chemically 
alter an ingredient  (see IV.B.4  for  more details  and additional   examples): 
11. A.   New  process  makes or  breaks chemical  bonds.  If yes  to 11 A,  B,  C,  D or E,  go to 
12. If not  sure  to 11 A, B,  C, D and E,  go to 13.  If no to 11 A,  B, C, D and E, go 
to 14. 
11. B.   New solvents  (except  tincture  or  water) or  post- extraction processing that 
changes chemical  composition  of mixture.  If yes to 11 A,  B, C, D or E, go to 
12. If not  sure  to 11 A, B,  C, D and E,  go to 13.  If no to 11 A,  B, C, D and E, go 
to 14. 
11. C.   New  manufacturing method (e.g., new agricultural  or fermentation  conditions) 
that significantly  changes  chemical composition.   If  yes to 11 A,  B, C, D  or E, go 
to 12.  If not  sure to 11 A,  B, C, D and E, go to 13.  If no to 11 A, B, C, D and E, 
go to 14.  
11. D.   Changes  in particle size that  also alter  physical and chemical properties  or 
biological  effects.  If  yes to 11 A,  B,  C,  D or E, go to 12. If not  sure to 11 A,  B, C, 
D and E,  go to 13.  If no to 11 A, B, C, D and E,  go to 14.   VIII.Appendix:  Decision Tree for NDI Notification 
11. E.   New  starting  materials  (e.g.,  different  part of a plant)  that change  the chemical 
composition  of the ingredient.  If  yes to 11 A,  B, C, D  or  E, go to 12.  If not  sure 
to 11 A,  B, C,  D and E, go to 13.  If no to 11 A,  B, C, D and E, go to 14.  
12. The NDI  has probably been chemically  altered. If so,  NDI notification required. 
13. The NDI  may have been chemically  altered. If so,  NDI  notification  will  be required. 
Consult with FDA. 
14. Is NDI  the intake  level  under  the intended conditions   of use,  the same  as, or  lower  than the 
intake from conventional   food use of the NDI?  (See  IV.B.3) If yes, go to 15. If  no, go to 16. 
15. Regulatory status of  the NDI  is  unchanged.  NDI adulteration standard (21 USC 
342(f)(1)(B)) applies.  NDI notification not  required. 
16. NDI  adulteration  standard (21 USC 342(f)(1)(B))  applies.  NDI notification not required, 
but recommended. 
17. NDI notification required. 
Document History 
  July 2011-- Original version of the draft guidance was issued. 
  August 2016 -- 2016 Revised Draft Guidance was issued. 
  March 2024 -- Level 2 Revisions. Final guidance entitled, "Dietary Supplements: New Dietary 
Ingredient Notification Procedures and Timeframes: Guidance for Industry" replaces from the 
2016  Revised Draft Guidance the following: 
o  Question IV.C.1 (first paragraph of the response) with Question III.B 
o  Section V.A with Section III 
o  Section V.B with Section IV