2016 Revised Draft Guidance for NDI Notifications

Premarket Notification for a New Dietary Ingredient

2016 Revised Draft Guidance for NDI Notifications

OMB: 0910-0330

Document [pdf]

Download: pdf | pdf

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Draft-Not for Implementation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Draft Guidance
This guidance is being distributed for comment purposes only.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that FDA considers your comment on this draft guidance before we begin work on the final
version of the guidance, submit either electronic or written comments on the draft guidance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of the draft guidance.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
August 2016
Replaces draft guidance issued July 2011

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Draft-Not for Implementation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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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?

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?

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?
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 haven’t 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?

Additional Issues to Consider Before Submitting an NDI Notification
1. What is a dietary ingredient?

Contains Nonbinding Recommendations
Draft-Not for Implementation
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?

NDI Notification Procedures and Timeframes
A.

Procedure for Submitting an NDI Notification
1.
2.
3.
4.
5.
6.

7.
8.
9.
10.
11.
12.

Who is required to submit an NDI notification?
What should be included in an NDI notification and how should it be presented?
How should the notification describe the NDI?
How should the notification describe the dietary supplement in which the NDI
will be used?
What information should not be in the NDI notification?
Should I explain how the information in the notification provides a basis to
conclude that the dietary supplement in which the NDI will be used will
reasonably be expected to be safe?
Does FDA accept NDI notifications electronically?
When must an NDI notification be submitted?
How many copies of an NDI notification should be submitted?
Where should an NDI notification be submitted?
How should published literature and other scientific information cited in the
notification be listed?
How should unpublished scientific work be described?

Contains Nonbinding Recommendations
Draft-Not for Implementation
13. Do I have to provide copies of publications cited in the notification to FDA?
14. May I use material published in languages other than English to support the safe
use of my NDI?
15. Should raw data be provided?
16. How should I identify information that I believe is trade secret or confidential
commercial information?
17. What signature and contact information should I provide?

What Happens After an NDI Notification Is Submitted?
1. When is an NDI notification considered to be filed?
2. What are examples of omissions that cause a notification to be incomplete?
3. What type of response may I expect to receive from FDA, and when?

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?

Contains Nonbinding Recommendations
Draft-Not for Implementation
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?

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 NDI’s history of
safe use?
4. What documentation of an NDI’s 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

Contains Nonbinding Recommendations
Draft-Not for Implementation

19.

20.
21.
22.
23.
24.
25.
26.

27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.

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?
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?
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?
Am I required to use only FDA-published safety test protocols?
What are some sources of safety testing protocols that can be used in testing
NDIs and dietary supplements?
What is the appropriate highest dose of an NDI to use in animal and human
safety studies?
What should I do to justify the use of a particular protocol?
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?
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?
Where can I find good examples of genotoxicity protocols that can be used in
conducting animal and human studies on NDIs?
What is the purpose of a subchronic oral toxicity study?
What is the appropriate duration for a subchronic oral toxicity study?
Where can I find more information and examples of a subchronic oral toxicity
study?
What is the purpose of reproductive toxicity and teratology studies?
Should I include a discussion of the reproductive and teratology studies in my
NDI notification?
Should I identify the “No Observed Adverse Effect Level” (NOAEL) for all test
substance-related changes in both reproductive and teratology test endpoints?
Where can I find sample protocols for reproductive and teratology studies?
What is the purpose of repeat-dose toxicity testing?
Am I required to conduct human clinical studies to assess the safety of my NDI
or the dietary supplement containing my NDI?
What kinds of human clinical studies are useful to assess the safety of an NDI or
dietary supplement containing an NDI?
What is the purpose of “repeat-dose” human studies, and how are such studies
classified?
Where can I find more information and examples of clinical protocols that can
be used in conducting human studies for NDIs and dietary supplements?
What information should I submit to demonstrate the safety of an NDI produced
by fermentation using microorganisms like bacteria or yeast?
What information should I submit to demonstrate the safety of a microbial NDI

Contains Nonbinding Recommendations
Draft-Not for Implementation
(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?

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

Contains Nonbinding Recommendations
Draft-Not for Implementation

Dietary Supplements: New Dietary
Ingredient Notifications and Related
Issues: Guidance for Industry1

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.

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;

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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
•
•

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
supplement” 2 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 Act’s 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.
FDA’s 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-2014title21/pdf/USCODE-2014-title21-chap9-subchapII-sec321.pdf
3
Pub. L. No. 111-353, 124 Stat. 3886 (2011).

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 Act’s 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:
o the level of the NDI in the dietary supplement, and
o 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
supplement’s 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 FDA’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 FDA’s views on the meaning of “marketing” and
“dietary ingredient” in the NDI definition.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 FDA’s 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.

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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 FDA’s 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Moley, Timothy, Steven Foster, and Dennis Awang. Herbs of Commerce. Austin, TX: American Herbal Products
Association, 1992.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 list 16 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 association’s
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.

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-Nutritionvol1.pdf

Contains Nonbinding Recommendations
Draft-Not for Implementation
FDA’s 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 item’s 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 ingredient’s 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 FDA’s 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 ingredient’s 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 FDA’s 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 organization’s records,
with that entity’s permission.
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?
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

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.

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
21

Contact information for the Office of Dietary Supplement Programs can be found on the title page.
Contact information for the Office of Dietary Supplement Programs can be found on the title page.

Contains Nonbinding Recommendations
Draft-Not for Implementation

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 FDA’s 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
substance’s 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

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

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.

22
23

•

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

Contact information for the Office of Dietary Supplement Programs can be found on the title page.
Statement of Agreement, 140 Cong. Rec. S14801 (daily ed. Oct. 7, 1994).

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).

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

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.

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?
Yes. We accept notifications that cover multiple dietary supplements and include
safety data for a range of doses, daily intake levels, and/or other variations in
conditions of use (e.g., serving size, duration of use, frequency of intake, target
population, dosage form, or different formulations of pre-DSHEA ingredients in
combination with the NDI). We recommend you submit safety data up to and
including the highest dose and daily intake level, but indicate any lower daily intake
levels at which the NDI may be marketed and include research that evaluates
statistically relevant data points, such as a range of daily intake levels, to strengthen
the safety analysis. FDA has received a number of notifications that cover a range
of doses and daily intake levels. These notifications are publicly available in the
NDI notification docket on www.regulations.gov. Contact FDA’s Office of Dietary
Supplement Programs for more information. 27
You may also submit a confidential “NDI master file” to FDA which contains the
manufacturing, specifications and other identity information needed to completely

26
27

Contact information for the Office of Dietary Supplement Programs can be found on the title page.
Contact information for the Office of Dietary Supplement Programs can be found on the title page.

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 NDI’s 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 singleserving 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;

Contains Nonbinding Recommendations
Draft-Not for Implementation
•

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 effects—such as low blood pressure, low heart rate,
gastrointestinal distress, and in severe cases, irregular heartbeat—may 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 NDI’s 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
firm’s 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,

Contains Nonbinding Recommendations
Draft-Not for Implementation
•

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 firm’s 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
notifier’s 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 NDI’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
2) Who was the previous notifier and what is that entity’s 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 (NDIB1) 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 A’s prior notification
covers the conditions of use of NDI-A1 in Manufacturer X’s 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 A’s notification, and a signed
authorization from Supplier A for Manufacturer X to use any non-public safety data
from A’s notification and the manufacturing master file. On the other hand, if
Manufacturer X cannot establish that NDI-B1 is the same as NDI-A1, X’s
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 A’s
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 X’s product and the formulation described in
28

See 21 U.S.C. 350b(a)(2).

Contains Nonbinding Recommendations
Draft-Not for Implementation
Supplier A’s 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 A’s 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 A’s notification.
Scenario 4: Ingredient Supplier A submits a notification for NDI-A4. Supplier A’s
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 A’s notification. Manufacturer X’s supplement will also contain some,
but not all, of the vitamins and minerals included in Supplier A’s notification. All
other conditions of use will be the same as those evaluated in A’s notification.
Analysis: Manufacturer X does not need to submit another notification because
Supplier A’s notification covers all the conditions of NDI-A4’s use in Manufacturer
X’s 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 Q’s competitors, Company Y.
Company Y received an acknowledgment letter without objection in response to its

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 indepth 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
ingredients that haven’t 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
New Dietary
Ingredient
(NDI)

NDI
notification
required?

NDI
adulteration
standard 29
applies?

Yes

See a) or b)

Yes

A dietary ingredient that was marketed
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
supply as an article used for food which
has
a) not been chemically altered
b) been chemically altered
A dietary ingredient that was NOT
marketed in the U.S. before October 15,
1994, AND was NOT present in the
food supply as an article used for food.

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.

Contains Nonbinding Recommendations
Draft-Not for Implementation

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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
•

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 Webster’s II New
Riverside University Dictionary (1994), “dietary” means “of or relating to diet” and
“diet” means “an organism’s 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).

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 metabolite 34
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 substances 35 and other indirect food
additives 36 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).

Contains Nonbinding Recommendations
Draft-Not for Implementation
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).

Contains Nonbinding Recommendations
Draft-Not for Implementation
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, FDA’s 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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. How do 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 ingredient’s 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).
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].
39

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

NDI Notification Procedures and Timeframes
A.

Procedure for Submitting an NDI notification
1. Who is required to submit an NDI notification?
Either the manufacturer or distributor of a dietary supplement that contains an NDI,
or the manufacturer or distributor of the NDI, must notify FDA at least 75 days

41
42

See Pharmanex v. Shalala, 2001 WL 741419, at *4 & n.5 (D. Utah March 30, 2001).
Id. at *3.

Contains Nonbinding Recommendations
Draft-Not for Implementation
before marketing the article in the U.S., 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 (21 U.S.C. 350b(a); 21 CFR 190.6(a)). Although FDA does
review notifications from manufacturers and distributors of NDIs, notifications from
ingredient manufacturers do not eliminate the requirement for a notification from the
manufacturer or distributor of the dietary supplement in which the NDI will be used
unless the prior notification for the NDI: (1) included a description of the dietary
supplement with the information required by 21 CFR 190.6(b); and (2) provided the
history of use or other evidence of safety on the basis of which the notifier
concluded that the dietary supplement would reasonably be expected to be safe
under its labeled conditions of use. See questions IV.C.1 and IV.C.5 for more
information.
2. What should be included in an NDI notification and how should it be
presented?
The required elements of an NDI notification are listed in 21 CFR 190.6(b). FDA’s
recommendations for additional information to include are provided in the template
below.
The NDI notification should be well organized to facilitate an efficient and timely
FDA review. We recommend that the notification be organized by sections, with
continuous and consecutive pagination throughout the notification. Each subject
area should begin with a new page to facilitate division of the notification among
reviewers. The page number should appear in the same general location on every
page.
Recommended Template for Organizing an NDI Notification
I.

Cover Letter

Consumer Safety Officer
Office of Dietary Supplement Programs (HFS-810)
Center for Food Safety and Applied Nutrition
Food and Drug Administration
Department of Health and Human Services
5001 Campus Drive
College Park, MD 20740
DEAR SIR OR MADAM:
The undersigned, _____________, (Name of the primary contact person designated
by the manufacturer or distributor that is submitting the notification) submits this
NDI notification under section 413(a)(2) of the Federal Food, Drug, and Cosmetic
Act with respect to ___________________________________(Name of the dietary

Contains Nonbinding Recommendations
Draft-Not for Implementation
supplement containing the NDI), which contains the following new dietary
ingredient:
___________________________________________________________________ .
[For herbs and other botanicals, the name must include the Latin binomial name,
including the author citation (21 CFR 190.6(b)(2)).]
Additional information necessary to uniquely characterize the new dietary
ingredient:
_______________________________________________________________
•
•

•

If the NDI is a botanical or is derived from a botanical, the notification
should specify the part of the botanical that is the source of the new dietary
ingredient (e.g., leaf, bark, root).
Examples of information sufficient to uniquely characterize an NDI that is a
single molecular entity could include the common or usual name of the
molecular entity, the chemical identity, the chemical structural formula as
noted in ChemIDPlus Advanced, PubChem, or International Union of Pure
and Applied Chemistry (IUPAC), and the Chemical Abstracts Service (CAS)
registry number (if available).
NDIs consisting of more than one molecule should be described in a way
that accurately communicates the basic nature of the ingredient and its
characterizing ingredients or components. Examples:
o Bacteria should be described by Latin binomial name and strain
designation.
o Unusual forms of botanicals should be identified (e.g., immature
apples or malted barley.)
o If a botanical is grown or cultured to incorporate an unusual
constituent (e.g., selenium yeast), that fact should be disclosed.
If the NDI was the subject of a previous NDI notification submitted by you or
by the manufacturer or distributor from which you obtain the NDI, please
include the docket report number, which you can find in FDA’s letter
responding to the notification.

_____________________________________
(Signature of the contact person designated by the manufacturer or distributor)
[This signature is required by 21 CFR 190.6(b)(5) and should be the primary
contact, i.e., the person who represents the notifier in any discussions with FDA and
who designates any additional contact persons in the notification or in subsequent
correspondence.]
Primary Contact:
(Typed or printed name, title, address, telephone number and, if available, email
address and facsimile number of the primary contact person.)

Contains Nonbinding Recommendations
Draft-Not for Implementation

Additional Contacts:
(Typed or printed name, title, address, telephone number and, if available, email
address and facsimile number of each additional contact person.)
Contact persons can be agents, employees, officers, consultants, or attorneys.
II.
Table of Contents
The table of contents should consist of a listing of the sections of the notification in
the order in which they appear, along with the beginning page number of each
section. Each section of the notification should begin on a new page.
III.

Body of the Notification
A. Administrative
1. Description of the NDI, the dietary supplement containing the NDI,
and the conditions of use of the dietary supplement (see questions V.A.3,
V.A.4, and VI.A.19).
2. Identification of information believed to be trade secret or confidential
commercial information, including the basis for identifying the
information as such (see question V.A.16)
3. Safety narrative for the dietary supplement (see question VI.C.3)
B. Attachments used to establish identity
[Provide only the information that identifies your NDI and dietary
supplement. Do not provide efficacy data unless it is included in references
that also provide identity information.]
1. Detailed description of the identity of the new dietary ingredient and
the dietary supplement.
2. Manufacturing methods and practices to establish identity and safety
3. Specifications to identify dietary ingredients, other ingredients, and
contaminants, including the analytical methods used to establish each.
4. Identity References
This subsection should contain reprints or photocopies of the full text
of all published and unpublished identity references that have not
already been included in other subsections of the Identity section.

Contains Nonbinding Recommendations
Draft-Not for Implementation
C. Safety and Toxicology Attachments
[Provide only the information that formed the basis for your conclusion that
the dietary supplement containing the new dietary ingredient is reasonably
expected to be safe. Do not provide efficacy data unless it is included in
studies that also provide safety information.]
1.
2.
3.
4.
5.
6.
7.

Comprehensive Safety Profile for the NDI (see question VI.C.2).
Toxicology Studies
Human Studies
Other Studies
History of Use
Other Evidence of Safety
Other Safety and Toxicology References
This subsection should contain reprints or photocopies of the full text
of all published and unpublished safety and toxicology references
that have not already been included in other subsections of the Safety
and Toxicology section.

IV. Complete List of References
3. How should the notification describe the NDI?
Your notification should: (1) specify which of the dietary ingredient categories in
section 201(ff)(1) of the FD&C Act the NDI belongs to and explain the basis for
your conclusion; (2) describe the manufacturing process used to make the NDI,
including process controls; (3) describe the physical properties and chemical or
molecular composition and structure of the NDI; and (4) include a specification
sheet (preferably in table form) that describes the critical identity and safety
attributes of the NDI, including the purity and strength of the NDI and the levels and
identities of any impurities and contaminants. See section VI.A for further
information.
4. How should the notification describe the dietary supplement in which the
NDI will be used?
The notification should contain a description of the dietary supplement in which the
NDI will be used, including: (1) the level of the NDI in the dietary supplement; (2)
the identity and level of any other dietary ingredients and non-dietary ingredients
(e.g., binders and fillers) in the dietary supplement; (3) a description of the
manufacturing process of the dietary supplement, including process controls; (4) a
specification sheet for the dietary supplement that describes its critical safety
attributes; and (5) 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 of the dietary supplement, a discussion of the ordinary conditions of use

Contains Nonbinding Recommendations
Draft-Not for Implementation
of the dietary supplement. The conditions of use should include the serving form
(e.g., tablet, capsule, powder, etc.), serving size (e.g., weight or volumetric measure
per serving), frequency of use (e.g., number of servings per day and interval
between servings), duration of use, instructions for use, target population, excluded
populations (if any), and any other restrictions on use. For purposes of FDA’s
review, daily lifetime use by all age groups and other populations at the highest
described serving size and number of servings will be assumed, unless the
notification specifies otherwise.
5. What information should not be in the NDI notification?
The notification should only contain data or information, as described in the safety
narrative or comprehensive safety profile, that helps provide a basis for the safety of
the NDI or the dietary supplement containing the NDI. It should not contain general
or extraneous information. For example, data or information that is used primarily
to substantiate a claim about the efficacy of the ingredient or supplement is not
useful unless it also contains information that pertains to safety. In addition, the
requirement to notify FDA within 30 days after marketing a supplement with a
labeling claim described in section 403(r)(6) of the FD&C Act (21 U.S.C. 343(r)(6))
cannot be met by submitting the required information in a premarket NDI
notification. 43 An NDI notification should not include published review articles
about other products, or publications and websites that promote other products,
unless the information in the articles or websites can be specifically linked to the
NDI or dietary supplement that is the subject of the notification.
6. Should I explain how the information in the notification provides a basis to
conclude that the dietary supplement in which the NDI will be used will
reasonably be expected to be safe?
Yes. Your notification should include a dietary supplement safety narrative
containing your objective evaluation of the history of use or other evidence of safety
cited in the notification, along with an explanation of how the evidence of safety
provides a basis to conclude that the dietary supplement containing the new dietary
ingredient, when used under the conditions described in the notification, will
reasonably be expected to be safe. See question VI.C.3 for further information.

The regulation governing these notifications is 21 CFR 101.93. Please refer to this regulation for instructions on
where and how to submit a notification of a dietary supplement labeling claim under 21 U.S.C. 343(r)(6). Notifications
for labeling claims are not reviewed by the same staff who review NDI notifications.

Contains Nonbinding Recommendations
Draft-Not for Implementation
7. Does FDA accept NDI notifications electronically?
Yes, you may submit an NDI notification electronically through FDA’s electronic
submissions gateway at https://www.access.fda.gov. You also have the option of
continuing to submit paper NDI notifications for us to review.
8. When must an NDI notification be submitted?
If you are the manufacturer or distributor of a dietary supplement containing an NDI
for which a notification is required (i.e., 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), you must submit your NDI notification at least 75 days before
you introduce the dietary supplement into interstate commerce or deliver it for
introduction into interstate commerce (21 U.S.C. 350b(a); 21 CFR 190.6(a)). If you
are the manufacturer or distributor of the NDI, you must submit your NDI
notification at least 75 days before you introduce the NDI into interstate commerce
or deliver it for introduction into interstate commerce (21 U.S.C. 350b(a); 21 CFR
190.6(a)).
9. How many copies of an NDI notification should be submitted?
You should submit an original and one copy of the NDI notification. If the NDI
notification is a paper submission, the original should be a paper document. For the
copy, FDA accepts either paper or an exact copy of the original scanned into an
electronic file in PDF format on a CD-ROM disk.
10. Where should an NDI notification be submitted?
Submit your NDI notification to: Consumer Safety Officer, Office of Dietary
Supplement Programs (HFS-810), Center for Food Safety and Applied Nutrition,
Food and Drug Administration, 5001 Campus Drive, College Park, MD 20740.
You may also submit an NDI notification electronically through FDA’s electronic
submissions gateway at https://www.access.fda.gov.
11. How should published literature and other scientific information cited in
the notification be listed?
Publications and other scientific references cited in the notification should be listed
in a reference section at the end of the notification (see suggested notification format
in question V.A.2). The reference section should include the reference number or
short descriptor used to cite each study or publication in the body of the notification.
The list of references should include unpublished work as well as publications.

Contains Nonbinding Recommendations
Draft-Not for Implementation
12. How should unpublished scientific work be described?
The more complete the description of the data and methods in an unpublished study
report, the more easily FDA reviewers will be able to evaluate whether the data
support the safe use of the dietary supplement containing the NDI. Abstracts or
cursory summaries of data (e.g., “a 90-day study in 5 rats failed to show any
toxicity”) do not provide enough detail to be useful as a basis for a safety
determination.
13. Do I have to provide copies of publications cited in the notification to FDA?
Yes. All references to published information offered in support of the notification
must be accompanied by reprints or photocopies of such references (21 CFR
190.6(b)(4)). You should not submit only the abstract or bibliographic citation of
any publication or other material with your notification; instead, submit a photocopy
or reprint of the full text. Do not submit abstracts that are the only published report
of a scholarly or scientific work. Because abstracts do not contain sufficient
information to judge the reliability of the scientific conclusions drawn in the study
and generally do not undergo the rigorous review and editing used to evaluate other
publications, they do not provide data that are useful in evaluating the safety of an
NDI.
14. May I use material published in languages other than English to support the
safe use of my NDI?
Yes, material written in a foreign language may be used as part of the basis for a
conclusion that the NDI will reasonably be expected to be safe under the conditions
of its intended use in the dietary supplement; however, the material must be
accompanied by an accurate and complete English translation (21 CFR 190.6(b)(4)).
15. Should raw data be provided?
The level of detail that should be provided (raw data vs. summary) depends on how
important the data in question are to the conclusion of safety and also whether the
data suggest a safety problem. The more critical the data are to the overall
evaluation, the more detail is needed. Data summaries (e.g., a table containing the
average value and range or standard deviation for each parameter measured in a
safety study or the peaks in a spectrum or chromatogram) are usually sufficient
unless the data suggest that some values are outside of the acceptable range, in
which case the individual values (raw data) should be provided. During review of
the notification, FDA may request submission of raw data or other additional
information. If the additional information is a substantive amendment, FDA will
reset the filing date and start a new 75-day review period (see 21 CFR 190.6(d)).
16. How should I identify information that I believe is trade secret or

Contains Nonbinding Recommendations
Draft-Not for Implementation
confidential commercial information?
As provided in 21 U.S.C. 350b(a)(2) and 21 CFR 190.6(e), after the 90th day after
the filing date of the notification, all information in the notification will be placed on
public display, except for any information that is trade secret or confidential
commercial information (CCI).
We recommend that you clearly identify any information in the notification that you
believe is trade secret or CCI—either by marking the information where it appears
in the notification or by identifying this information in a separate document that
accompanies the notification—and that you explain the basis for this belief.
Likewise, if you believe there is no trade secret or CCI contained in the notification,
we request that you state this in your notification.
Trade secret information may consist of any commercially valuable plan, formula,
process, or device that is used for the making, preparing, compounding, or
processing of trade commodities and that can be said to be the end product of either
innovation or substantial effort (21 CFR 20.61(a)). There must be a direct
relationship between the trade secret and the productive process; for example,
information relating to the manufacturing process (see 21 CFR 20.61(a)). Examples
of trade secret information might include manufacturing methods and product
composition (if different from what is declared on the label), product specifications
needed to protect proprietary composition information (including proprietary
analytical methods used to evaluate the product), and certificates of analysis.
CCI covers information that is related to a business or trade and is “confidential” (21
CFR 20.61(b)). In the case of information that FDA requires to be submitted, such
as an NDI notification, the information is “confidential” if its disclosure is likely to
cause substantial harm to the competitive position of the submitter. 44 Examples of
CCI might include sales statistics, dollar volume, amount or source of income (e.g.,
a company’s list of customers), profits or losses, expenditures (of any person, firm,
partnership, corporation, or association), names of suppliers or subcontractors, or
brand of equipment.
FDA believes that the following data and information contained in a notification are
generally not trade secrets or CCI and, therefore, would be available for public
disclosure after the 90th day after receipt of the notification by FDA:
(1) Information about history of use or other safety information related to the NDI or
the dietary supplement, including both published and unpublished studies.
(2) All correspondence and written summaries of oral discussions relating to the
44

National Parks & Conservation Ass’n v. Morton, 498 F.2d 765 (D.C. Cir. 1974).

Contains Nonbinding Recommendations
Draft-Not for Implementation
notification, except specific information that is exempt from disclosure under 21
CFR 20.61.
17. What signature and contact information should I provide?
The signature of the person designated by the notifier is required by 21 CFR
190.6(b)(5). This person should be the primary contact, who represents the notifier
in any discussions with FDA and who designates any additional contact persons in
the notification or in subsequent correspondence. The typed or printed name, title,
address, telephone number and, if available, email address and facsimile number of
the primary contact person should be listed at the end of the cover letter that
accompanies the notification (see suggested notification format in question V.A.2)
so that FDA can reach him or her when necessary. The typed or printed names,
titles, addresses, telephone numbers and, if available, email addresses and facsimile
numbers of additional contact persons for the notification should be listed after the
contact information for the primary contact. Contact persons can be agents,
employees, officers, consultants, or attorneys for the notifier.

What Happens After an NDI Notification Is Submitted?
1. When is an NDI notification considered to be filed?
The date when FDA receives a complete notification is the date of filing. A
complete notification is a notification that contains all the information required by
21 CFR 190.6. The date of filing is the start of the 75-day premarket review period
during which the manufacturer or distributor of a dietary supplement containing an
NDI may not market the dietary supplement (21 U.S.C. 350b(a)(2); 21 CFR
190.6(c)). If the notification does not meet the requirements of 21 CFR 190.6, a
member of FDA’s Office of Dietary Supplement Programs will contact the notifier
to determine how long it will take for the notifier to provide the missing
information. If the notifier can provide the information within 14 days, FDA will
file the notification upon receipt of the missing information. If the notifier cannot
provide the missing information within 14 days, FDA will consider the notification
incomplete and will mail a letter so informing the notifier. Upon request, members
of the New Dietary Ingredient Review Team will provide advice on how to prepare
a notification that meets the requirements of 21 CFR 190.6.
2. What are examples of omissions that cause a notification to be incomplete?
An incomplete notification does not satisfy the notification requirement found in
section 413(a)(2) of the FD&C Act (21 U.S.C. 350b(a)(2)); therefore, if the dietary
supplement containing the NDI is marketed, it is deemed to be adulterated under
section 402(f) of the FD&C Act (21 U.S.C. 342(f)) unless the notifier has amended
the notification to supply the missing information at least 75 days before the dietary
supplement is introduced or delivered for introduction into interstate commerce (21

Contains Nonbinding Recommendations
Draft-Not for Implementation
U.S.C. 350b(a)). FDA does not evaluate safety or identity information in
incomplete NDI notifications.
The following are examples of omissions that make a notification incomplete:
•

Material in a language other than English that is either not translated or is
translated inaccurately.

•

Citations to published literature for which a full copy of the publication is
not provided.

•

A notification that is not signed, or contact information that is inaccurate
and does not permit FDA to establish contact with the notifier.

•

Submitting a copy of the notification that is not the same as the original.

3. What type of response may I expect to receive from FDA, and when?
Within 75 days after FDA files your notification, you may expect a letter
acknowledging receipt of the notification and stating the date on which the
notification was filed. Examples of the types of response letters FDA commonly
sends include:
•

Letter of acknowledgment without objection;

•

Letter listing deficiencies that make the notification incomplete under
21 CFR 190.6;

•

Objection letter raising safety concerns based on information in the
notification or identifying gaps in the history of use or other evidence of
safety; and

•

Letter raising other regulatory issues with the NDI or dietary supplement
(e.g., the NDI is not a dietary ingredient under 21 U.S.C. 321(ff)(1), or
the product is excluded from the definition of “dietary supplement” under
21 U.S.C. 321(ff)(2) because it is not intended for ingestion).

The letter may contain information about our review of your notification, and it may
ask you to submit additional information if your notification is incomplete or raises
safety or identity questions. The letter also contains a report number that identifies
the notification in the FDA docket. If you provide FDA with an email address in
your notification, FDA will send the response letter to that email address on the day
the response letter is mailed.

Contains Nonbinding Recommendations
Draft-Not for Implementation

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.
55

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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
In–House Method Name)
Appearance: Color/physical
state
Dietary ingredient identity
Dietary ingredient assay
Related substances:
Total related substances

White to off white/powder

Visual, R-015451

Matches reference standard
a ± b mg/capsule

HPLC, R-020301
HPLC, R-020301

No more than (NMT) 0.5% of
total peak area of the dietary
ingredient

HPLC, R-020301

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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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:
o Reaction conditions in the synthesis and purification process.
o The process and quality controls used in the manufacturing
process; for example, temperature, time, pH, shielding gas, etc.
o Flow diagrams of the manufacturing process.
o Composition: Provide the identity and quantity (including units
and any ranges) for each component.
o A description of how undesirable byproducts of manufacturing
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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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;

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

Contains Nonbinding Recommendations
Draft-Not for Implementation
•

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-andsifted, 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
•

Quantitative limits on contaminants that must be controlled to ensure the
NDI’s 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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-Date 47 or the List of Prokaryotic Names with Standing in
Nomenclature 48). 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-nomenclatureup-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.]

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

Contains Nonbinding Recommendations
Draft-Not for Implementation
(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).

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 supplement’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 NDI’s
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 NDI’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 beef—foods 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 cow’s 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 NDI’s 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 NDI’s history of use should I submit?
Documentation of an NDI’s 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

Contains Nonbinding Recommendations
Draft-Not for Implementation
“Estimating Dietary Intake of Substances in Food” 49; section III.G, “Intake
Estimate,” in “Recommendations for Submission of Chemical and Technological
Data for Direct Food Additive Petitions” 50; 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 ingredient’s 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 NDI’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 safetyrelated 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 substance’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 plant’s 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.)

Contains Nonbinding Recommendations
Draft-Not for Implementation
Table 3: Safety Testing Recommendations Matrix

Docum ented
Historical
Use

Proposed Use
of the NDI

Daily Chronic

Interm ittent:
Less Than
Historical Use
(see question
VI.B.14)

Daily Chronic

Interm ittent:
Greater Than
Historical Use
(see question
VI.B.19)

Daily Chronic

Daily Chronic:
Less Than
Historical Use
(see question
VI.B.14)

Daily Chronic

Daily Chronic:
Greater Than
Historical Use
(see question
VI.B.16)

Interm ittent

Interm ittent:
Less Than
Historical Use
(see question
VI.B.14)

Interm ittent

Interm ittent:
Greater Than
Historical Use
(see question
VI.B.18)

Tw oStudy
Genetic
Toxicity
Battery[1]

ThreeStudy
Genetic
Toxicity
Battery[1]

14-Day
RangeFinding
Oral Study
in Anim als

90-Day
Subchronic
Oral Study
in
Anim als[3]

OneMultiGeneration
Generation
Rodent
Rodent
Reproductive Reproductive
Study [2]
Study[2]

One-Year
Chronic Toxicity
Teratology
or Tw o-Year
Study in
Carcinogenesis
Anim als[2]
Study in
Anim als*

SingleDose
Repeat-Dose
Tolerability Tolerability
and/or
and/or ADME
ADME
Study in
Study in
Anim als
Anim als
and/or
and/or
Hum ans*
Hum ans*

Documented history of use should be sufficient as evidence of safety.

Contains Nonbinding Recommendations
Draft-Not for Implementation

Tw oStudy
Genetic
Toxicity
Battery[1]

ThreeStudy
Genetic
Toxicity
Battery[1]

14-Day
RangeFinding
Oral Study
in Anim als

90-Day
Subchronic
Oral Study
in
Anim als[3]

OneMultiGeneration
Generation
Rodent
Rodent
Reproductive Reproductive
Study [2]
Study[2]

One-Year
Chronic Toxicity
Teratology
or Tw o-Year
Study in
Carcinogenesis
Anim als[2]
Study in
Anim als*

SingleDose
Repeat-Dose
Tolerability Tolerability
and/or
and/or ADME
ADME
Study in
Study in
Anim als
Anim als
and/or
and/or
Hum ans*
Hum ans*

Docum ented
Historical
Use

Proposed Use
of the NDI

Interm ittent

Daily Chronic:
Less Than
Historical Use
(see
questionVI.B.15)

Interm ittent

Daily Chronic:
Greater Than
Historical Use
(see question
VI.B.17)

X [3]

No History

Daily Chronic
(see question
VI.B.20)

X [3]

No History

Interm ittent (see
question VI.B.20)

X [3]

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.

Contains Nonbinding Recommendations
Draft-Not for Implementation

21. Am I required to use only FDA-published safety test protocols?
No. You should use your own judgment in selecting among FDA’s 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 FDAregulated 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 Development 53;

•

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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
tolerated dose (MTD) (see definition in section VII). Lower doses are used to establish the doseresponse 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 I identify 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 substance’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
Rodents.” 57 Protocols for non-rodent studies are in OECD Guideline 409, “Repeated Dose 90Day 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 multigeneration 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_9789264070721en.
59

Organisation for Economic Co-operation and Development. OECD Guidelines for the Testing of Chemicals, Guideline 415: OneGeneration Reproduction Toxicity Study. Paris: OECD Publishing; May 1983. Available at:
http://www.oecd.org/chemicalsafety/risk-assessment/1948458.pdf

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 EPA’s “Harmonized Test Guidelines,” 63 and for
medicinal products, see ICH’s “Safety Guidelines” 64). In particular, “Detection of Toxicity to
Reproduction for Medicinal Products & Toxicity to Male Fertility” 65 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. Repeatdose 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.

Organisation for Economic Co-operation and Development. OECD Guidelines for the Testing of Chemicals, Guideline 416: TwoGeneration 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.oecdilibrary.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-thereproduction-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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
36. Am I 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 repeatdose 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 FDA’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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
Food” 67 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 Industry—M3 (R2) Nonclinical Safety
Studies for the Conduct of Human Clinical Trials and Marketing Authorization for
Pharmaceuticals” 68 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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 FDA 69 prior to submitting an NDI
notification for an NDI that contains nanomaterials or otherwise involves the application of
nanotechnology. 70

Contact information for the Office of Dietary Supplement Programs can be found on the title page.
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
70

Contains Nonbinding Recommendations
Draft-Not for Implementation

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 supplement’s 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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 noeffect 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 supplement’s
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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 (90day) 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
91

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 intra x Uf extrap x Uf inter)
•

Uf intra: 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 anyone—the 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.

•

Uf inter: 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.

•

Uf extrap: 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
92

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.
93

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 intra x Uf extrap x Uf inter =10x20x10 = 2,000. The ADI is
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 supplement’s 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
94

Contains Nonbinding Recommendations
Draft-Not for Implementation
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 FDA’s 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.

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

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Curtis D. Klaassen, ed. Casarett and Doull’s 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).

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

Hayes, A. Wallace, editor. Principles and Methods of Toxicology. 5th ed. New York: Informa Healthcare USA, Inc; 2008.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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.

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.

Contains Nonbinding Recommendations
Draft-Not for Implementation
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

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 manufacturer’s 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.

File Type	application/pdf
File Title	NDI Revised Draft Guidance - August 2016
Author	FDA
File Modified	2024-01-18
File Created	2016-08-09