Proposed Rule2026-22273
Infant Formula Nutrient Requirements
Primary source
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Published
November 2, 2026
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA or we) proposes to amend the regulations on nutrient specifications and labeling for infant formula as part of its phased, comprehensive review of infant formula nutrients. This action, if finalized, would amend the minimum and/or maximum levels of four required nutrients, change the unit of measure for certain nutrients, change the permitted source to meet one of the nutrient requirements, and amend the content of the required labeling. This action also includes a comprehensive assessment of four additional nutrients for which we conclude that the current required levels remain appropriate and reflect the best available scientific evidence on infant nutritional requirements and safe intake levels.
Full Text
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[Federal Register Volume 91, Number 210 (Monday, November 2, 2026)]
[Proposed Rules]
[Pages 69040-69089]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2026-22273]
[[Page 69039]]
Vol. 91
Monday,
No. 210
November 2, 2026
Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 107 and 184
Infant Formula Nutrient Requirements; Proposed Rule
Federal Register / Vol. 91, No. 210 / Monday, November 2, 2026 /
Proposed Rules
[[Page 69040]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 107 and 184
[Docket No. FDA-2026-N-10832]
RIN 0910-AJ34
Infant Formula Nutrient Requirements
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA or we) proposes to amend
the regulations on nutrient specifications and labeling for infant
formula as part of its phased, comprehensive review of infant formula
nutrients. This action, if finalized, would amend the minimum and/or
maximum levels of four required nutrients, change the unit of measure
for certain nutrients, change the permitted source to meet one of the
nutrient requirements, and amend the content of the required labeling.
This action also includes a comprehensive assessment of four additional
nutrients for which we conclude that the current required levels remain
appropriate and reflect the best available scientific evidence on
infant nutritional requirements and safe intake levels.
DATES: Either electronic or written comments on the proposed rule must
be submitted by March 2, 2027.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of March 2, 2027. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked, and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2026-N-10832 for ``Infant Formula Nutrient Requirements.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday, 240-402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' We will review
this copy, including the claimed confidential information, in our
consideration of comments. The second copy, which will have the claimed
confidential information redacted/blacked out, will be available for
public viewing and posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>. Submit both
copies to the Dockets Management Staff. If you do not wish your name
and contact information to be made publicly available, you can provide
this information on the cover sheet and not in the body of your
comments and you must identify this information as ``confidential.''
Any information marked as ``confidential'' will not be disclosed except
in accordance with 21 CFR 10.20 and other applicable disclosure law.
For more information about FDA's posting of comments to public dockets,
see 80 FR 56469, September 18, 2015, or access the information at:
<a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents, the
plain language summary of the proposed rule of not more than 100 words
as required by the ``Providing Accountability Through Transparency
Act,'' or the electronic and written/paper comments received, go to
<a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in
brackets in the heading of this document, into the ``Search'' box and
follow the prompts and/or go to the Dockets Management Staff, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: With regard to the proposed rule:
Carrie Assar, Office of Critical Foods, Human Foods Program, Food and
Drug Administration, 5001 Campus Dr., College Park, MD 20740, 240-402-
1453; or Barbara Little, Office of Regulation and International
Programs, Human Foods Program, Food and Drug Administration, 5001
Campus Dr., College Park, MD 20740, 240-402-2378. With regard to the
information collection: Christopher Colburn, Office of Operations, Food
and Drug Administration, Three White Flint North 10A-12M, 11601
Landsdown St., North Bethesda, MD 20852, 301-796-8758,
<a href="/cdn-cgi/l/email-protection#f8a8aab9ab8c999e9eb89e9c99d690908bd69f978e"><span class="__cf_email__" data-cfemail="5d0d0f1c0e293c3b3b1d3b393c7335352e733a322b">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose and Coverage of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
IV. Legal Authority
V. Description of the Proposed Rule
A. Scope
B. Approach and Assumptions Used in Scientific Assessments
C. Chloride
D. Selenium
E. Iodine (Proposed Sec. 107.100(a))
F. Potassium
G. Vitamin A (Proposed Sec. Sec. 107.10(a)(2), (b)(1), and
107.100(a) and (g))
H. Sodium
I. Vitamin D (Proposed Sec. Sec. 107.10(a)(2), (b)(1), and
107.100(a))
[[Page 69041]]
J. Manganese (Proposed Sec. 107.100(a))
VI. Proposed Effective/Compliance Dates
VII. Preliminary Economic Analysis of Impacts
A. Introduction
B. Overview of Benefits, Costs, and Transfers
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. Request for Comments
XIII. References
I. Executive Summary
A. Purpose and Coverage of the Proposed Rule
Under Operation Stork Speed, FDA is taking steps to enhance its
efforts to ensure the ongoing quality, safety, nutritional adequacy,
and resilience of the domestic infant formula supply (<a href="https://www.fda.gov/food/infant-formula-homepage/operation-stork-speed">https://www.fda.gov/food/infant-formula-homepage/operation-stork-speed</a>). As
part of this effort, FDA conducted a scientific review of a subset of
nutrient requirements for infant formula to ensure that infant formula
provides adequate nutrition to support the growth and development of
infants from birth through 12 months of age while avoiding excessive
intakes that could pose health risks. This is the first comprehensive
update and review of infant formula nutrients by the FDA since 1998 and
part of FDA's strategic, phased approach to evaluating available
scientific evidence for a comprehensive review of infant formula
nutrients, as announced as part of Operation Stork Speed. This proposed
rule assesses 8 of the 30 required nutrients in infant formula. The
proposed rule, if finalized, would amend the minimum and/or maximum
levels of four required nutrients--iodine, vitamin A, vitamin D, and
manganese--and establish a maximum level for manganese. Additionally,
the proposed rule, if finalized, would change the unit of measure for
vitamin A and vitamin D, change the permitted source to meet the
vitamin A requirement, and amend the content of the required labeling.
This action also includes a comprehensive assessment of four additional
nutrients--chloride, selenium, potassium, and sodium--for which we
conclude that the current required levels remain appropriate. FDA
intends to address the remaining infant formula nutrient specifications
through subsequent proposed rules followed by one final rule covering
all infant formula nutrient requirement changes. Lastly, the proposed
rule, if finalized, would amend infant formula labeling requirements to
change the unit of measure for vitamin A from International Units (IU)
to microgram Retinol Activity Equivalents ([mu]g RAE), and change the
unit of measure for vitamin D from IU to micrograms ([mu]g). The rule
would also provide that vitamin A and vitamin D content may be
voluntarily declared in IU in parentheses immediately following the
declarations in [mu]g RAE and [mu]g, respectively.
Additionally, in accordance with the OMB ``Final Information
Quality Bulletin for Peer Review'' (<a href="https://www.federalregister.gov/documents/2005/01/14/05-769/final-information-quality-bulletin-for-peer-review">https://www.federalregister.gov/documents/2005/01/14/05-769/final-information-quality-bulletin-for-peer-review</a>), FDA intends to conduct an external peer review on all
influential scientific information used to inform development of any
final rule.
B. Summary of the Major Provisions of the Proposed Rule
The proposed rule, if finalized, would:
<bullet> Increase the required minimum level of iodine in infant
formula from 5 [micro]g/100 kilocalories (kcal) to 15 [micro]g/100 kcal
and decrease the required maximum level of iodine from 75 [micro]g/100
kcal to 50 [micro]g/100 kcal;
<bullet> Change the unit of measure for vitamin A in infant formula
from IU to [mu]g RAE (1 IU retinol = 0.3 [mu]g RAE);
<bullet> Decrease the required minimum level of vitamin A in infant
formula from 250 IU/100 kcal (75 [mu]g RAE/100 kcal) to 70 [mu]g RAE/
100 kcal (233 IU/100 kcal) and decrease the required maximum level from
750 IU/100 kcal (225 [mu]g RAE/100 kcal) to 120 [mu]g RAE/100 kcal (400
IU/100 kcal);
<bullet> Limit permitted forms of vitamin A that contribute to
minimum and maximum vitamin A content from both preformed vitamin A and
beta-carotene to preformed vitamin A only;
<bullet> Change the unit of measure for vitamin D in infant formula
from IU to [mu]g (1 IU = 0.025 [mu]g);
<bullet> Increase the required minimum level of vitamin D in infant
formula from 40 IU/100 kcal (1 [mu]g/100 kcal) to 2 [mu]g/100 kcal (80
IU/100 kcal) and increase the required maximum level from 100 IU/100
kcal (2.5 [mu]g/100 kcal) to 3 [mu]g/100 kcal (120 IU/100 kcal);
<bullet> Decrease the required minimum level for manganese in
infant formula from 5 [mu]g/100 kcal to 1 [mu]g/100 kcal and establish
a maximum level for manganese in infant formula of 50 [mu]g/100 kcal.
C. Legal Authority
We are issuing this proposed rule consistent with our authority in
sections 201(z), 403(j), 412(i), and 701(e) of the Federal Food, Drug,
and Cosmetic Act (FD&C Act) (21 U.S.C. 321(z), 343(j), 350a(i), and
371(e)).
D. Costs and Benefits
This proposed rule, if finalized, would update the nutrient
specifications for infant formula to reflect the best available
scientific evidence on infant nutritional requirements and safe intake
levels. Vitamin D is a fat-soluble vitamin essential for calcium
absorption, skeletal mineralization, and the prevention of rickets.
Clinical symptoms of vitamin D deficiency include hypocalcemia (i.e.,
low blood calcium levels), hypophosphatemia (i.e., low blood phosphorus
levels), tetany, and rickets. We quantify benefits to formula-fed
infants from avoided healthcare costs associated with vitamin D
deficiency-induced late-onset hypocalcemia. This approach captures the
most severe and acute clinical manifestation of vitamin D deficiency
and therefore represents a lower bound on the rule's total societal
benefits. Additional benefits include reduced risk of inadequate iodine
intake, excessive vitamin A exposure, and excessive manganese exposure
in formula-fed infants; these benefits are described qualitatively. We
quantify costs to infant formula manufacturers from relabeling,
reformulation, and administrative costs associated with Before First
Processing notification submissions. Additional costs would include FDA
review costs associated with those submissions. We estimate that the
annualized benefits over 10 years would range from $18.8 million to
$171.7 million, with a primary estimate of $80.9 million, at a 7
percent discount rate and from $20.9 million to $191.0 million, with a
primary estimate of $90.0 million, at a 3 percent discount rate. The
annualized costs would range from $8.4 million to $31.7 million, with a
primary estimate of $17.6 million, at a 7 percent discount rate and
from $8.3 million to $31.6 million, with a primary estimate of $17.6
million, at a 3 percent discount rate.
[[Page 69042]]
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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25(OH)D.............................. 25-hydroxy vitamin D.
AAP.................................. American Academy of Pediatrics.
AI................................... Adequate Intake.
ALA.................................. Alpha-linolenic acid.
AR................................... Average Requirement.
ARA.................................. Arachidonic acid.
BMIC................................. Breast Milk Iodine Concentration.
BSSL................................. Bile-Salt-Stimulated Lipase.
CDRR................................. Chronic Disease Risk Reduction
Intake.
CFR.................................. Code of Federal Regulations.
CFSAN................................ Center for Food Safety and
Applied Nutrition.
CI................................... Confidence Interval.
D-A-CH............................... German, Austrian, and Swiss
Nutrition Societies.
DHA.................................. Docosahexaenoic acid.
DRI.................................. Dietary Reference Intake.
EAR.................................. Estimated Average Requirement.
EFSA................................. European Food Safety Authority.
EFSA NDA Panel....................... EFSA Panel on Nutrition, Novel
Foods and Food Allergens.
EPA.................................. Eicosapentaenoic acid.
ESPGHAN.............................. European Society for Paediatric
Gastroenterology, Hepatology and
Nutrition.
EU................................... European Union.
FAO.................................. Food and Agricultural
Organization.
FDA.................................. Food and Drug Administration.
FD&C Act............................. Federal Food, Drug, and Cosmetic
Act.
FITS................................. Feeding Infants and Toddlers
Study.
FR................................... Federal Register.
FSANZ................................ Food Standards Australia New
Zealand.
GABA................................. Gamma-Aminobutyric Acid.
GUL.................................. Guidance Upper Level.
HFP.................................. Human Foods Program.
HHS.................................. U.S. Department of Health and
Human Services.
ICCIDD............................... International Council for Control
of Iodine Deficiency Disorders.
iHMNutD.............................. Interim Human Milk Nutrient
Profile Data.
IOM.................................. Institute of Medicine.
IQR.................................. Interquartile range.
IU................................... International Unit.
Kcal................................. Kilocalorie.
Kg................................... Kilogram.
kJ................................... Kilojoule.
L.................................... Liter.
LA................................... Linoleic acid.
LOAEL................................ Lowest Observed Adverse Effect
Level.
LSRO................................. Life Sciences Research Office.
mEq.................................. Milliequivalent.
mg................................... Milligram.
MILQ................................. Mothers, Infants, and Lactation
Quality.
MIREC................................ Maternal-Infant Research on
Environmental Chemicals.
mmol................................. Millimole.
MoH.................................. Ministry of Health.
NASEM................................ National Academy of Sciences,
Engineering, and Medicine.
ND................................... Not Determined.
NHANES............................... National Health and Nutrition
Examination Survey.
NHMRC................................ National Health and Medical
Research Council.
NOAEL................................ No Observed Adverse Effect Level.
Oz................................... Ounce.
PRA.................................. Paperwork Reduction Act.
PRI.................................. Population Reference Intake.
PRIA................................. Preliminary Regulatory Impact
Analysis.
RAE.................................. Retinol Activity Equivalents.
RDA.................................. Recommended Dietary Allowance.
RE................................... Retinol Equivalents.
RfD.................................. Reference Dose.
RFI.................................. Request for Information.
RNI.................................. Recommended Nutrient Intake.
Secretary............................ Secretary of HHS.
SE................................... Standard error.
TDS.................................. Total Diet Study.
[micro]g............................. Microgram.
UIC.................................. Urinary Iodine Concentration.
UL................................... Tolerable Upper Intake Level.
UNICEF............................... United Nations Children's Fund.
[[Page 69043]]
U.S.C................................ United States Code.
USDA................................. U.S. Department of Agriculture.
VAD.................................. Vitamin A Deficiency.
WHO.................................. World Health Organization.
WIC.................................. U.S. Department of Agriculture's
Special Supplemental Nutrition
Program for Women, Infants, and
Children.
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III. Background
The Infant Formula Act of 1980 added section 412 of the FD&C Act,
establishing requirements for infant formulas, including nutrient
content requirements, and authorizing the Secretary of Health and Human
Services (HHS) to revise these requirements. In the Federal Register of
October 30, 1985 (50 FR 45106), FDA issued a final rule revising the
infant formula nutrient requirements of the Infant Formula Act of 1980
(Pub. L. 96-359, 94 Stat. 1190), which was codified at Sec. 107.100
(21 CFR 107.100). In 1995, FDA's Center for Food Safety and Applied
Nutrition (CFSAN), now known as the Human Foods Program (HFP),
contracted the Life Sciences Research Office (LSRO) of the American
Society for Nutritional Sciences to provide evidence-based
recommendations on compositional requirements for infant formula, with
Health Canada serving as a cosponsor. The assessment was conducted in
consultation with expert scientists and professional organizations. The
1998 LSRO Panel report represents our last comprehensive review of the
required infant formula nutrients although comprehensive updates to the
nutrient requirements were not proposed after the report (Ref. 1). In
2015, we updated the table in Sec. 107.100 to add the mineral selenium
to the list of required nutrients and to establish minimum and maximum
levels of selenium in infant formula (80 FR 35834, June 23, 2015). The
table in Sec. 107.100 specifies that infant formulas must contain 30
nutrients; the table specifies minimum levels for each nutrient and
maximum levels for 10 of the 30 nutrients.
On March 18, 2025, HHS and FDA announced ``Operation Stork Speed,''
a set of actions and initiatives to expand options for safe, reliable,
and nutritious infant formula for American families, including a
comprehensive infant formula nutrient review (<a href="https://www.fda.gov/food/infant-formula-homepage/operation-stork-speed">https://www.fda.gov/food/infant-formula-homepage/operation-stork-speed</a>).
On May 14, 2025, FDA issued a Request for Information (RFI) as a
first step in the comprehensive nutrient review process (90 FR 20475,
May 14, 2025). Specifically, the RFI sought information that would help
us determine whether there is a need to revise the existing nutrient
requirements in Sec. 107.100, taking into consideration any new
scientific data or information related to infant formula nutrients,
including international infant formula standards. The comment period
closed on September 11, 2025.
IV. Legal Authority
Section 412(i) of the FD&C Act establishes requirements for the
nutrient content of infant formula. Section 412(i) of the FD&C Act
contains a table listing the required infant formula nutrients with
respective minimum and, as applicable, maximum required levels. Section
412(i)(2) of the FD&C Act authorizes the Secretary, and by delegation
the Commissioner of Food and Drugs (Commissioner), to revise the list
of required nutrients and to revise the level of any required nutrient.
In addition, section 412(i)(1) of the FD&C Act, as amended by the Food
and Drug Omnibus Reform Act of 2022 (commonly referred to as FDORA
(Pub. L. 117-328)), requires the Secretary, and by delegation the
Commissioner, to review the table of required nutrients ``every 4 years
as appropriate,'' taking into consideration ``any new scientific data
or information related to infant formula nutrients, including
international infant formula standards.'' The table of required
nutrients is codified at Sec. 107.100.
The nutrition information labeling requirements for infant formula
are codified at Sec. 107.10 (21 CFR 107.10). If finalized, the
proposed rule would amend the label required in Sec. 107.10(a)(2) to
change the unit of measure for vitamin A in infant formula from IU to
[mu]g RAE and to change the unit of measure for vitamin D in infant
formula from IU to [mu]g. The rule would also amend Sec. 107.10(b)(1)
to provide that vitamin A and vitamin D content may be voluntarily
declared in IU in parentheses immediately following the declarations in
[mu]g RAE and [mu]g, respectively. ``Infant formula'' is defined as a
food for ``special dietary use'' under section 201(z) of the FD&C Act.
Under sections 403(j) and 701(e) of the FD&C Act for foods for special
dietary uses, the Secretary, and by delegation the Commissioner, may
prescribe regulations requiring information concerning the vitamin and
mineral content of the food to be provided on the label to fully inform
purchasers as to the value of the food for such uses. Thus, FDA has the
authority to revise the statement of the content of nutrients required
for infant formula labeling in Sec. 107.10 under sections 201(z),
403(j), 412(i), and 701(e) of the FD&C Act. If the proposed revisions
to Sec. 107.10 are finalized, FDA will provide an opportunity for
filing objections and requests for a formal evidentiary public hearing
under 21 CFR part 12.
V. Description of the Proposed Rule
A. Scope
The proposed rule, if finalized, would apply to products that meet
the statutory definition of ``infant formula'' in section 201(z) of the
FD&C Act. Section 201(z) of the FD&C Act defines infant formula as ``a
food which purports to be or is represented for special dietary use
solely as a food for infants by reason of its simulation of human milk
or its suitability as a complete or partial substitute for human
milk.'' FDA regulations define an ``infant'' as a person not more than
12 months of age (21 CFR 105.3(e) and 106.3).
B. Approach and Assumptions Used in Scientific Assessments
The proposed rule evaluates eight of the 30 required nutrients in
infant formula. For each nutrient, FDA reviewed the physiological role
and health consequences of deficiency or excess, relevant nutrient
reference values from major expert bodies, human milk composition data,
international regulatory standards, and recent scientific evidence.
This nutrient-by-nutrient approach culminates in an evidence evaluation
and rationale section that explains FDA's basis for either proposing
changes to current minimum and/or maximum specifications or concluding
that existing levels remain appropriate.
In sections V.C through V.J of this document, we present FDA's
nutrient-specific evaluations, including the scientific basis for
proposed changes to minimum and maximum specifications and the
rationale for maintaining current specifications where appropriate.
These nutrient-specific
[[Page 69044]]
evaluations are based on comprehensive nutrient-specific assessments,
which we reference herein and have included in the docket. As required
by section 412(i)(1) of the FD&C Act, FDA considered scientific
information and data since the last comprehensive review of infant
formula in 1998 as well as infant formula nutrient requirements in
international standards. FDA also reviewed and considered comments
submitted in response to the RFI.
FDA conducted a comprehensive evidence scan of peer-reviewed
literature using the PubMed database to identify English-language
publications regarding chloride, iodine, manganese, potassium,
selenium, sodium, vitamin A, and vitamin D. Searches were individually
constructed to account for the distinct characteristics of each
nutrient. The queries utilized specific Medical Subject Headings
(commonly referred to as MeSH) and keywords focused on general
pharmacokinetics, nutritional requirements, deficiency, and toxicity
for human infants 0 to 12 months of age. To capture updated evidence,
search parameters targeted literature published from the end of the
previous 1998 LSRO report review periods through May 2026. This
corresponded to search start dates of 1989 for manganese; 1992 for
vitamin D; 1995 for chloride, potassium, sodium, vitamin A, and iodine;
and 2015 for selenium, which corresponds to FDA''s final rule, ``The
Addition of Minimum and Maximum Levels of Selenium to Infant Formula
and Related Labeling Requirements'' (80 FR 35834, June 23, 2015). FDA
considered study design among other factors when prioritizing the
literature reviewed, which included meta-analyses, randomized
controlled trials, clinical trials, and observational studies. While,
for example, traditional literature reviews and case reports were
generally excluded from the primary evidence scan used to evaluate
nutrient specifications, FDA notes that such literature was
incorporated where necessary to provide clinical, historical, or
toxicological context. The population of interest focused on healthy,
full-term infants. This target population included infants with low
birth weight or who were small for gestational age but excluded preterm
infants and those with conditions requiring specialized formulas.
Finally, the selected outcomes prioritized evidence regarding minimum
dietary requirements, maximum safe levels, clinical signs of deficiency
or toxicity, and adverse nutrient interactions.
To evaluate nutrient reference values, FDA considered
recommendations from several expert bodies, including the National
Academies of Science, Engineering, and Medicine (NASEM), the European
Food Safety Authority (EFSA), the Australian National Health and
Medical Research Council (NHMRC)/New Zealand Ministry of Health (MoH),
and the German, Austrian, and Swiss nutrition societies (D-A-CH). These
organizations, utilizing expert committees, develop nutrient reference
values, including Dietary Reference Intakes (DRIs), which are science-
based benchmarks used to assess and plan diets for healthy populations.
Grounded in rigorous expert review across multiple countries and
methodologies, these values serve as appropriate inputs for evaluating
both the adequacy and safety of nutrient intakes in infant populations.
Nutrient reference values developed by these expert committees
include several types of recommendations: Estimated Average Requirement
(EAR), Recommended Dietary Allowance (RDA), Adequate Intake (AI), and
Tolerable Upper Intake Level (UL). The EAR represents the average daily
intake estimated to meet the needs of half of healthy individuals in
each life stage. EFSA uses an equivalent term, Average Requirement
(AR). The RDA is derived mathematically from the EAR (EAR plus two
standard deviations) and is set to meet the needs of nearly all (97-98
percent) healthy individuals (Ref. 2); the Food and Agriculture
Organization (FAO) of the United Nations/World Health Organization
(WHO) and EFSA use equivalent terms: the Recommended Nutrient Intake
(RNI) and Population Reference Intake (PRI), respectively (Refs. 3, 4).
When insufficient scientific evidence exists to establish an EAR--and
thus an RDA--an AI is established instead, based on experimentally
derived intake levels or observed mean nutrient intakes in healthy
populations (Ref. 2). The UL represents the highest average daily
intake level likely to pose no risk of adverse health effects (Ref. 2).
These reference values provide science-based benchmarks for assessing
both the adequacy and safety of nutrient intakes in infant populations
and are incorporated into each nutrient section if available.
FDA considered human milk composition data, where appropriate, as a
primary source of evidence, recognizing that human milk serves as the
gold standard for infant nutrition during, at minimum, the first 6
months of life, and that most nutrient AIs for infants are based on
observed nutrient concentrations in human milk.\1\ Mature human milk is
the stage of lactation established approximately 2 weeks postpartum,
following colostrum and transitional milk, and is characterized by a
relatively stable nutrient composition compared with earlier phases
(Ref. 5). For the purposes of FDA's review, human milk collected 21
days or more postpartum was considered mature. In addition, for the
purposes of this review, FDA converted nutrient concentrations in human
milk from per liter (L) to per 100 kcal using an assumed energy density
of approximately 650 kcal/L for mature human milk. This value
represents a well-supported midpoint estimate that is consistent with
the range of values reported across multiple independent data sources
and accounts for the natural variability in human milk energy content
across lactation stages and populations (Refs. 6, 7, 8, 9, 10). FDA
acknowledges that this value represents a midpoint within a range of
plausible estimates and commits to updating this reference value as
new, nationally representative data from North American populations
become available. Therefore, FDA requests comment on the use of
approximately 650 kcal/L in mature milk for calculations performed in
this proposed rule including the references that were used to derive
this value.
---------------------------------------------------------------------------
\1\ For the purposes of this notice of proposed rulemaking, FDA
converted nutrient concentrations in human milk from per liter (per
L) to per 100 kcal using an assumed energy density of approximately
650 kcal/L for mature human milk. This value represents a well-
supported midpoint estimate that is consistent with the range of
values reported across multiple independent data sources and
accounts for the natural variability in human milk energy content
across lactation stages and populations. The most directly
applicable North American data are provided by the iHMNutD project,
which reported a weighted mean energy density of 67.4 kcal per 100
grams (approximately 695 kcal/L) based on nine studies comprising
208 participants from the United States (Ref. 8). The MILQ study
reported median energy density values that varied by lactation
stage, with approximately 650 kcal/L at 18-31 days and stabilizing
at approximately 597-602 kcal/L from 3-4 months onward, with a
pooled median of approximately 607 kcal/L for 1-6 months (Ref. 10).
A systematic review reported approximately 620 kcal/L for mature
milk from exclusively breastfed infants aged 3-6 months (Ref. 9),
and a probabilistic modeling study reported approximately 650 kcal/L
for infants aged 1-3 months and approximately 617 kcal/L for infants
aged 3-6 months (Ref. 6). The reference value of approximately 650
kcal/L is also consistent with the central reference value
identified by EFSA, which served as the basis for EFSA's recommended
permitted energy range for infant formula (Ref. 7). FDA acknowledges
that this value represents a midpoint within a range of plausible
estimates and commits to updating this reference value as new,
nationally representative data from North American populations
become available.
---------------------------------------------------------------------------
Two recent publications provide updated human milk nutrient
composition data that were considered in this review, along with other
relevant studies as discussed in the sections
[[Page 69045]]
below. The Mothers, Infants and Lactation Quality (MILQ) study was
designed to establish reference values for nutrient concentrations in
human milk from well-nourished women with minimal nutrient
supplementation and dietary fortification across geographically diverse
populations. The study collected human milk samples from 1,242 women in
Bangladesh, Brazil, Denmark, and The Gambia at multiple time points
throughout the first 8.5 months of lactation (Ref. 11). Concentrations
of macronutrients, water-soluble vitamins, fat-soluble vitamins, and
minerals were quantified using validated analytical methods. Milk
volume was measured simultaneously, enabling calculation of total
nutrient transfer to the infant (Ref. 11). The other study developed
interim human milk nutrient profile data (iHMNutD) for use in North
American food composition databases through a literature synthesis of
eligible North American data from three previously published systematic
reviews covering the period 1980-2022 and one large Canadian
biomonitoring study (Ref. 8). Data were restricted to mature milk from
term-born infants collected within the first 6 months of lactation
using nutrient-specific collection and analytical methods. Values were
reviewed by subject matter experts and accompanied by data flags to
communicate uncertainty where data were limited (Ref. 8).
FDA reviewed international infant formula standards and
recommendations from Codex Alimentarius, the European Union (EU),
Australia, New Zealand, Canada, and China, among others, to inform its
assessment of appropriate nutrient specifications while also
considering differences in methodology and regulatory philosophy. Codex
Alimentarius and some non-U.S. countries use the term ``infant
formula'' to refer to formula intended for infants 0-6 months of age
and the term ``follow-on formula'' to refer to formula intended for
infants 6-12 months of age. In the United States, there is not a
regulatory distinction between formula intended for infants 0-6 months
of age and formula intended for infants 6-12 months of age; both are
considered ``infant formula,'' as defined in 21 CFR 106.3 and section
201(z) of the FD&C Act. We considered data on nutrient function and
interactions, clinical outcomes associated with deficiency or excess
intake, U.S. dietary intake data, and other evidence relevant to
evaluating minimum and maximum nutrient levels in infant formula. Where
relevant, FDA notes distinctions between maximums and guidance upper
levels (GULs) established in some international standards. Unlike
maximums, GULs apply to nutrients for which sufficient information for
a science-based risk assessment is not available; rather, they are
derived based on meeting nutritional requirements of infants and an
established history of apparent safe use. In general, from a nutrition
perspective, it is best that nutrient contents in infant formulas do
not exceed GULs unless higher levels cannot be avoided (Ref. 12).
To estimate infant exposure to nutrients from infant formula, FDA
assumed typical infant formula intakes of 0.78 L/day for infants 0-6
months of age and 0.6 L/day for infants 7-12 months of age, accounting
for the introduction of complementary foods in the second half of
infancy. These intake volumes are based on observed consumption
patterns in breastfed infants and are consistent with the assumptions
used by NASEM (Ref. 2) and similar to assumptions used by other expert
bodies in establishing nutrient reference values. Assuming a standard
infant formula energy density of 20 kcal/oz (676 kcal/L), these volumes
correspond to approximately 527 kcal/day for infants 0-6 months of age
and approximately 406 kcal/day for infants 7-12 months of age. FDA
requests comment on all aspects of its assumptions to calculate the
kcal consumed per day for infants 0-6 months of age and infants 7-12
months of age, including the assumption of the energy density of infant
formula.
For certain nutrients, FDA also considered a high consumer scenario
based on data from three cycles of the National Health and Nutrition
Examination Survey (NHANES), using the 90th percentile of energy intake
from infant formula among non-breastfed infants to evaluate potential
nutrient exposures at the upper end of the consumption distribution
(Refs. 13, 14, 15, 16, 17, 18). Evaluation of typical consumption
scenarios (i.e., mean, representing the average diet) informed the
assessment of minimum specifications to ensure adequate nutrient
intakes, while both typical and high-consumer scenarios informed the
assessment of maximum specifications to ensure appropriate safety
margins.
C. Chloride
The current requirements for chloride in infant formula are a
minimum level of 55 milligrams (mg)/100 kcal and a maximum level of 150
mg/100 kcal (Sec. 107.100). Based on our analysis of scientific
information and data since the 1998 comprehensive study of infant
formula nutrients (LSRO Panel report), including infant formula
chloride requirements in international standards, we conclude that the
required chloride levels in Sec. 107.100 remain appropriate.
1. Background
Chloride is an essential mineral that serves critical physiological
functions in infants, including maintenance of acid-base balance,
regulation of fluid and electrolyte homeostasis, and production of
hydrochloric acid for digestion (Refs. 19, 20). Chloride works closely
with sodium, potassium, and bicarbonate as electrically charged
particles in body fluids to help regulate membrane electrical charge,
facilitate nutrient absorption, and generate signals in muscles and
nerves (Ref. 20). Chloride also helps keep mucus moist and fluid in the
lungs and other organs through a process controlled by the Cystic
Fibrosis Transmembrane Conductance Regulator channel; when this channel
malfunctions, it causes cystic fibrosis (Ref. 20). Most dietary
chloride intake comes from sodium chloride (i.e., table salt) added to
food during processing or at the table (Refs. 19, 20).
a. Health Consequences of Chloride Deficiency
A deficiency in chloride can result in metabolic alkalosis (i.e., a
condition in which blood becomes excessively alkaline) (Ref. 21). The
most well-documented cases of chloride deficiency in the United States
occurred during 1978-1979, when approximately 150 infants in the United
States developed hypochloremic metabolic alkalosis after consuming
improperly formulated soy protein-based infant formulas (Ref. 22).
These formulas contained chloride levels as low as 1-2 milliequivalents
(mEq)/L (approximately 5-11 mg/100 kcal) (Refs. 22, 23, 24), and
symptoms were observed in some infants consuming formula with 5.1 mEq/L
(approximately 27 mg/100 kcal) (Ref. 1). Infants with acute chloride
deficiency exhibited a failure to thrive, lethargy, loss of appetite,
and weakness. Other laboratory abnormalities included low blood and
urine chloride levels with metabolic alkalosis, low blood potassium
levels, and red blood cells in the urine (Refs. 24, 25). This public
health incident helped lead to the enactment of the Infant Formula Act
of 1980 (Pub. L. 96-359).
Long-term followup studies of the infants in the United States
affected by the chloride deficiency crisis identified subtle
neurodevelopmental effects in children who experienced severe
[[Page 69046]]
chloride deficiency during infancy, particularly affecting language
skills (Refs. 22, 26).
b. Health Consequences of Excess Chloride Intake
Hyperchloremia is a condition in which blood chloride levels exceed
the normal range. Hyperchloremia typically results from medical
disorders or clinical treatments rather than dietary chloride intake,
and excessive chloride consumption through infant formula or other food
is unlikely to be a cause of hyperchloremia (Ref. 20).
In its 2005 assessment, NASEM found no research examining the
consequences of chronic overconsumption of chloride in infants (Ref.
19). Available evidence regarding harmful effects of excess chloride
consumption in infants remains sparse. FDA's review identified no
significant new scientific evidence concerning adverse outcomes from
excessive dietary chloride consumption during infancy since NASEM's
2005 report (Ref. 27).
2. Nutrient Reference Values
a. NASEM (United States)
NASEM established AIs for chloride for infants in 2005 as part of
its comprehensive report, Dietary Reference Intakes for Water,
Potassium, Sodium, Chloride, and Sulfate (Ref. 19). NASEM established
an AI of 180 mg/day for infants 0-6 months of age and an AI of 570 mg/
day for infants 7-12 months of age. NASEM established these AIs based
on the sodium content of human milk, assuming chloride adequacy in
equimolar amounts to sodium, because most dietary chloride is consumed
as sodium chloride. The calculation for infants 7-12 months of age
accounted for the introduction of complementary foods at this age.
b. European Food Safety Authority (EFSA)
The EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA)
published a comprehensive Scientific Opinion on dietary reference
values for chloride in 2019 (Ref. 20), in which it established an AI of
300 mg/day for infants 7-11 months of age. EFSA did not establish an AI
for chloride in infants 0-6 months of age, but, through a comprehensive
review of human milk studies from others of term infants in Western
populations, the EFSA Panel determined an approximate midpoint of
chloride concentration in mature human milk to be 400 mg (11.3
millimole (mmol))/L and estimated infant intake of 320 mg/day from
exclusive breastfeeding.
The EFSA Panel also reviewed a study that calculated physiological
requirements of chloride in infants and that recommended an intake of
120 mg/day throughout the first year of life. EFSA noted that the
amount of chloride provided by human milk during the first 6 months of
life (approximately 320 mg/day) is substantially higher than this
calculated physiological requirement, suggesting either that the
approach underestimates actual needs or that human milk provides
chloride beyond minimal physiological requirements (Ref. 20).
c. D-A-CH (Germany, Austria, Switzerland)
In 2017, D-A-CH established an AI for chloride of 300 mg/day for
infants 0-4 months of age, and 450 mg/day for infants 4-12 months of
age (Ref. 28). Because intake data from complementary foods were
unavailable, the 4-12 months value was extrapolated from the 0-4-month
group's values, adjusting for differences in average body weight.
d. UL
Establishing a UL requires evidence from studies that test multiple
levels of intake and identify the point at which adverse effects begin
to occur; however, available data were insufficient to support such a
determination for chloride in infants (Ref. 19). Consequently, neither
NASEM (Ref. 19) nor EFSA (Ref. 20) established a UL for chloride in
infants. In its 2005 assessment, EFSA observed that chloride
consumption levels in European populations surpassed the amounts needed
for normal physiological function (Ref. 29). EFSA also recognized that
higher consumption of chloride in the form of sodium chloride
correlated with increased risk of high blood pressure (Refs. 20, 29).
Nevertheless, EFSA determined that the available scientific evidence
was inadequate to establish a specific numerical value for an upper
limit (Ref. 20). Similarly, NASEM noted that ``as with other nutrients,
an intake of sodium or chloride markedly above the AI is not
warranted'' (Ref. 19).
e. Comparison of International Recommendations
Table 1 shows the chloride AIs established by NASEM, EFSA, and D-A-
CH.
Table 1--Adequate Intakes and Tolerable Upper Intake Levels of Chloride
----------------------------------------------------------------------------------------------------------------
Age range Adequate intake Tolerable upper intake
Organization Year (months) (mg/day) level
----------------------------------------------------------------------------------------------------------------
NASEM........................... 2005 0-6 180 ND
7-12 570 ND
EFSA............................ 2019 7-11 300 ND
D-A-CH.......................... 2017 0-4 300 ND
4-12 450 ND
----------------------------------------------------------------------------------------------------------------
ND: not determined.
The considerable variation in chloride recommendations across
international expert bodies reflects fundamental differences in
methodology and data sources (Ref. 27). Despite these methodological
differences, all expert bodies used human milk composition as the
primary basis for chloride AIs and assessed that there is insufficient
evidence to establish a UL.
3. Human Milk Composition
Maternal diet and nutritional status do not affect how much
chloride is present in human milk (Refs. 20, 30). Multiple studies have
characterized chloride concentrations in mature human milk from mothers
with term pregnancies. The direct measurements of chloride
concentrations in mature human milk resulted in values ranging from 339
to 547 mg/L across individual study timepoints (Refs. 31, 32, 33, 34,
35) and a pooled weighted mean of 416 mg/L (n=5 studies and 139
participants) (Ref. 8) and reflect the natural variability observed in
human milk.
The MILQ study (Ref. 36) provides comprehensive recent data on
human milk mineral composition, from 1,242 women in Bangladesh, Brazil,
Denmark, and The Gambia. The MILQ study
[[Page 69047]]
reported sodium concentrations, not chloride. In converting sodium to
chloride on an equimolar basis, substantially lower values are obtained
than with direct measurements of chloride in milk (Ref. 27).
The discrepancy suggests either that chloride and sodium may not be
present in exactly equimolar amounts in human milk or that different
analytical methods, study populations, or periods yield systematically
different results. NASEM's approach of establishing chloride AIs based
on equimolar conversion from sodium may underestimate actual chloride
concentrations when based on sodium measurements alone (Ref. 27).
4. International Regulatory Standards for Infant Formula
Chloride specifications for infant formula vary among international
regulatory bodies and expert organizations, though most align closely
with Codex Alimentarius standards. The Codex Alimentarius Commission, a
program that establishes internationally recognized standards,
specifies a minimum of 50 mg/100 kcal and a maximum of 160 mg/100 kcal.
These specifications apply to both infant formula (for 0-6 months of
age) (Ref. 12) and follow-on formula (for 6-12 months of age) (Ref.
37). The EU, based on recommendations from EFSA (Ref. 7), specifies a
minimum of 60 mg/100 kcal and a maximum of 160 mg/100 kcal (Ref. 38).
The EU minimum assumes that infants 0-6 months of age consume 500 kcal/
day and require 300 mg/day of chloride. Other countries have adopted or
proposed to adopt specifications aligned with Codex Alimentarius,
including Food Standards Australia New Zealand (Ref. 39), Health Canada
(Ref. 40), and China (Ref. 41); however, China has different standards
for follow-on formulas for infants 6-12 months of age (approximately
220 mg/100 kcal maximum for 6-12 months) (Ref. 42).
In its 1998 comprehensive review of infant formula nutrients, LSRO
recommended a minimum of 50 mg/100 kcal and a maximum of 160 mg/100
kcal. The LSRO Panel based the minimum recommendation on the mean minus
one standard deviation value for the chloride concentration of human
milk, which was approximately 320 mg/L (48 mg/100 kcal) (Ref. 30),
rounded up to 50 mg/100 kcal for the minimum specification. The LSRO
Panel found no evidence to suggest that chloride is absorbed
differently from infant formula compared to human milk, supporting the
use of human milk composition data as the basis for the specification.
For the maximum chloride content of 160 mg/100 kcal, the LSRO Panel
based this on the 90th percentile of FDA analyses of infant formulas
available at that time, rather than on safety concerns, as no evidence
supported that excessive chloride intake caused adverse effects in
children.
Table 2 shows the requirements and recommendations of these
international regulatory bodies and organizations.
Table 2--International Standards and/or Recommendations for Chloride in Infant Formula
----------------------------------------------------------------------------------------------------------------
Age range Minimum (mg/100 Maximum (mg/100
Organization (months) kcal) kcal) Reference
----------------------------------------------------------------------------------------------------------------
U.S. Current Standards.............. 0-12 55 150 21 CFR 107.100.
LSRO \1\............................ 0-12 50 160 LSRO, 1998.
Codex Alimentarius.................. 0-12 50 160 CXS 72-1981, CXS 156-1987.
EU.................................. 0-12 60 160 Commission Delegated
Regulation (EU) 2016/127.
Australia \2\....................... 0-12 50 159 FSANZ P1028.
Canada \3\.......................... 0-12 50 160 Health Canada, 2025.
China............................... 0-6 50 159 GB 10765-2021.
6-12 ND 218 GB 10766-2021.
----------------------------------------------------------------------------------------------------------------
\1\ Recommended ranges.
\2\ Values converted from per 100 kJ to per 100 kcal (1 kcal = 4.184 kJ).
\3\ Reflects proposed compositional requirements for infant formula.
5. Recent Scientific Evidence on Chloride Intake
A 2006 analysis of electrolyte intake in infants from the 2002
Feeding Infants and Toddlers Study (FITS) reported mean chloride
intakes of 290 mg/day for infants 4-5 months of age and 761 mg/day for
infants 6-11 months of age based on equimolar conversion of sodium to
chloride (Ref. 43). Mean intakes exceeded NASEM's AI for both age
groups. For infants 6-11 months of age, chloride intakes ranged from
approximately 50 percent of the AI at the 10th percentile (276 mg/day)
to approximately 260 percent at the 90th percentile (1,493 mg/day).
Although there are several limitations of the FITS study (Ref. 27), the
FITS data nonetheless provide useful information demonstrating that
most infants--whether breastfed or consuming infant formulas meeting
current specifications--along with age-appropriate complementary foods,
achieve chloride intakes that meet or exceed established AIs.
6. Evidence Evaluation and Rationale
Based on the review of available literature, NRVs, and
international standards, we conclude that the current minimum level of
55 mg/100 kcal and maximum level of 150 mg/100 kcal for chloride in
Sec. 107.100 remain appropriate.
a. Maintaining the Minimum Specification of 55 mg/100 kcal
The current minimum required level of 55 mg/100 kcal of chloride
provides a 2- to 11-fold margin above the deficiency-causing levels of
5-27 mg/100 kcal associated with the 1978-1979 chloride-deficiency
crisis. Given the severity of the consequences of the chloride-
deficiency crisis in 1978-1979 and the lack of functional biomarkers
for chloride status (i.e., early indicators of chloride inadequacy), we
determine that the substantial margin is appropriate.
Although methodological variability exists in measuring chloride
levels in human milk, human milk composition data support the current
required minimum. The current minimum of 55 mg/100 kcal falls between
and aligns well with direct chloride measurements in human milk
(approximately 52 to 84 mg/100 kcal, with a pooled weighted mean of 64
mg/100 kcal) (Refs. 1, 8, 20, 28, 31 through 35). When chloride
measurements are derived from converting sodium concentrations to
chloride, the chloride measurements are far lower than direct chloride
measurements, suggesting that chloride and sodium are not present in
exactly equimolar amounts in human milk (Refs. 8, 27, 36). Given the
uncertainty associated with chloride measurements
[[Page 69048]]
derived from converting sodium concentrations to chloride, the current
minimum appropriately reflects direct chloride measurement data while
providing a conservative safety margin.
The current minimum ensures that infant formula provides chloride
intakes that pose low risk of deficiency relative to established AIs
(Ref. 27). Our current specification of 55 mg/100 kcal falls within the
international consensus range, and no compelling evidence from other
jurisdictions suggests that lowering the minimum would provide any
benefit. Doing so would reduce the safety margin above the established
deficiency threshold without corresponding nutritional justification
(Ref. 27).
b. Maintaining the Maximum Specification of 150 mg/100 kcal
The current maximum of 150 mg/100 kcal substantially exceeds the
median human milk chloride content while maintaining a prudent upper
limit for sole-source infant nutrition. No compelling evidence supports
either raising or lowering this specification (Ref. 27).
Although expert bodies have not established a UL for chloride in
infants due to limited data (Refs. 19, 20, 29), the absence of an
established UL reflects insufficient dose-response data regarding
adverse effects rather than confirmation that all intake levels are
safe (Ref. 27).
The current maximum provides a substantial margin above the
chloride content of human milk (Ref. 27). FDA's current maximum of 150
mg/100 kcal provides an additional conservative margin below both
LSRO's recommendation and the international standard of approximately
160 mg/100 kcal.
History of use and available intake data support safety at the
current maximum. The current maximum would provide 791 mg/day for a 0-
6-month-old infant and 609 mg/day for a 6-12-month-old infant consuming
typical daily infant formula intakes. These chloride amounts have not
been associated with adverse effects in clinical use since the chloride
requirements were established in the Infant Formula Act of 1980. An
analysis of 2002 FITS data (Ref. 43) reported mean sodium intakes
corresponding to estimated chloride intakes of 290 mg/day (4-5 months
of age) and 761 mg/day (6-11 months of age), although these estimates
included intake from all dietary sources, not solely infant formula.
We have considered whether raising the maximum to align with the
international consensus of approximately 160 mg/100 kcal would be
warranted and conclude that it is not necessary to ensure adequate
infant nutrition. While such harmonization could provide modest
additional manufacturing flexibility and align U.S. standards with
international regulatory agencies, the difference between the current
U.S. maximum and the international standard is relatively small (6.7%
or 10 mg/100 kcal). No evidence suggests that the current maximum is
inadequate, constrains appropriate formulation, or that chloride
intakes between 150 and 160 mg/100 kcal provide nutritional advantages
to infants beyond those achieved at the present maximum of 150 mg/100
kcal. Manufacturers have successfully met the current specification
since the 1980s without reported difficulties. Therefore, we conclude
that the slightly lower maximum provides an additional conservative
margin without imposing undue manufacturing constraints (Ref. 27).
c. Consideration of the Evidence Base
We acknowledge several uncertainties in the evidence base that
support maintaining the current specifications. There is wide
variability in reported human milk chloride concentrations across
studies (171-547 mg/L or approximately 26-84 mg/100 kcal for mature
milk) primarily from discrepancies between direct chloride measurements
and sodium-based estimates, lack of functional biomarkers for chloride
status, and individual variability in infant requirements. Given these
uncertainties, the serious consequences of dietary chloride deficiency,
and the lack of evidence of adverse effects from current
specifications, we believe a conservative approach is warranted and
that the current required minimum level of 55 mg/100 kcal and maximum
level of 150 mg/100 kcal should be retained (Ref. 27).
D. Selenium
At the time FDA initially established nutrient specifications for
infant formula, selenium was not recognized as an essential nutrient
and was not one of the nutrients required by statute in infant formula.
However, in 1989, an RDA for selenium for infants 0-6 months of age was
established (Ref. 44), and in 2000, AI levels and ULs were established
for infants 0-6 and 7-12 months of age (Ref. 45). In 2015, FDA added
selenium as a required nutrient in infant formula with a minimum of 2
[micro]g/100 kcal and a maximum of 7 [micro]g/100 kcal (see 80 FR
35834, June 23, 2015). Based on our analysis of the scientific
information and data since the addition of minimum and maximum levels
of selenium to the infant formula requirements in 2015, including
infant formula selenium requirements in international standards, we
conclude that the required selenium levels in Sec. 107.100 remain
appropriate.
1. Background
Selenium is an essential trace element for humans that functions
largely through its incorporation into proteins known as
selenoproteins. The known biological functions of selenium include
defense against oxidative stress, regulation of thyroid hormone action,
and regulation of the oxidation/reduction status of vitamin C and other
molecules (Ref. 46). Selenium also provides protective effects against
toxicity of certain elements--including arsenic, lead, cadmium, and
mercury--by facilitating urinary excretion, reducing oxidative damage,
and forming biologically inactive complexes with these elements (Refs.
45, 47, 48). Infant selenium status is influenced by geographic
variation in the selenium content of soil and water, which shapes
maternal selenium intake and, in turn, the selenium content of human
milk. As a result, the selenium intake of breastfed infants varies by
geographic location (Ref. 46).
a. Health Consequences of Selenium Deficiency
Keshan disease, a cardiomyopathy that occurs almost exclusively in
children, has been associated with selenium deficiency. Keshan disease
has been reported in areas of China where the population has severe
selenium deficiency (Refs. 46, 49; 78 FR 22442 at 22443, April 16,
2013). Selenium deficiency has also been identified throughout the
lifespan in those who receive long-term parenteral nutrition (i.e.,
intravenous nutrition) not adequately supplemented with selenium.
Deficiency signs and symptoms include macrocytosis, loss of skin and
hair pigmentation, and, in severe cases, cardiomyopathy (Ref. 46).
b. Health Consequences of Excess Selenium Intake
Chronic selenium toxicity (selenosis) is rare but has been observed
in adults consuming diets containing excess levels of selenium due to
selenium supplementation (Ref. 46). Reported characteristics include
hair and nail brittleness and loss, gastrointestinal upsets, skin rash,
garlic breath odor, fatigue, irritability, and nervous system
abnormalities. Acute selenium toxicity
[[Page 69049]]
is rare, and the few reports in the literature of acute fatal or near
fatal selenium poisoning in adults occurred secondary to accidental
ingestion of selenium (Ref. 45).
2. Dietary Reference Intakes
a. NASEM
In 2000, NASEM established AI and UL values for selenium for
infants as part of its comprehensive report, Dietary Reference Intakes
for Vitamin C, Vitamin E, Selenium, and Carotenoids (Ref. 45). NASEM
did not find sufficient evidence to calculate an EAR for selenium for
infants during the first year of life and, therefore, did not have a
basis to set an RDA for selenium for infants. This contrasts with the
1989 Food and Nutrition board recommendation, which had established an
RDA for infants extrapolated from adult values (Ref. 44). NASEM's 2000
report instead determined that, due to the lack of functional criteria
of selenium status in infants to accurately reflect dietary intake,
recommended intakes should be based on an AI reflecting observed mean
intakes of infants fed principally with human milk.
NASEM established an AI of 15 [micro]g/day for infants 0-6 months
of age and an AI of 20 [micro]g/day for infants 7-12 months of age.
NASEM's basis for deriving an AI for the first 6 months of life was the
average intake by full-term infants born to healthy, well-nourished
mothers and exclusively fed human milk (Ref. 45). The AI for infants 7-
12 months of age was derived from using the data of infants 0-6 months
of age, extrapolated upward to account for increased body size and the
introduction of complementary foods.
NASEM established a UL of 45 [micro]g/day for selenium for infants
0-6 months of age by relying on the concentration of selenium in human
milk, which is not associated with known adverse effects. The UL of 60
[micro]g/day for infants 7-12 months of age was extrapolated to account
for increased body size (Ref. 45).
b. EFSA
EFSA published dietary reference values for selenium in 2014 (AI)
and 2023 (UL) (Refs. 50, 51). EFSA did not establish an AI for selenium
in infants 0-6 months of age. For infants 7-11 months of age, EFSA
established an AI of 15 [micro]g/day (Ref. 49).
EFSA established ULs of 45 [micro]g/day for infants 4-6 months of
age and 55 [micro]g/day for infants 7-11 months of age. EFSA
acknowledged that there are no direct data to support derivation of a
UL for infants; however, given that there is no evidence that infants
are more susceptible to selenium toxicity than adults, the EFSA Panel
considered it appropriate to extrapolate ULs from adults to infants
(Ref. 51). The EFSA Panel noted that these ULs are consistent with
human milk concentrations.
c. FAO/WHO
The joint FAO/WHO Consultation established RNI levels of 6
[micro]g/day for infants 0-6 months of age and 10 [micro]g/day for
infants 7-12 months of age based on the selenium content of human milk
from international surveys, which averaged 18.5 [mu]g/L, combined with
data on milk consumption by exclusively breastfed infants (Ref. 3).
d. D-A-CH (Germany, Austria, Switzerland)
In 2015, D-A-CH established an AI for selenium of 10 [micro]g/day
for infants 0-4 months of age, based on the selenium content of human
milk. Values were adjusted for body weight to establish an AI of 15
[micro]g/day for infants 4-12 months of age. No UL was determined (Ref.
52).
e. Australian NHMRC/New Zealand MoH
Australia and New Zealand established AIs and ULs in 2005 (Ref.
53). The AI of 12 [micro]g/day for infants 0-6 months of age was
calculated by multiplying the average intake of human milk (0.78 L/day)
and the average selenium content in human milk of 15 [micro]g/L based
on several key studies (Refs. 54, 55, 56). The AI of 60 [micro]g/day
for infants 7-12 months of age was extrapolated from that of the
younger infants on a metabolic weight basis, with considerations for
the introduction of complementary foods.
The UL for young infants was based on the studies showing that a
human milk concentration of 60 [micro]g/L was not associated with
adverse effects (Ref. 57). This gives a no observed adverse effect
level (NOAEL) of 47 [micro]g/day (7 [micro]g/kg body weight).
f. Comparison of international recommendations
Table 3 shows the selenium AIs established by NASEM, EFSA, FAO/WHO,
D-A-CH, and Australian NHMRC/New Zealand MoH.
Table 3--Adequate Intakes and Tolerable Upper Intake Levels of Selenium
----------------------------------------------------------------------------------------------------------------
Age range Tolerable upper intake
Organization Year (months) Adequate intake level
----------------------------------------------------------------------------------------------------------------
NASEM........................... 2000 0-6 15 [micro]g/day 45 [micro]g/day.
7-12 20 [micro]g/day 60 [micro]g/day.
EFSA............................ 2014 (AI) 4-6 ND 45 [micro]g/day.
2023 (UL) 7-11 15 [micro]g/day 55 [micro]g/day.
FAO/WHO......................... 2004 0-6 6 [micro]g/day * ND.
7-12 10 [micro]g/day * ND.
D-A-CH.......................... 2015 0-4 10 [micro]g/day ND.
4-12 15 [micro]g/day ND.
Australian NHMRC/New Zealand MoH 2005 0-6 12 [micro]g/day 45 [micro]g/day.
7-12 15 [micro]g/day 60 [micro]g/day.
----------------------------------------------------------------------------------------------------------------
Values established are RNI levels.
The substantial variation in selenium recommendations across
international expert bodies reflects fundamental differences in
methodology and data sources (Ref. 49).
3. Human Milk Composition
a. Selenium Concentration in Human Milk
Maternal diet and nutritional status affect the amount of selenium
present in human milk. The average selenium content of mature human
milk sampled between 2- and 6-months lactation appears to be relatively
constant within a population group. However, selenium content in human
milk varies greatly based on maternal selenium intakes, including
variability in selenium soil content (Ref. 45).
[[Page 69050]]
There is wide interindividual variation in the selenium content of
human milk, and the selenium content of hind milk (i.e., milk at the
end of an infant feeding) is greater than that of the fore milk (i.e.,
milk at the beginning of the feeding). Studies report average selenium
concentrations of mature human milk of 10 to 23 [micro]g/L (with a
range of 6 to 39 [micro]g/L) (Refs. 45, 49).
b. Recent Data
The MILQ study (Ref. 36) reported a pooled median selenium
concentration of 9 [micro]g/L in human milk collected from mothers of
infants 1-6 months of age, representing only 50 percent of the NASEM
reference concentration of 18 [micro]g/L used to establish the current
AI. The study suggested that the current NASEM AI may overestimate
selenium concentrations in human milk from well-nourished populations
and called for updated recommendations informed by these study data
(Ref. 36). The iHMNutD study reported a pooled weighted mean selenium
concentration which converted to approximately 20.4 [micro]g/L (Ref.
8). A 2019 study (Ref. 58) measured milk selenium concentrations in
lactating Chinese women across three regions with varying selenium
status. Among mothers with optimal selenium intake, the Beijing milk
concentration was 27.8 [mu]g/L; combined with an average milk volume of
0.55 L/day, this yielded a calculated AI of 15.29 [mu]g/day for Chinese
infants 0-3 months of age, consistent with the current Chinese AI of 15
[mu]g/day for infants 0-6 months of age.
4. International Regulatory Standards for Infant Formula
Selenium specifications for infant formula vary among international
regulatory bodies and expert organizations (table 4). The Codex
Alimentarius Commission specifies a minimum of 1 [micro]g/100 kcal and
a GUL of 9 [micro]g/100 kcal for infant formula (0-6 months of age)
(Ref. 12), and a minimum of 2 [micro]g/100 kcal and GUL of 9 [micro]g/
100 kcal for follow-on formula (6-12 months of age) (Ref. 37). The EU
specifies a minimum of 3 [micro]g/100 kcal and a maximum of 8.6
[micro]g/100 kcal (Ref. 38). Other countries have adopted or proposed
to adopt specifications aligned with Codex Alimentarius, including Food
Standards Australia New Zealand (FSANZ) (Ref. 39), Health Canada (Ref.
40), and China (Refs. 41, 42).
The 1998 LSRO Panel report recommended a minimum selenium
requirement of 1.5 [micro]g/100 kcal and a maximum of 5 [micro]g/100
kcal. The minimum value approximated the estimated value for the mean
minus one standard deviation for the selenium concentration in human
milk in countries in which selenium deficiency has not been recognized
in breastfed infants. This recommended minimum level would provide an
estimated 7.5 [micro]g/day of selenium for young infants exclusively
fed infant formula, an amount below the 1989 RDA (10 [micro]g/day). The
LSRO Panel was aware that there were disparities between some of its
recommendations for nutrient levels in infant formulas and the 1989
RDAs; however, the history of use for a large population in which
selenium deficiency had not been reported was regarded as a reasonable
basis for recommending a minimum value for selenium in infant formula
(Ref. 1; 78 FR 22442 at 22443, April 16, 2013).
The 1998 LSRO Panel report recommended a maximum selenium level for
infant formula of 5 [micro]g/100 kcal (33.5 [micro]g/L). This
recommendation was based on the upper limit of the range of selenium in
human milk, which was considered to represent a history of use for a
large population in which selenium toxicity had not been reported. The
LSRO Panel report also indicated that, on a body weight basis, this
level is far below the intake associated with the development of
selenosis in adults (Ref. 1; 78 FR 22442 at 22444-22445).
Table 4 shows the requirements and recommendations of these
international regulatory bodies and organizations.
Table 4--International Standards and/or Recommendations for Selenium in Infant Formula
----------------------------------------------------------------------------------------------------------------
Minimum Maximum
Organization Age range ([micro]g/100 ([micro]g/100 References
kcal) kcal)
----------------------------------------------------------------------------------------------------------------
U.S. Current Standards.............. 0-12 2 7 21 CFR 107.100.
(months)
LSRO \1\............................ 0-12 1.5 5 LSRO, 1998.
(months)
Codex Alimentarius.................. 0-6 1 9 (GUL) CXS 72-1981.
(months)
6-12 2 9 (GUL) CXS 156-1987.
(months)
EU.................................. 0-12 3 8.6 Commission Delegated
(months) Regulation (EU) 2016/127.
Australia \2\....................... 0-12 2 9 (GUL) FSANZ P1028.
(months)
Canada \3\.......................... 0-12 1 9 Health Canada, 2025.
(months)
China............................... 0-6 3 8.6 GB 10765-2021.
(months)
6-12 2 8.6 GB 10766-2021.
(months)
----------------------------------------------------------------------------------------------------------------
\1\ Recommended ranges.
\2\ Values converted from per 100 kJ to per 100 kcal (1 kcal = 4.184 kJ).
\3\ Reflects proposed compositional requirements for infant formula.
5. Recent Scientific Evidence on Selenium Intake
A randomized dose-response trial of healthy term infants from birth
to 16 weeks of age fed infant formula containing selenium at three
different concentrations and a breastfed reference group found that
infants fed the formula containing a selenium level of 1.9 [micro]g/100
kcal received sufficient selenium to meet their nutritional needs and
that much of the selenium above the level of 1.9 [micro]g/100 kcal was
eliminated from the body (Ref. 59). An analysis of a randomized
controlled trial investigating maternal selenium status during
pregnancy and lactation in relation to infant birth outcomes across
[[Page 69051]]
898 mother-infant dyads in Guatemala, India, and Pakistan concluded
that maternal selenium supplementation did not impact serum selenium
concentrations in populations at high risk for deficiency, suggesting
that supplementation may not overcome the impact of low dietary intake
and the high demands of pregnancy and early lactation (Ref. 60).
However, the authors noted that larger studies in high-risk regions are
needed to further clarify the relationship between maternal selenium
deficiency and infant outcomes (Ref. 60).
6. Evidence Evaluation and Rationale
Based on our review of available scientific data, information, and
international standards, we conclude that the current minimum of 2
[micro]g/100 kcal and maximum level of 7 [micro]g/100 kcal for selenium
in Sec. 107.100 remain appropriate.
a. Maintaining the Minimum Specification of 2 [micro]g/100 kcal
The current minimum of 2 [micro]g/100 kcal is based primarily on
two sources of evidence. First, NASEM's AI of 15 [micro]g/day for
infants 0-6 months of age, converted to an energy basis assuming 100
kcal/kg body weight/day intake, yields approximately 2.1 [micro]g/100
kcal. FDA rounded this to 2 [micro]g/100 kcal for the minimum
specification (Refs. 45, 49). The current minimum provides adequate
selenium to meet established AIs. For a 0-6-month-old infant consuming
a typical daily infant formula intake, infant formula at the minimum
specification provides 10.5 [micro]g/day, which represents 70 percent
of the NASEM AI of 15 [micro]g/day (Refs. 45, 49). While this
percentage may appear modest, it is important to note that the AI is
based on the mean intake from human milk and is intended to meet or
exceed the needs of nearly all individuals in the population (Refs. 45,
49). Second, the randomized dose-response trial described in section
V.D.5 of this document provides direct clinical evidence supporting
this minimum level, demonstrating that 1.9 [micro]g/100 kcal was
sufficient to achieve selenium status indicators comparable to
breastfed infants (Ref. 59). Additionally, the current minimum also
aligns well with international standards (Ref. 49).
Moreover, recent evidence from the MILQ study suggests that the
pooled median total selenium intake from human milk is 7.3 [micro]g/day
from 1 to 6 months postpartum, representing only 49 percent of the
NASEM AI (Ref. 36). This finding raises questions about whether the
NASEM AI may overestimate infant selenium requirements, as the MILQ
study population of well-nourished mothers and healthy, normally
developing infants showed no evidence of selenium deficiency despite
intakes well below the established AI. However, the current minimum
specification of 2 [micro]g/100 kcal, providing 10.4 [micro]g/day,
exceeds the MILQ median intake by 42 percent, offering a conservative
margin of safety.
The minimum specification also accounts for potential differences
in bioavailability. The U.S. minimum was established as a level
providing sufficient amounts to account for potential differences in
bioavailability among various infant formula types, including a
conservative estimate of 50 percent relative bioavailability of
selenium from soy protein-based formulas compared to human milk (Ref.
1). This conservative approach ensures that all formula types,
regardless of protein source, provide adequate selenium.
Human milk composition data support the current minimum. The
current minimum of 2 [micro]g/100 kcal exceeds the estimated median
value of 1.3 [micro]g/100 kcal from the MILQ study by approximately 54
percent, providing a safety margin to account for population
variability and potential differences in bioavailability (Refs. 36,
49). The MILQ study authors noted that the substantially lower
concentrations as compared with NASEM estimates suggested that the
differences may be due to maternal dietary selenium intake, which
varies with regional soil selenium content (Ref. 36). The lower MILQ
study values as compared with other studies may reflect populations
with lower selenium intake rather than indicating that lower
concentrations are adequate (Refs. 8, 36, 49, 58). Data from other
well-nourished populations (Refs. 8, 58) support selenium
concentrations closer to the NASEM reference value. The wide geographic
variability in human milk selenium concentrations underscores the
importance of maintaining a minimum specification that ensures adequacy
across diverse populations and accounts for the serious health
consequences of selenium deficiency, including Keshan disease (Ref.
49).
b. Maintaining the Maximum Specification of 7 [micro]g/100 kcal
The current maximum is based on safety considerations. NASEM
established a UL of approximately 7 [micro]g/kg/day for infants 0-6
months of age, which approximates 7 [micro]g/100 kcal (Ref. 45). The UL
is defined as ``the highest daily intake level that is likely to pose
no risk of adverse health effects in almost all individuals in a life
stage group'' (Ref. 45). NASEM established this UL by relying on data
on the concentration of selenium in human milk, which is not associated
with known adverse effects.
The current maximum substantially exceeds median human milk content
while maintaining a prudent limit (Ref. 49). Although the current
maximum is approximately 5.4 times the median human milk concentration
from the MILQ study population, the studies conducted in mothers with
optimal selenium intake (North American data) and from well-nourished
populations (in China) reported reference values of approximately 3.1
[micro]g/100 kcal and 4.2 [micro]g/100 kcal, respectively (Refs. 8, 49,
58). Relative to these higher reference values from populations with
optimal selenium intake, the current maximum of 7 [micro]g/100 kcal
represents approximately 2.3 times the North American median and 1.7
times the concentration in milk from optimally nourished Chinese
mothers.
The current maximum is conservative compared to most international
standards. The current maximum is lower than the Codex Alimentarius
GUL, the FSANZ GUL, and the Health Canada, EU, and China maximums (Ref.
49). The LSRO recommendation of a maximum selenium level for infant
formula of 5 [micro]g/100 kcal was based on the upper limit of the
range of selenium in human milk and represented a history of use for a
large population in which selenium toxicity had not been reported. The
current maximum is higher than the LSRO recommendation but aligns with
the NASEM UL, reflecting a conservative approach based on safety
considerations while providing additional manufacturing flexibility
(Ref. 49).
History of use also supports safety at the current maximum. The
current maximum has demonstrated safety in practice since the level
went into effect in 2016. Manufacturers have successfully met the
current specification since 2016 without reported difficulties,
suggesting that the current maximum does not impose undue constraints.
c. Consideration of the Evidence Base
There is wide variability in reported human milk selenium
concentrations across studies and geographic regions, reflecting
differences in maternal selenium intake, which is highly dependent on
regional soil selenium
[[Page 69052]]
content. There are limited recent data from U.S. populations
specifically, methodological variability across studies, and
uncertainty about bioavailability differences between infant formula
types and human milk. Recent evidence suggests that populations at high
risk of selenium deficiency may have higher needs during pregnancy and
lactation that cannot be easily met through supplementation alone and
that selenium status can decline substantially during lactation even
with supplementation (Ref. 60). Given these uncertainties, the
associated consequences of dietary selenium deficiency (i.e., Keshan
disease), the potential for selenium status to decline during
lactation, and the lack of evidence of adverse effects from current
specifications, we believe a conservative approach in maintaining the
required minimum level of 2 [micro]g/100 kcal and maximum level of 7
[micro]g/100 kcal is warranted.
E. Iodine (Proposed Sec. 107.100(a))
The current requirements for iodine in infant formula are a minimum
level of 5 [micro]g/100 kcal and a maximum level of 75 [micro]g/100
kcal (Sec. 107.100). Based on our analysis of scientific information
and data since the 1998 comprehensive study of infant formula nutrients
(Ref. 1), including infant formula iodine requirements in international
standards, we propose to amend Sec. 107.100(a) to increase the
required minimum to 15 [micro]g/100 kcal and decrease the required
maximum to 50 [micro]g/100 kcal.
1. Background
Iodine is an essential micronutrient whose primary physiological
role is as an essential component of the thyroid hormones that regulate
protein synthesis, enzymatic activity, and metabolic processes critical
to normal growth and development (Refs. 1, 61). In infants, thyroid
hormones are particularly important for myelination of the central
nervous system, which is most active in the perinatal period and during
early postnatal development; iodine deficiency during this critical
window can irreversibly impair neuromotor development (Ref. 62).
Iodine (I<INF>2</INF>) refers to the elemental form, while iodide
(I-) is the reduced, ionic form that predominates in food, water, and
the body. Most dietary iodine is rapidly converted to iodide in the
gastrointestinal tract prior to absorption (Ref. 62). Infant formula
and human milk contain iodine primarily in the iodide form. In
regulatory and nutritional contexts, the term ``iodine'' is used
conventionally to refer to total iodine intake regardless of chemical
form, and this convention is followed throughout this document.
a. Health Consequences of Iodine Deficiency
Iodine deficiency disorders identified throughout the lifespan
include intellectual disability, hypothyroidism, goiter, cretinism, and
varying degrees of growth and developmental abnormalities resulting
from inadequate thyroid hormone production (Ref. 62). Fetal iodine
deficiency resulting in cretinism occurs in areas where endemic goiters
exist, generally in association with iodine intakes less than 25
[micro]g/day (Ref. 1). Infants are among the most vulnerable
populations for iodine deficiency because their intrathyroidal iodine
stores are small, daily thyroid hormone turnover rates per body weight
are higher than at any other time of life, and they are entirely
dependent on dietary iodine from human milk or infant formula (Refs.
61, 62). Deficiencies of vitamin A, selenium, or iron can exacerbate
the effects of iodine deficiency (Refs. 61, 62).
b. Health Consequences of Excess Iodine Intake
High iodine intakes have been associated with thyroiditis, goiter,
hypothyroidism, hyperthyroidism, and sensitivity reactions (Ref. 62).
Excess iodine can be harmful to infants, particularly premature
infants, because excretion mechanisms may be unable to accommodate high
intake levels, potentially resulting in transient hypothyroidism (Refs.
1, 61).
2. Nutrient Reference Values
a. NASEM
NASEM established AI values for iodine for infants in 2001 based on
the observed mean iodine intake of infants exclusively fed human milk
(Ref. 62). NASEM established an AI of 110 [micro]g/day for infants 0-6
months of age and an AI of 130 [micro]g/day for infants 7-12 months of
age. The AI for infants 7-12 months of age was extrapolated from the AI
for younger infants using a metabolic weight ratio (Ref. 62). NASEM
judged the UL to be not determinable for infants due to insufficient
data on adverse effects and concern about the infant's ability to
handle excess amounts (Ref. 62).
b. EFSA
EFSA published dietary reference values for iodine in 2014 (Ref.
63). EFSA did not establish an AI for iodine in infants 0-6 months of
age, during which period exclusive breastfeeding is assumed to provide
an adequate iodine supply. For infants 7-11 months of age, EFSA
established an AI of 70 [micro]g/day based on the urinary iodine
concentration (UIC) threshold (100 [micro]g/L) from school-age
children, extrapolated to infants using age-adjusted urinary volumes
and body weight. The EFSA Panel concluded that an iodine intake of 90
[micro]g/day is adequate for the majority of infants, and, since there
is no reason to assume that infants from birth to 6 months of age need
more iodine than infants in the second half of the first year of life,
an intake of 70 [micro]g/day is adequate for the majority of infants
from birth to 12 months of age (Ref. 63). EFSA did not establish a UL
for iodine for infants.
c. WHO
WHO, together with the United Nations Children's Fund (UNICEF) and
the International Council for Control of Iodine Deficiency Disorders
(ICCIDD), established an RNI of 90 [micro]g/day for children under 5
years of age (0-59 months) based on physiological evidence that
positive iodine balance requires iodine intake of at least 15 [micro]g/
kg/day, approximating 90 [micro]g/day for a 6-month-old infant weighing
6 kg (Refs. 64, 65). The recommended value supports normal thyroid
hormone production without stressing the iodide trapping mechanism.
While a UL for infants was not established, daily intakes exceeding 180
[micro]g/day were not expected to provide additional health benefit and
may be associated with impaired thyroid function. However, the
Consultation set upper limits of probable safe intake for infants at
150 [micro]g/kg/day (0-6 months of age) and 140 [micro]g/kg/day (7-12
months of age) (Ref. 64).
d. D-A-CH (Germany, Austria, Switzerland)
D-A-CH established a reference value for daily iodine intake for
infants of 80 [micro]g/day for infants 0-12 months of age in 2025 (Ref.
66). This value represents a doubling of the previous D-A-CH reference
value of 40 [micro]g/day. According to the D-A-CH reference values, the
updated iodine recommendation for infants differs methodologically from
the previous reference value and allows the revised reference value to
be expressed as a recommended intake rather than an estimated value
(Refs. 61, 66). No UL was determined.
e. Australian NHMRC/New Zealand MoH
Australia and New Zealand established AIs for iodine in 2006 (Ref.
53). The AI for infants 0-6 months of age was calculated by multiplying
the
[[Page 69053]]
average intake of human milk (0.78 L/day) by the average concentration
of iodine in human milk (115 [micro]g/L), consistent with the 2001
recommendation (Ref. 64), in addition to other studies, yielding an AI
of 90 [micro]g/day. The AI for infants 7-12 months of age was
extrapolated from that of younger infants using a metabolic weight
ratio, yielding an AI of 110 [micro]g/day. No UL was determined (Ref.
53).
f. Comparison of International Recommendations
Table 5 shows the iodine AIs established by NASEM, EFSA, WHO, D-A-
CH, and NHMRC/MoH.
Table 5--Adequate Intakes and Tolerable Upper Intake Levels of Iodine
----------------------------------------------------------------------------------------------------------------
Age range Adequate intake Tolerable upper intake
Organization Year (months) ([micro]g/day) level
----------------------------------------------------------------------------------------------------------------
NASEM........................... 2001 0-6 110 ND
7-12 130 ND
EFSA............................ 2014 7-11 70 ND
WHO............................. 2001 0-12 * 90 ND
D-A-CH.......................... 2025 0-12 80 ND
Australian NHMRC/New Zealand MoH 2006 0-6 90 ND
7-12 110 ND
----------------------------------------------------------------------------------------------------------------
* Values established are RNI levels.
The variation in iodine recommendations across international expert
bodies reflects differences in methodology, data sources, and the
timing of each review (Ref. 61). A key methodological difference across
all bodies is the degree to which human milk iodine data are used as
the primary reference. Unlike many other minerals, iodine in human milk
is not homeostatically regulated (i.e., automatically kept at a
consistent level by the body) but directly reflects maternal iodine
status and population-level iodine exposure. Consequently, human milk
iodine concentrations vary substantially across populations and over
time, and the choice of reference population for human milk data has a
direct and substantial effect on the resulting AI (Refs. 36, 61, 67).
3. Human Milk Composition
There is wide variability in milk iodine concentrations across
populations, driven by differences in national salt iodization
policies, dietary patterns, geographic variability, and dietary
supplement use (Ref. 61). Consequently, no single human milk iodine
concentration can be considered universally representative. The large,
multi-country MILQ study ultimately chose not to generate pooled iodine
reference values or percentile curves because of this between-country
variability, unlike its approach to other minerals (Ref. 36).
4. International Regulatory Standards for Infant Formula
Iodine specifications for infant formula vary considerably among
international regulatory bodies and expert organizations (see table 6).
The current U.S. specification of 5 [micro]g/100 kcal (minimum) to 75
[micro]g/100 kcal (maximum) is an outlier relative to international
standards. Specifically, the U.S. minimum falls below the current
minimum thresholds established by major international regulatory
frameworks, while the U.S. maximum exceeds their corresponding upper
levels.
Across the international regulatory frameworks assessed, minimum
iodine specifications range from 10 to 15 [micro]g/100 kcal, while
maximum levels or GULs range from 29 to 60 [micro]g/100 kcal. Codex
Alimentarius, FSANZ, and Health Canada share identical specifications
(10 [micro]g/100 kcal minimum; 60 [micro]g/100 kcal maximum or GUL)
(Refs. 12, 37, 39, 40). China also has a maximum of 60 [micro]g/100
kcal with a higher minimum of 15 [micro]g/100 kcal (Refs. 41, 42). The
EU specifies the narrowest range, with a minimum of 15 [micro]g/100
kcal and a maximum of 29 [micro]g/100 kcal (Ref. 38). The EU minimum
was derived from EFSA's 2014 scientific opinion, which determined that
a minimum iodine content of 14 [micro]g/100 kcal (rounded up to 15
[micro]g/100 kcal) is necessary for an infant consuming approximately
500 kcal/day to achieve an adequate intake of 70 [micro]g/day (Ref. 7).
The 1998 LSRO Panel report recommended a minimum of 8 [micro]g/100
kcal and a maximum of 35 [micro]g/100 kcal (Ref. 1). The LSRO minimum
was based on the then-current RDA for iodine of 40 [micro]g/day for
infants 0-6 months of age, which translates to 8 [micro]g/100 kcal for
a 5 kg infant consuming 100 kcal/kg/day (Ref. 44). Human milk was not
used as the reference standard. Data obtained from iodine balance
studies further support this level, estimating the dietary requirement
at no more than 8.6 [micro]g/kg/day (Ref. 1). The LSRO recommended
maximum of 35 [micro]g/100 kcal represented approximately the 75th
percentile of FDA analyses of marketed formulas and was considered the
lowest feasible value at the time (Ref. 1). The LSRO Panel considered
the U.S. maximum of 75 [micro]g/100 kcal to be too high.
Table 6 shows the requirements and recommendations of these
international bodies and organizations.
Table 6--International Standards and/or Recommendations for Iodine in Infant Formula
----------------------------------------------------------------------------------------------------------------
Minimum Maximum
Organization Age range ([micro]g/100 ([micro]g/100 Reference
(months) kcal) kcal)
----------------------------------------------------------------------------------------------------------------
U.S. Current Standards.............. 0-12 5 75 21 CFR 107.100.
LSRO \1\............................ 0-12 8 35 LSRO, 1998.
Codex Alimentarius.................. 0-12 10 60 (GUL) CXS 72-1981, CXS 156-1987.
EU.................................. 0-12 15 29 Commission Delegated
Regulation (EU) 2016/127.
Australia \2\....................... 0-12 10 60 (GUL) FSANZ P1028.
Canada \3\.......................... 0-12 10 60 Health Canada, 2025.
China............................... 0-12 15 60 GB 10765-2021, GB 10766-
2021.
----------------------------------------------------------------------------------------------------------------
\1\ Recommended ranges.
[[Page 69054]]
\2\ Values converted from per 100 kJ to per 100 kcal (1 kcal = 4.184 kJ).
\3\ Reflects proposed compositional requirements for infant formula.
5. Recent Scientific Evidence on Iodine Intake
The most direct evidence on iodine requirements in early infancy
comes from a 2016 balance study in formula-fed infants 2-5 months of
age (Ref. 68). The study found that zero iodine balance was achieved at
approximately 70 [mu]g/day and found iodine retention to be linear up
to 300 [mu]g/day with no evidence of down-regulation (Ref. 68). These
findings led the authors to propose an EAR of 72 [mu]g/day and an RDA
of 80 [mu]g/day, suggesting the current AI of 110 [mu]g/day for infants
0-6 months of age may be set too high. The study also proposed a
urinary iodine concentration threshold of approximately 125 [mu]g/L as
indicative of adequacy, slightly above the WHO cutoff of 100 [mu]g/L
(Ref. 68). An additional study to evaluate iodine status in settings
with universal salt iodization supports these estimates (Refs. 61, 69).
Moreover, a 2022 secondary analysis of a randomized controlled
trial (Ref. 70) provided independent corroboration of the proposed EAR.
Median UICs were greater than or equal to 100 [mu]g/L at all ages from
1 to 12 months, and more than 98 percent of infants met the proposed
EAR of 72 [mu]g/day. These findings support the appropriateness of the
lower estimated iodine requirement derived from the 2016 balance study
(Refs. 61, 68, 70).
These newer estimates are broadly consistent with established
reference values. WHO, together with UNICEF and ICCIDD, established an
RNI of 90 [micro]g/day for children under 5 years of age (0-59 months)
and identified a UIC of greater than or equal to 100 [mu]g/L as
indicative of adequate iodine nutrition, while noting that daily
intakes exceeding 180 [mu]g/day are not expected to provide additional
health benefit (Refs. 64, 65). A narrative review of the literature
from 1960 to 2007 proposed an iodine requirement of greater than or
equal to 15 [mu]g/kg/day (>=90 [mu]g/day) for full-term infants (Ref.
71). Further, the 2016 balance study suggests that the true AR may sit
somewhat below the established RNI, though the difference between the
proposed RDA (80 [mu]g/day) and the established RNI (90 [mu]g/day) is
modest, and both fall below NASEM's current AIs of 110 and 130 [mu]g/
day.
Studies conducted in populations with high environmental iodine
exposure have documented adverse thyroid outcomes in infants and young
children at elevated iodine intakes. A cross-sectional study documented
subclinical hypothyroidism in 7.4 percent and elevated thyroglobulin in
15.8 percent of participants 6-24 months of age in a population with
high environmental iodine exposure (Ref. 72). An observational study
found that high iodine intakes were associated with subclinical
hypothyroidism in 9 percent of children and elevated thyroglobulin in
13 percent at 3-year followup (Ref. 73).
The excess iodine exposures represented in these studies arise
primarily from environmental sources and supplementation rather than
from infant formula, and, in some cases, involve intake levels far
exceeding those achievable through formula feeding alone. The studies
were also conducted in populations with iodine exposure profiles
markedly different from typical U.S. infants, limiting direct
generalizability. Nevertheless, the thyroid and growth outcomes
observed across these populations provide useful context for
understanding the biological consequences of sustained elevated iodine
intake in early infancy, a period of particular vulnerability to
disruption of thyroid function (Ref. 61).
6. Evidence Evaluation and Rationale
a. Rationale for Increasing the Minimum Specification to 15 [mu]g/100
kcal
The current minimum specification of 5 [micro]g/100 kcal has not
been updated since 1985 (50 FR 45106, October 30, 1985) and is no
longer supported by more recently available scientific evidence. At
this level, an infant 0-6 months of age would receive only
approximately 26 [micro]g/day of iodine, representing 24 percent of the
NASEM AI of 110 [micro]g/day (Ref. 62) and 29 percent of the WHO RNI of
90 [micro]g/day (Ref. 65) (see table 7). An infant 6-12 months of age
would receive approximately 20 [micro]g/day at the current minimum,
representing 16 percent of the NASEM AI of 130 [micro]g/day and 23
percent of the WHO RNI of 90 [micro]g/day. Intakes at both age groups
fall below even the experimentally derived EAR of 72 [micro]g/day (Ref.
68), representing 37 percent and 28 percent of that threshold for
infants 0-6 months and 6-12 months of age, respectively, the most
conservative available estimate of average iodine requirement. The 1998
LSRO Panel also recommended a higher minimum of 8 [micro]g/100 kcal
based on the then-current RDA of 40 [micro]g/day for infants 0-6 months
of age (Ref. 1).
Table 7--Estimated Daily Iodine Intake at the Current and Proposed Minimum Specifications Expressed as a
Percentage of Nutrient Reference Values
----------------------------------------------------------------------------------------------------------------
Energy Estimated
intake from iodine
Typical infant formula intake \1\ infant intake % NASEM AI % WHO RNI % Balance % Balance
formula ([micro]g/ study EAR study RDA
(kcal/day) day)
----------------------------------------------------------------------------------------------------------------
Current Minimum Specification (5 [micro]g/100 kcal)
----------------------------------------------------------------------------------------------------------------
0-6 months............................ 527 26.3 24 29 37 33
6-12 months........................... 406 20.3 16 23 28 25
----------------------------------------------------------------------------------------------------------------
Proposed Minimum Specification (15 [micro]g/100 kcal)
----------------------------------------------------------------------------------------------------------------
0-6 months............................ 527 79.1 72 88 110 99
6-12 months........................... 406 60.9 47 68 85 76
----------------------------------------------------------------------------------------------------------------
Reference values used: NASEM AI: 110 [micro]g/day (0-6 months of age) and 130 [micro]g/day (6-12 months of age)
(Ref. 62); WHO RNI: 90 [micro]g/day (0-12 months of age) (Ref. 65); 2016 balance study EAR (proposed): 72
[micro]g/day; and 2016 balance study RDA (proposed): 80 [micro]g/day (Ref. 68).
\1\ Typical intake based on assumed formula consumption of 0.78 L/day (0-6 months of age) and 0.60 L/day (6-12
months of age) at 676 kcal/L.
[[Page 69055]]
FDA acknowledges that, at typical intake volumes, the proposed
minimum of 15 [micro]g/100 kcal does not fully meet the NASEM AI or WHO
RNI for either age group, reflecting a challenge of setting a minimum
specification for a nutrient with varying nutrient reference values
among expert bodies. The NASEM AIs are based on the mean intake from
human milk and are intended to reflect observed intakes in healthy
populations rather than a minimum requirement threshold. The proposed
minimum is intended to ensure an adequate iodine provision consistent
with the best available evidence on iodine requirements in infancy
(Ref. 61).
The current U.S. minimum of 5 [micro]g/100 kcal is the lowest of
any major regulatory jurisdiction. All other major international
regulatory frameworks have established minimums of 10 to 15 [micro]g/
100 kcal: Codex Alimentarius, FSANZ, and Health Canada specify a
minimum of 10 [micro]g/100 kcal, while the EU and China specify a
minimum of 15 [micro]g/100 kcal (table 6). The proposed minimum of 15
[micro]g/100 kcal aligns with the standards from the EU and China and
represents a scientifically supported improvement over the current U.S.
minimum.
Since the 1998 LSRO Panel report (Ref. 1), the evidence base has
expanded substantially (see Refs. 68, 69, 70, 74) and consistently
supports a minimum above the current 5 [micro]g/100 kcal (Ref. 61).
Additionally, a few comments in response to FDA's 2025 RFI on nutrient
requirements for infant formula express support for increasing the
minimum iodine level (90 FR 20475, May 14, 2025).
b. Rationale for Decreasing the Maximum Specification to 50 [micro]g/
100 kcal
The current FDA maximum of 75 [micro]g/100 kcal has not been
revised since 1985 (50 FR 45106, October 30, 1985). At this level, an
infant 0-6 months of age consuming a typical daily infant formula
intake would receive approximately 396 [micro]g/day of iodine, and an
infant 6-12 months of age consuming a typical daily infant formula
intake would receive approximately 305 [micro]g/day. These levels
substantially exceed upper levels of probable safe intake (Ref. 75), as
well as estimated intakes associated with subclinical thyroid
dysfunction in several applicable studies (Refs. 72, 73).
The limitations of the current maximum are further illustrated by
NHANES-derived estimates of energy intake from infant formula among
high consumers (Refs. 13, 14, 15, 16, 17, 18). At the 90th percentile
of energy intake from infant formula (836 kcal/day for infants 0-6
months of age and 794 kcal/day for infants 6-12 months of age), the
current maximum of 75 [micro]g/100 kcal would provide iodine intakes of
approximately 627 [micro]g/day and 596 [micro]g/day, respectively.
These findings reinforce the need for a significant downward
revision of the maximum specification, particularly given the absence
of a formal UL for infants and the linear iodine retention observed
across intake levels (Ref. 69). Because no UL has been established for
infants by any major international expert body (Ref. 62), the safety
margin between the current maximum and any established toxicity
threshold cannot be precisely quantified, a significant limitation that
further underscores the need for a decrease (Ref. 61).
As discussed in section V.E.5 of this document, other major
international regulatory frameworks have established GULs or maximums
substantially below the current U.S. maximum of 75 [micro]g/100 kcal:
Codex Alimentarius, FSANZ, Health Canada, and China specify a GUL or
maximum of 60 [micro]g/100 kcal, and the EU specifies a maximum of 29
[micro]g/100 kcal (table 6). In 1998, the LSRO Panel report explicitly
concluded that the current maximum of 75 [micro]g/100 kcal was too high
and recommended a maximum of 35 [micro]g/100 kcal based on the 75th
percentile of FDA analyses of marketed formulas at the time (Ref. 1).
The proposed maximum of 50 [micro]g/100 kcal represents a substantial
reduction from the current maximum and falls within international
consensus and available scientific evidence to reduce risk of excessive
exposure while allowing manufacturing flexibility.
Since the 1998 LSRO Panel report, several lines of evidence have
emerged that support reducing the maximum specification. A Technical
Consultation document noted that daily intakes exceeding 180 [micro]g/
day are not expected to provide additional health benefit and may be
associated with impaired thyroid function (Ref. 75). Consistent with
this, studies conducted in populations with high environmental iodine
exposure have documented adverse thyroid outcomes in infants and young
children at elevated iodine intakes (Refs. 72, 73). A balance study
(Ref. 68) further found that iodine retention was linear across all
intake levels up to 300 [micro]g/day, with no evidence of homeostatic
down-regulation (i.e., the body's ability to automatically reduce
absorption or increase excretion to prevent excess buildup) at higher
intakes, suggesting that infants do not have robust mechanisms to limit
iodine retention at high intakes and that higher formula iodine
concentrations may result in proportionally higher retention with
uncertain long-term consequences. FDA considers that these findings,
while derived from populations with environmental iodine excess rather
than formula-fed infants, provide the best available evidence for
understanding the biological consequences of sustained elevated iodine
intake in early infancy and collectively support a significant downward
revision of the maximum (Ref. 61).
At 50 [micro]g/100 kcal, an infant 0-6 months of age consuming a
typical daily infant formula intake would receive approximately 264
[micro]g/day of iodine, and an infant 6-12 months of age consuming a
typical daily infant formula intake would receive approximately 203
[micro]g/day of iodine. Among higher consumers, NHANES-derived
estimates of energy intake from infant formula indicate that, at the
90th percentile of energy intake from infant formula (836 kcal/day for
infants 0-6 months of age and 794 kcal/day for infants 6-12 months of
age), the proposed maximum of 50 [micro]g/100 kcal would permit iodine
intakes of approximately 418 [micro]g/day and 397 [micro]g/day,
respectively (Refs. 13, 14, 15, 16, 17, 18, 61).
FDA acknowledges that these intakes exceed 180 [micro]g/day, the
level above which additional health benefits are unlikely (Ref. 75);
however, they are below the probable safe upper limits of 150 [micro]g/
kg/day for infants 0-6 months of age (reference weight: 6 kg) and 140
[micro]g/kg/day for infants 7-12 months of age (reference weight: 8.9
kg). Using the reference weights identified in the report, these
correspond to absolute upper limits of approximately 900 [micro]g/day
and 1,246 [micro]g/day, respectively (Ref. 64). In populations with
excess environmental exposure to iodine, reports of subclinical
hypothyroidism in infants and young children have been documented
(Refs. 72, 73). However, the evidence from these studies is derived
from populations with environmental iodine excess rather than routine
feeding of formula-fed infants, and the generalizability of these
findings to U.S. formula-fed infants is uncertain. Because no UL has
been established for infants, the percentage of UL at the proposed
maximum cannot be calculated: a significant limitation that FDA
acknowledges. The proposed maximum reflects a conservative approach
based primarily on international regulatory alignment, rather than a
formally derived safety margin (Ref. 61).
[[Page 69056]]
F. Potassium
The current requirements for potassium in infant formula are a
minimum level of 80 mg/100 kcal and a maximum level of 200 mg/100 kcal
(Sec. 107.100). Based on our analysis of scientific information and
data since the 1998 LSRO Panel report (Ref. 1), including infant
formula potassium requirements in international standards, we conclude
that the required potassium levels in Sec. 107.100 remain appropriate.
1. Background
Potassium is an essential nutrient that serves critical
physiological functions in infants, including regulation of cell
volume, membrane transport, cardiac conduction, nerve signaling, and
muscle contraction (Ref. 76). Most of the potassium in the body is
found inside cells; potassium and sodium are interrelated and function
together across cell membranes to regulate cell volume and membrane
transport. Potassium also plays a role in regulating water and acid-
base balance in the blood and tissues (Ref. 76). Potassium metabolism
is tightly controlled over a wide range of dietary intakes, primarily
regulated via the kidneys. Assessing potassium status is difficult
because most potassium in the body resides inside cells, and no
sensitive biomarker exists that can characterize the distribution of
potassium requirements in healthy populations (Refs. 76, 77).
a. Health Consequences of Potassium Deficiency
Hypokalemia (i.e., low blood potassium; serum potassium <=3.5 mmol/
L) can result from inadequate intake, excessive losses, or
transcellular shifts in potassium. Hypokalemia from dietary inadequacy
alone is rare in healthy individuals because the kidney efficiently
conserves potassium at low dietary intakes (Ref. 77). Potassium
depletion studies conducted in adults over short periods have shown
that very low intakes (0-390 mg/day) can lead to hypokalemia.
Inadequate potassium intake may also contribute to impaired glycemic
control (Ref. 78). However, in clinical settings, hypokalemia is more
commonly caused by abnormal losses of potassium (renal or
gastrointestinal) or medications promoting transcellular shifts (Ref.
76).
b. Health Consequences of Excess Potassium Intake
In healthy individuals with normal kidney function, excess
potassium is efficiently excreted and toxicity from dietary sources is
unlikely. Hyperkalemia (i.e., high blood potassium) is of greater
concern in individuals with chronic kidney disease, diabetes, heart
failure, adrenal insufficiency, or those taking certain medications. In
addition, there is no evidence that high intakes of potassium cause
hyperkalemia or other adverse effects in adults with normal kidney
function (Ref. 77).
2. Nutrient Reference Values
a. NASEM
NASEM published DRIs for water, potassium, sodium, chloride, and
sulfate in 2005 and published an updated report specific to sodium and
potassium in 2019 (Refs. 19, 76). Because no EAR could be established
due to the absence of a sensitive biomarker of potassium status and
limitations in available balance study data, the committee established
AI values for potassium in infants based on estimated potassium intakes
from human milk (Ref. 76). The AI for infants 0-6 months of age was set
at 400 mg/day, derived by multiplying the average human milk intake
(0.78 L/day) by the average human milk potassium concentration (515 mg/
L) from a meta-analysis of 15 studies focusing on the first 6 months of
lactation. The AI for infants 7-12 months of age was set at 860 mg/day,
based on estimated intakes from human milk plus an estimated potassium
intake from complementary foods of approximately 600 mg/day, derived
from NHANES 2003-2010 and FITS 2016 data (Ref. 76). The AI for infants
0-6 months of age is unchanged from the 2005 DRI report, while the AI
for infants 7-12 months of age was increased from 700 mg/day (2005) to
860 mg/day (2019), reflecting updated estimates of complementary food
contributions (Refs. 19, 76).
No UL has been established for potassium in infants. The 2019 NASEM
committee concluded that ``there is insufficient evidence of potassium
toxicity risk within the apparently healthy population to establish a
potassium Tolerable Upper Intake Level (UL)'' (Ref. 76).
b. EFSA
The EFSA Panel established an AI of 750 mg/day for infants 7-11
months of age, extrapolated from the adult AI using isometric scaling
and a growth factor (Ref. 79). No AI was established for infants 0-6
months of age. The EFSA NDA Panel estimated an approximate midpoint
potassium concentration in mature human milk of 500 mg/L based on data
from multiple studies of women from Western countries (Ref. 79).
c. D-A-CH
The D-A-CH reference values established estimated values of 400 mg/
day for infants 0-4 months of age and 600 mg/day for infants 4-12
months of age. The authors based the 0-4-month estimate on an average
human milk intake of 750 mL/day and a mean potassium content of 500 mg/
L. They calculated the 4-12-month estimate by extrapolating from the
younger group's value and adjusting for differences in reference body
weight (Ref. 80).
d. Australian NHMRC/New Zealand MoH
NHMRC/MoH (2006) (Ref. 53) derived the AI for infants 0-6 months of
age as 400 mg/day, calculated by multiplying the average human milk
intake (0.78 L/day) by the average human milk potassium concentration
(500 mg/L). NHMRC/MoH derived an AI of 700 mg/day for infants 7-12
months of age, calculated by assuming an average 0.6 L/day of human
milk intake plus 440 mg/day from complementary foods.
e. Comparison of International Recommendations
Table 8 shows AIs of potassium for NASEM, D-A-CH, EFSA, and NHMRC/
MoH.
Table 5--Adequate Intakes and Tolerable Upper Intake Levels of Iodine
----------------------------------------------------------------------------------------------------------------
Age range Adequate intake Tolerable upper intake
Organization Year (months) (mg/day) level
----------------------------------------------------------------------------------------------------------------
NASEM........................... 2019 0-6 400 ND
7-12 860 ND
D-A-CH.......................... 2017 0-4 400 ND
4-12 600 ND
EFSA............................ 2016 7-11 750 ND
[[Page 69057]]
Australian NHMRC/New Zealand MoH 2006 0-6 400 ND
7-12 700 ND
----------------------------------------------------------------------------------------------------------------
There is consistency across international bodies in the AI
established for young infants (0-6 months of age). Divergence in AIs
for older infants (7-12 months of age) across international bodies is
primarily attributable to methodological differences in estimating
potassium intake from complementary foods. EFSA used a different
approach entirely, extrapolating from the adult AI using isometric
scaling rather than observed infant intake data.
3. Human Milk Composition
Maternal dietary intake does not strongly influence human milk
potassium concentrations (Ref. 76). Human milk potassium concentrations
decline over the course of lactation (Ref. 79). Four sources informed
the analysis of potassium concentrations in human milk: the 2019 NASEM
meta-analysis (Ref. 76), the 2016 EFSA NDA Panel review (Ref. 79), the
iHMNutD study (Ref. 8), and the MILQ study (Ref. 36).
In 2019, NASEM conducted a meta-analysis of 15 longitudinal and
cross-sectional studies (1980-2017) and estimated mean potassium
concentrations of 515 mg/L (95 percent confidence interval (CI):
472.76-557.81 mg/L) for the 0-6-month interval and 437 mg/L (95 percent
CI: 367.89-505.22 mg/L) for the 7-12-month interval (Ref. 76). The 2016
EFSA Panel reviewed data from eight studies (1982-2012) and derived an
estimate of approximately 500 mg/L as the midpoint concentration (Ref.
79). The iHMNutD study identified 10 eligible North American studies
(1980-2024; total n = 905) and estimated a weighted mean potassium
concentration of 573 <plus-minus> 75 mg/L (Ref. 8). Additionally, the
MILQ study, the most comprehensive recent data, reported a pooled
median of 542 mg/L (interquartile range (IQR): 485-609 mg/L) from 1 to
6 months of lactation (Ref. 36).
Across all four sources, central estimates of potassium
concentration in mature human milk ranged from approximately 500 to 573
mg/L (Refs. 8, 36, 76, 79). The NASEM estimate for human milk potassium
content for infants 7-12 months of age (437 mg/L) (Ref. 76) was notably
lower than the estimate for younger infants, consistent with the
expected decline in potassium concentration over the course of
lactation. While estimates derived from NASEM, EFSA, and the iHMNutD
study show a degree of consistency, this convergence should be
interpreted with some caution, as the three analyses draw from an
overlapping body of foundational literature, particularly studies
conducted in North American populations during the 1980s and 1990s
(Ref. 77). The MILQ study (Ref. 36) provides broader geographic
evidence consistent with the range of concentrations observed in North
American estimates.
4. International Regulatory Standards for Infant Formula
The current U.S. minimum requirement for potassium aligns with the
EU and meets or exceeds the minimum levels set by most other
international bodies. The U.S. maximum of 200 mg/100 kcal exceeds most
international standards, with only China's standard for infants 6-12
months of age (225 mg/100 kcal) surpassing it (see table 9).
In its 1998 comprehensive review, the LSRO Panel recommended a
potassium range of 60-160 mg/100 kcal for infants 0-12 months of age.
The recommended minimum was derived from the mean minus one standard
deviation of potassium concentrations in mature human milk, with no
evidence identified to suggest differences in potassium bioavailability
between human milk and infant formula. The recommended maximum of 160
mg/100 kcal was based on the 90th percentile of FDA analyses of
commercially available infant formulas at the time (Ref. 1).
Table 9 shows the requirements and recommendations of these
international regulatory bodies and organizations.
Table 9--International Standards and/or Recommendations for Potassium in Infant Formula
----------------------------------------------------------------------------------------------------------------
Age range Minimum (mg/100 Maximum (mg/100
Organization (months) kcal) kcal) Reference
----------------------------------------------------------------------------------------------------------------
U.S. Current Standards.............. 0-12 80 200 21 CFR 107.100.
LSRO \1\............................ 0-12 60 160 LSRO, 1998.
Codex Alimentarius.................. 0-12 60 180 CXS 72-1981, CXS 156-1987.
EU.................................. 0-12 80 160 Commission Delegated
Regulation (EU) 2016/127.
Australia \2\....................... 0-12 60 180 FSANZ P1028.
Canada \3\.......................... 0-12 60 180 Health Canada, 2025.
China............................... 0-6 70 180 GB 10765-2021.
6-12 75 225 GB 10766-2021.
----------------------------------------------------------------------------------------------------------------
\1\ Recommended ranges.
\2\ Values converted from per 100 kJ to per 100 kcal (1 kcal = 4.184 kJ).
\3\ Reflects proposed compositional requirements for infant formula.
5. Recent Scientific Evidence on Potassium Intake
Several U.S.-based national dietary surveys have assessed potassium
intake in U.S. infants and toddlers, consistently demonstrating that
most infants meet or exceed established AIs for potassium. Data are
available primarily from three iterations of FITS (FITS 2002, 2008, and
2016) (Refs. 43, 81, 82, 83) and from NHANES 2009-2012 (Ref. 84).
Mean potassium intakes for infants 0-6 months of age generally met
or exceeded the AI of 400 mg/day. Mean intakes ranged from
approximately 570 to 700 mg/day across datasets. At the 10th
percentile, intakes ranged from
[[Page 69058]]
approximately 387 to 414 mg/day across FITS 2008 and FITS 2016, close
to the AI, suggesting that most infants in this age group had potassium
intakes at or above the recommended level.
Mean potassium intakes for infants 7-12 months of age consistently
exceeded the current AI of 860 mg/day and ranged from approximately
1,085 to 1,225 mg/day across three FITS iterations and NHANES 2009-
2012. The 10th percentile of usual potassium intake ranged from
approximately 650 to 791 mg/day across available studies, falling below
the current AI of 860 mg/day. While most infants had adequate intakes,
a small proportion had intakes near or below the AI.
Several methodological limitations should be considered. Potassium
intake estimates rely on proxy-reported 24-hour dietary recalls subject
to recall bias. Human milk volumes were not directly measured but
estimated using standardized assumptions, and some analyses excluded
the youngest infants from intake modeling. The available data do not
include information on health outcomes associated with potassium intake
levels. As such, the extent to which current intakes translate to
clinical outcomes cannot be determined from these data alone (Ref. 77).
6. Evidence Evaluation and Rationale
Based on the review of available scientific data, information, and
international standards, we conclude that the current minimum level of
80 mg/100 kcal and maximum level of 200 mg/100 kcal for potassium in
Sec. 107.100 remain appropriate.
a. Maintaining the Minimum Specification of 80 mg/100 kcal
The current minimum of 80 mg/100 kcal is consistent with human milk
potassium concentrations and provides potassium intakes that meet or
exceed established AIs when applied to typical formula consumption
patterns. The most current estimates of human milk potassium
concentration range from approximately 77 to 88 mg/100 kcal (derived
from 500 to 573 mg/L at a typical energy density of 650 kcal/L) (Refs.
8, 36, 76, 77, 79). The current minimum falls within this range.
Applied to typical formula consumption patterns, the current
minimum provides potassium intakes that meet or exceed NASEM (2019) AIs
for both infant age groups. For an infant 0-6 months of age consuming a
typical daily infant formula intake, the minimum specification of 80
mg/100 kcal provides approximately 422 mg/day, which is 105 percent of
the AI of 400 mg/day. For an infant 7-12 months of age consuming a
typical daily infant formula intake, the minimum provides approximately
324 mg/day from formula alone. When combined with the estimated
complementary food contribution of approximately 600 mg/day (Ref. 76),
total intake would be approximately 920 mg/day, which is 107 percent of
the AI of 860 mg/day. These calculations demonstrate that the current
minimum supports adequate potassium intake across the first year of
life (Ref. 77).
Population intake data provide contextual support for maintaining
the current minimum. Across several large national surveys, mean
potassium intakes for infants 0-6 months of age ranged from
approximately 570 to 700 mg/day, and for infants 6-12 months of age
ranged from approximately 1,085 to 1,225 mg/day, with all mean
estimates exceeding the respective AIs (Refs. 43, 81, 82, 83, 84).
The current U.S. minimum is consistent with or above international
regulatory standards. FDA considered whether the minimum should be
lowered to 60 mg/100 kcal to align with Codex Alimentarius, FSANZ,
Health Canada, and LSRO; however, lowering the minimum to 60 mg/100
kcal would reduce the daily potassium intake from formula for infants
0-6 months of age to approximately 78 percent of the AI, reducing the
margin of adequacy for infants consuming formula as their sole source
of nutrition. Maintaining the current minimum of 80 mg/100 kcal is
supported by human milk composition data and U.S. population intake
data and falls within the range of minimums set by international
standards. FDA has not identified evidence that the current minimum is
nutritionally insufficient or presents manufacturing challenges.
b. Maintaining the Maximum Specification of 200 mg/100 kcal
The current maximum of 200 mg/100 kcal was originally established
based on the potassium content of cow milk, which was considered to
represent a significant but tolerable burden on the kidneys for healthy
infants with normal renal function (Ref. 85). After reviewing the
available scientific evidence, FDA concludes that this maximum remains
appropriate (Ref. 77).
No authoritative body has established a UL for potassium in infants
(Refs. 1, 76, 77, 79). However, the current maximum of 200 mg/100 kcal
has been in effect since the 1980 Infant Formula Act was enacted
without documented adverse effects attributable to potassium intake
from infant formula in healthy infants (Ref. 77).
The current maximum of 200 mg/100 kcal provides a substantial
margin above the potassium content of human milk (approximately 77-88
mg/100 kcal), positioned at approximately 227-260 percent of the mean
mature human milk potassium content on a per-calorie basis (Ref. 77).
Applied to typical infant formula daily consumption, the current
maximum would provide approximately 1,054 mg/day for an infant 0-6
months of age and approximately 812 mg/day from formula alone for an
infant 7-12 months of age. These intakes substantially exceed the AIs
but remain well below the levels associated with adverse effects in
healthy infants with normal renal function (Refs. 1, 77).
Internationally, maximum specifications range from 160 to 180 mg/
100 kcal for infants 0-6 months of age and up to 225 mg/100 kcal for
infants 6-12 months of age, with the U.S. maximum of 200 mg/100 kcal
falling within the upper portion of this range (see table 9). FDA
considered whether the maximum should be lowered to align with the
international consensus range and concludes that such a change is not
warranted at this time. No UL has been established for potassium in
infants, no documented adverse effects from dietary potassium intake at
the current maximum have been identified, and lowering the maximum
would reduce manufacturing flexibility without a demonstrated safety
benefit. The LSRO Panel's recommended maximum of 160 mg/100 kcal was
based on the 90th percentile of FDA analyses of infant formulas on the
market at that time, rather than on safety concerns (Ref. 1). FDA also
considered whether the maximum should be raised and concludes this is
not warranted. No evidence was identified suggesting that higher
potassium levels in infant formula would provide nutritional benefits
(Ref. 77).
c. Consideration of the Evidence Base
FDA acknowledges several uncertainties in the evidence base. No
sensitive biomarker of potassium status has been identified that can be
used to assess adequacy at the population level (Refs. 76, 79). The AIs
for infants are derived from observed intake data rather than
experimental determination of requirements, and the AI for infants 7-12
months of age is sensitive to assumptions about complementary food
contributions. Human milk potassium concentrations vary across studies,
stages of lactation, and populations. Population intake data are based
on proxy-reported dietary recalls not linked to health outcomes. Given
these limitations, FDA considers that
[[Page 69059]]
maintaining the current specifications, which have a demonstrated
history of safe use, is appropriate in the absence of compelling
evidence for change (Ref. 77).
G. Vitamin A (Proposed Sec. Sec. 107.10(a)(2), (b)(1), and 107.100(a)
and (g))
The current requirements for vitamin A in infant formula are a
minimum level of 250 IU/100 kcal (75 [mu]g RAE/100 kcal) and a maximum
level of 750 IU/100 kcal (225 [mu]g RAE/100 kcal) (21 CFR 107.100).
Based on our analysis of scientific information and data since the 1998
LSRO Panel report (Ref. 1), including infant formula vitamin A
requirements in international standards, we propose to decrease the
required minimum to 70 [mu]g RAE/100 kcal (233 IU/100 kcal) and
decrease the maximum specification to 120 [mu]g RAE/100 kcal (400 IU/
100 kcal) for vitamin A in infant formula in Sec. 107.100(a). We also
propose changes to the unit of measure from IU to [mu]g RAE in Sec.
107.10(a)(2), (b)(1), and Sec. 107.100(a). Finally, we propose to
change which forms of vitamin A may contribute to the minimum and
maximum vitamin A content calculations from both preformed vitamin A
and beta-carotene to preformed vitamin A only in newly established
Sec. 107.100(g).
1. Background
Vitamin A is a fat-soluble vitamin and essential nutrient that
supports vision, immune function, cell growth and differentiation, and
embryonic development (Ref. 86). These functions are especially
critical during infancy, a period of rapid growth and immune system
development. The term ``vitamin A'' encompasses preformed vitamin A
(i.e., retinol and retinyl esters) and provitamin A carotenoids such as
beta-carotene, which the body can convert to active vitamin A. Infants
are born with limited hepatic vitamin A stores even when mothers are
well-nourished during pregnancy, making adequate postnatal intake from
human milk or infant formula essential (Refs. 62, 86, 87, 88).
a. Factors Affecting Absorption
Preformed vitamin A absorption efficiency is generally 70-90
percent (Refs. 62, 87). However, exclusively formula-fed infants may
absorb vitamin A less efficiently than breastfed infants because bile-
salt-stimulated lipase (BSSL), which is present in human milk but
absent from infant formula, facilitates hydrolysis of retinyl esters.
Formula-fed infants rely solely on endogenous digestive enzymes for
this process (Ref. 1). Unlike preformed vitamin A, the absorption and
conversion of provitamin A carotenoids such as beta-carotene are far
more variable (5-65 percent), depending on factors such as the food
source, genetics, vitamin A status, and health status. The extent to
which infants can absorb and convert beta-carotene to active vitamin A
remains poorly understood (Refs. 62, 87, 89).
b. Health Consequences of Vitamin A Deficiency
Vitamin A deficiency (VAD) is a major public health concern in low-
and middle-income countries, affecting an estimated 190 million
preschool-age children globally (Ref. 90). Xerophthalmia is a well-
documented consequence of VAD, encompassing a spectrum of ocular
manifestations from night blindness to corneal ulceration and blindness
(Refs. 87, 88, 91). VAD is also associated with increased morbidity and
mortality from infectious diseases and impaired iron mobilization
contributing to anemia (Refs. 62, 87, 91). In the United States and
other high-income countries, clinical VAD is uncommon in healthy term
infants receiving adequate nutrition, though infants with fat
malabsorption disorders (e.g., cystic fibrosis, cholestatic liver
disease) are at elevated risk (Ref. 91).
c. Health Consequences of Excess Vitamin A Intake
Vitamin A is fat soluble and is stored primarily in the liver
(Refs. 62, 87). Excessive intake of preformed vitamin A can cause
hypervitaminosis A, a toxic condition caused by having too much vitamin
A in the body. Provitamin A carotenoids are not associated with
toxicity, because their absorption and conversion are downregulated at
high intakes (Ref. 89). Acute toxicity in infants may manifest as
bulging fontanelle, vomiting, irritability, and headache (Ref. 86).
Chronic toxicity symptoms may include fatigue, loss of appetite, hair
loss, bone pain, skin changes, and, in serious cases, liver damage,
decreased bone mineral density, and increased intracranial pressure. In
young children, doses as low as 450 [mu]g/kg/day have been reported to
cause hypervitaminosis A (Refs. 62, 88, 92).
2. Nutrient Reference Values
a. NASEM
NASEM established AIs for vitamin A in infants in 2001 based on the
mean vitamin A intake of infants fed human milk, as no functional
criteria of vitamin A status reflecting dietary response in infants
have been demonstrated. The AI for infants 0-6 months of age was set at
400 [mu]g RAE/day, derived from an average milk intake of 0.78 L/day
and average human milk vitamin A concentration of 485 [mu]g/L during
the first 6 months of lactation. The AI for infants 7-12 months of age
was set at 500 [mu]g RAE/day, based on extrapolation from the 0-6-month
AI plus estimated contributions from human milk and complementary
foods. NASEM did not consider contribution of carotenoids in human milk
in meeting the vitamin A requirement of infants (Ref. 61). The UL was
set at 600 [mu]g RAE/day for infants 0-12 months of age, derived from
case reports of hypervitaminosis A in infants, with a lowest observed
adverse effect level (LOAEL) of 6,000 [mu]g/day and an uncertainty
factor of 10 to account for the extrapolation from a LOAEL to a NOAEL.
NASEM acknowledged this UL was deliberately conservative (Ref. 62).
b. EFSA
The 2015 EFSA Panel derived dietary reference values for vitamin A
using a factorial approach (i.e., multiplying together a series of
known biological parameters) with pediatric-specific adjustments for
body weight, liver/body weight ratio, and growth, yielding a PRI of 250
[mu]g retinol equivalents (RE)/day for infants 7-11 months of age (Ref.
87). In 2024, EFSA proposed a UL of 600 [mu]g RE/day for all infants 4-
11 months of age, derived by allometric scaling from the adult UL (Ref.
89). EFSA noted that a UL of 500 [mu]g RE/day for infants 4-6 months of
age would be overconservative given that human milk secretion of
retinol is estimated at 424 [mu]g RE/day (midpoint concentration: 530
[mu]g/L x 0.8 L/day) during the first 6 months of lactation (Ref. 89).
c. Australian NHMRC/New Zealand MoH
NHMRC/MoH derived AIs for vitamin A in infants based on human milk
composition from a single multinational study (Ref. 53). The AI for
infants 0-6 months of age was set at 250 [micro]g retinol/day (as
retinyl esters), based on an average human milk intake of 0.78 L/day
and a retinol concentration of 310 [micro]g/L. The AI for infants 7-12
months of age was set at 430 [micro]g RE/day, based on an average human
milk intake of 0.6 L/day (approximately 186 [micro]g RE/day), plus an
estimated 244 [micro]g RE/day from complementary foods (including
vitamin A from retinol and carotenoids). The UL for infants 0-12 months
of age was set at 600 [micro]g RE/day, derived from case reports of
hypervitaminosis A in infants (Ref. 53).
[[Page 69060]]
d. FAO/WHO
The joint FAO/WHO Consultation estimated vitamin A requirements for
infants from observed retinol intakes of breastfed infants in
communities with good nutrition and no signs of deficiency (Ref. 3).
Notably, due to insufficient data to derive mean requirements for any
age group, the Consultation provided ``recommended safe intakes''
rather than true RNIs. The recommended safe intake for infants 0-6
months of age was set at 375 [micro]g RE/day, based on an average human
milk retinol concentration of approximately 1.75 [micro]mol/L (503
[micro]g/L x 0.75 L/day). The recommended safe intake for infants 7-12
months of age was increased to 400 [micro]g RE/day, accounting for a
decline in average milk intake to 0.65 L/day and increased mortality
risk in vitamin A-deficient populations from 6 months of age onward
(Ref. 3).
e. Comparison of International Recommendations
Table 10 shows the vitamin A AIs established by NASEM, EFSA, NHMRC/
MoH, and FAO/WHO.
Table 10--Vitamin A Nutrient Reference Values
--------------------------------------------------------------------------------------------------------------------------------------------------------
Type of
Organization Year Type of reference Age range Value (per day) reference Age range Value (per day)
intake (months) intake (months)
--------------------------------------------------------------------------------------------------------------------------------------------------------
NASEM......................... 2001............. AI............... 0-6 400 [micro]g RAE UL............ 0-12 600 [micro]g
7-12 500 [micro]g RAE RAE.
EFSA.......................... 2015 (PRI)....... PRI.............. 4-6 ND.............. UL............ 4-11 600 [micro]g RE.
2024 (UL)........ 7-11 250 [micro]g RE.
Australian NHMRC/New Zealand 2006............. AI............... 0-6 250 [micro]g UL............ 0-12 600 [micro]g RE.
MoH. 7-12 retinyl esters.
430 [micro]g RE.
FAO/WHO....................... 2004............. Recommended Safe 0-6 375 [micro]g RE. UL............ .............. ND.
Intake. 7-12 400 [micro]g RE.
--------------------------------------------------------------------------------------------------------------------------------------------------------
1 [micro]g RE = 1 [mu]g retinol + 6 [mu]g [szlig]-carotene + 12 [mu]g other pro-vitamin A carotenoids.
1 [micro]g RAE = 1 [mu]g retinol + 12 [mu]g [szlig]-carotene + 24 [mu]g other pro-vitamin A carotenoids.
Authoritative bodies differ fundamentally on whether infant vitamin
A requirements should be derived from observed intakes from human milk
or through a factorial approach. NASEM (Ref. 62), FAO/WHO (Ref. 3), and
NHMRC/MoH (Ref. 53) all used human milk composition, but the wide
variation in mean retinol concentrations across studies explains why
these bodies arrived at different values despite using the same general
approach. None of the bodies reviewed incorporated provitamin A
carotenoid contributions from human milk into reference values for
infants 0-6 months of age due to unknown bioconversion efficiency in
this age group. With respect to ULs, NASEM, NHMRC/MoH, and EFSA
converged on 600 [micro]g RAE/day or 600 [micro]g RE/day despite
different derivation methods, strengthening confidence in this value
for evaluating maximum levels (Ref. 86).
FDA believes the NASEM AIs are the most appropriate choice for
assessing minimum vitamin A requirements in infant formula, as they
represent the most conservative estimates and best ensure that infant
nutritional needs are met (Ref. 86).
3. Human Milk Composition
Vitamin A in human milk is present almost exclusively as retinyl
esters in the lipid fraction of the milk (Ref. 93). Retinol
concentration is highly dependent on fat content, is substantially
higher in colostrum than in mature milk, and reflects both maternal
vitamin A status and recent dietary intake (Ref. 93).
Three primary data sources inform FDA's assessment of vitamin A
concentrations in mature human milk. These sources were selected based
on recent publication dates, robust study designs, validated analytical
methods, and inclusion of healthy, full-term mother-infant dyads (Ref.
86). A 2022 meta-analysis pooled data from 76 studies that used high-
performance liquid chromatography-based retinol measurements totaling
9,171 samples across 33 geographically diverse countries (Ref. 94).
Studies involving vitamin A supplementation were excluded. Country was
identified as a significant source of variance (Ref. 94). The authors
proposed the mean early mature milk concentration of 402.4 [mu]g/L as
the reference concentration for DRI revision in infants up to 6 months
of age (Ref. 94). The MILQ study (Ref. 95) provides the most
comprehensive recent data on retinol concentrations in human milk using
validated analytical methods from well-nourished, unsupplemented
populations across four countries. Median milk retinol concentrations
were highest in early lactation (886 [micro]g/L) and stabilized from 3
months onward (450-460 [micro]g/L) (Ref. 95). The iHMNutD study
reported a pooled weighted mean of 36.09 [micro]g/100 g (approximately
372 [micro]g/L) (Ref. 8); however, this value was based on a limited
number of studies and participants, introducing uncertainty (Ref. 8).
FDA acknowledges several limitations relevant to the estimates from
human milk studies that introduce uncertainty in cross-study
comparisons, including small sample sizes, geographic variability,
inconsistent collection protocols, and the absence of milk fat
adjustment for retinol concentrations (see Ref. 86). Notwithstanding
this, FDA considers that these three sources support a plausible range
of approximately 370-460 [mu]g/L (approximately 57-71 [mu]g RAE/100
kcal) as the best current estimate of vitamin A concentration in mature
human milk, with higher concentrations observed in early mature milk.
This range informs FDA's proposed minimum vitamin A specification in
infant formula.
4. International Regulatory Standards for Infant Formula
Vitamin A specifications for infant formula vary among
international regulatory bodies and expert organizations, though most
have adopted or proposed to adopt specifications that generally align
with Codex Alimentarius standards (see table 11). The Codex
Alimentarius specifies a minimum of 60 [mu]g RE/100 kcal and a maximum
of 180 [mu]g RE/100 kcal for infant formula (for infants 0-6 months of
age) (Ref. 12). For follow-on formula (for infants 6-12 months of age),
Codex Alimentarius specifies a higher minimum of 75 [mu]g RE/100 kcal
with the same maximum (Ref. 37).
FSANZ and Health Canada specify the same maximum as Codex
[[Page 69061]]
Alimentarius but do not specify a higher minimum for infants 6-12
months of age, maintaining 60 [mu]g RE/100 kcal for infants 0-12 months
of age (Refs. 39, 40). The EU and China have higher minimums and/or
lower maximums than Codex Alimentarius. The EU, based on
recommendations from EFSA (Ref. 7), specifies a minimum of 70 [mu]g RE/
100 kcal and a maximum of 114 [mu]g RE/100 kcal, applicable to both
infant formula and follow-on formula (Ref. 38). The EU minimum of 70
[mu]g RE/100 kcal was set to ensure that infants consuming
approximately 500 kcal/day receive at least 350 [mu]g RE/day (Ref. 7).
The EU reduced the maximum from 180 [mu]g RE/100 kcal to 114 [mu]g RE/
100 kcal (Ref. 96), resulting in a daily vitamin A intake of
approximately 570 [mu]g RE/day (assuming 500 kcal/day), just under the
UL of 600 [mu]g RE/day. China also specifies a lower maximum of 150
[mu]g RE/100 kcal for infant formula (Ref. 41), although the maximum
for follow-on formula is consistent with Codex Alimentarius (Ref. 42).
The LSRO Panel report recommended a minimum preformed vitamin A
content of infant formulas of 60 [mu]g RE/100 kcal and a maximum of 150
[mu]g RE/100 kcal (Ref. 1), noting that a minimum above the estimated
vitamin A concentration in human milk (approximately 30 [mu]g RE/100
kcal) was appropriate to account for lower absorption efficiency in
formula-fed infants due to the absence of BSSL (Refs. 1, 86).
Table 11 shows the requirements and recommendations of these
international bodies and organizations.
Table 11--International Standards and/or Recommendations for Vitamin A in Infant Formula
----------------------------------------------------------------------------------------------------------------
Minimum Maximum
Organization Age range ([micro]g RE/ ([micro]g RE/ Permitted Reference
(months) 100 kcal) 100 kcal) sources
----------------------------------------------------------------------------------------------------------------
U.S. Current Standards \1\ 0-12 75 (250 IU).... 225 (750 IU)... Preformed 21 CFR 107.100.
\2\. retinol:
retinol,
retinyl
acetate,
retinyl
palmitate (21
CFR 184.1930).
Beta-carotene
may be used in
infant formula
as a source of
vitamin A (21
CFR 184.1245).
LSRO \3\.................... 0-12 60............. 150............ Preformed LSRO, 1998.
vitamin A.
Codex Alimentarius.......... 0-6 60............. 180............ Preformed CXS 72-1981.
6-12 75............. 180............ retinol, while CXS 156-1987.
any contents
of carotenoids
should not be
included in
the
calculation
and
declaration of
vitamin A
activity.
EU.......................... 0-12 70............. 114............ Preformed Commission
vitamin A. Delegated
Regulation
(EU) 2016/127.
Australia \4\............... 0-12 59............. 180............ Retinol: FSANZ P1028.
vitamin A
(retinol),
vitamin A
acetate
(retinyl
acetate),
vitamin A
palmitate
(retinyl
palmitate),
retinyl
propionate.
Provitamin A:
beta-carotene.
Canada \5\.................. 0-12 60............. 180............ Retinol Health Canada,
contents shall 2025.
be provided by
preformed
retinol, while
any contents
of carotenoids
should not be
included in
the
calculation
and
declaration of
vitamin A.
China....................... 0-6 60............. 150............ Vitamin A only GB 10765-2021.
6-12 months 75............. 180............ includes GB 10766-2021.
preformed
retinol, and
does not
include any
carotene
components
when vitamin A
is calculated
and claimed.
----------------------------------------------------------------------------------------------------------------
\1\ Values converted from international units (1 IU = 0.3 [micro]g RAE). See Section V.G.6.a, ``Rationale for
Changing the Unit of Measure from IU to [micro]g RAE,'' for additional information on RE and RAE conversions.
\2\ Vitamin A content may also be declared on the label in units of [micro]g RE--when these declarations are
made, they shall appear in parentheses immediately following the declarations in IU (21 CFR 107.10(b)(1)).
\3\ Recommended ranges.
\4\ Values were converted from per 100 kJ to per 100 kcal (1 kcal = 4.184 kJ).
\5\ Reflects proposed compositional requirements for infant formula.
5. Recent Scientific Evidence on Vitamin A Intake
Several U.S.-based national dietary surveys have assessed vitamin A
intake in U.S. infants and toddlers, including the FITS (FITS 2008 and
FITS 2016) and NHANES (NHANES 2009-2012 and NHANES 2015-2020) (Refs.
81, 82, 84, 86, 97). Mean intakes for infants 0-6 months of age ranged
from approximately 582 to 637 [mu]g RAE/day, and for infants 6-12
months of age from approximately 669 to 794 [mu]g RAE/day. Preformed
vitamin A constituted 88 percent of total vitamin A intake for infants
0-6 months of age and 74 percent for infants 6-12 months of age, with
the remainder derived from provitamin A carotenoids (Ref. 97). The
proportion of infants with vitamin A intakes exceeding the UL ranged
from 21 to 39 percent depending on study and age group (Refs. 81, 82,
84).
Important methodological differences must be considered when
interpreting these data. Treatment of human milk varies substantially
across studies. NHANES-based analyses exclude or cannot quantify human
milk contributions, while FITS-based analyses estimate them through
imputation. Infant dietary supplement inclusion differs across studies,
and supplement use was reported in 8.8-23 percent of infants (Refs. 81,
82). Finally, carotenoid-derived vitamin A is disaggregated from
preformed vitamin A only in one available study (Ref. 97), limiting
comparisons of retinol versus carotenoid contributions.
Overall, the available studies support the conclusion that current
vitamin A intakes in U.S. infants are adequate and that a significant
proportion have
[[Page 69062]]
intakes approaching or exceeding the UL. It should be noted, however,
that the available dietary intake data do not include information on
health outcomes associated with vitamin A intake levels (Ref. 86).
6. Evidence Evaluation and Rationale
Based on the review of available scientific data, information, and
international standards, we propose to decrease the current minimum
specification for vitamin A from 75 to 70 [mu]g RAE/100 kcal and to
decrease the current maximum specification for vitamin A from 225 to
120 [mu]g RAE/100 kcal in Sec. 107.100. We also propose a change to
the unit of measure for vitamin A in Sec. Sec. 107.10(a)(2) and (b)(1)
and 107.100 from IU to [mu]g RAE. Finally, we propose a change to the
form of vitamin A that may be used to meet the minimum and maximum
vitamin A specifications in Sec. 107.100 from both preformed vitamin A
and beta-carotene to preformed vitamin A only in Sec. 107.100(g) (see
table 11).
a. Rationale for Changing the Unit of Measure From IU to [micro]g RAE
Expert scientific bodies recommend expressing vitamin A intake in
[micro]g RAE rather than IU, as these weight-based units more
accurately reflect the differing bioavailability and bioconversion of
preformed vitamin A and provitamin A carotenoids. This approach has
been widely adopted in dietary reference values and infant formula
vitamin A specifications (tables 10 and 11). In the United States,
vitamin A was expressed in RE in the 1989 National Research Council
Recommended Dietary Allowances (Ref. 44). An RE is a standardized unit
that captures how much bioavailable vitamin A the body derives from
dietary sources. The RAE unit was introduced by the U.S. DRI Committee
on vitamin A (Ref. 62) to reflect updated evidence on the
bioavailability of provitamin A carotenoids. Under the RE system, 6
[mu]g of beta-carotene was considered equivalent to 1 [mu]g of retinol;
under the RAE system, 12 [mu]g of beta-carotene is required to yield 1
[mu]g of retinol, meaning that the vitamin A activity attributed to
provitamin A carotenoids is half the amount obtained when expressed in
[mu]g RAE compared to [mu]g RE. Because preformed retinol contributes
equally under both systems (1 [mu]g retinol = 1 [mu]g RE = 1 [mu]g
RAE), the practical effect of this change is that total vitamin A
intake estimates are lower when carotenoid contributions are calculated
using [mu]g RAE rather than [mu]g RE. The IOM recommended expressing
vitamin A requirements in [mu]g RAE rather than [mu]g RE or IU to more
accurately reflect the bioavailability of vitamin A from mixed diets
and, accordingly, established the AIs for infants in [mu]g RAE (Ref.
86).
In the United States, when included voluntarily on food (other than
infant formula) and dietary supplement labels, vitamin A is declared in
[micro]g RAE following the recommendation from the NASEM Labeling
Committee that the units of measure be consistent with the DRI (81 FR
33742 at 33912, May 27, 2016); 21 CFR 101.9(c)(8)(iv)) (Ref. 98). We
are therefore proposing to change the units of measure for vitamin A in
infant formula from IU to [micro]g RAE, for consistency with both the
DRI and U.S. nutrition labeling regulations for other foods. We believe
this proposed change will benefit consumers, as it aligns the unit of
measure for vitamin A in infant formula with that already used for
general food and dietary supplement labeling in the United States, as
well as infant formula labeling outside the United States. The IU may
be voluntarily declared in parentheses immediately following the
declaration in [micro]g RAE, providing infant formula manufacturers
with flexibility and supporting continuity for consumers accustomed to
IU-based labeling. This change would also be more aligned with
international regulatory standards. If only preformed vitamin A is
permitted to meet the vitamin A requirement in infant formula, the
adoption of [micro]g RAE would not create a discrepancy with
international organizations that use [micro]g RE, since 1 [micro]g RAE
= 1 [micro]g RE = 1 [micro]g all-trans-retinol. The three units are
numerically equivalent when applied solely to preformed retinol. FDA
has developed a guidance document that provides detailed instructions
to assist manufacturers in converting from IU to [micro]g RAE (Ref.
99).
b. Rationale for Allowing Only Preformed Vitamin A To Meet Vitamin A
Specifications
Current U.S. regulation allows beta-carotene to be used in infant
formula as a source of vitamin A (Sec. 184.1245 (21 CFR 184.1245)).
Other international expert bodies, aside from FSANZ, allow only
preformed vitamin A as a source of vitamin A in infant formula (table
11). In its 1998 assessment, the LSRO recommended using only preformed
vitamin A to meet the minimum requirements in infant formula (Ref. 1).
NASEM did not include beta-carotene contributions when establishing the
AI for vitamin A for infants because the bioconversion of carotenoids
in milk and in infants is not known (Ref. 62). Because the efficiency
with which infants convert beta-carotene to active vitamin A is
unknown, relying on beta-carotene as a source of vitamin A in infant
formula may put infants at risk of vitamin A deficiency if the assumed
conversion does not occur as expected. Additionally, only preformed
retinols are considered when establishing the UL for vitamin A, as
provitamin A carotenoids are not known to cause vitamin A toxicity
(Ref. 62). Thus, excluding beta-carotene from the calculated vitamin A
content of infant formula would not increase the risk of vitamin A
toxicity (Ref. 1, 62, 86). Therefore, FDA is proposing to amend Sec.
107.100 to specify that vitamin A minimum and maximum levels must be
met through preformed vitamin A only. Beta-carotene, if used in infant
formula, shall not be considered to contribute to the required minimum
and maximum levels of vitamin A in infant formula (proposed Sec.
107.100(g)).
The use of beta-carotene in infant formula is addressed in Sec.
184.1245(c)(2). FDA proposes to amend Sec. 184.1245(c)(2) to list
infant formula among the foods in which beta-carotene may be used at
levels not to exceed current good manufacturing practice.
c. Decreasing the Minimum Specification From 75 [micro]g RAE/100 kcal
to 70 [micro]g RAE/100 kcal
The proposed minimum specification of 70 [micro]g RAE/100 kcal is
supported by DRIs, human milk composition data, bioavailability
considerations, manufacturing feasibility, and international standards,
and provides an appropriate margin of nutritional adequacy for formula-
fed infants. FDA relies on NASEM AIs as the most appropriate and
conservative reference values for vitamin A requirements in infant
formula. Notably, the AI is not equivalent to a minimum requirement,
but rather it represents an intake assumed to be adequate based on
observed intakes in healthy, breastfed infants (Ref. 62). At the
proposed minimum, an infant 0-6 months of age consuming a typical daily
infant formula intake would receive 369 [mu]g RAE/day (92 percent of
the NASEM AI of 400 [mu]g RAE/day). For infants 6-12 months of age
consuming a typical daily infant formula intake, the proposed minimum
would provide 284 [mu]g RAE/day from formula. NASEM estimated that
complementary foods provide approximately 244 [mu]g/day, yielding a
combined intake of approximately 528 [mu]g/day (106 percent of the
NASEM AI of 500 [mu]g RAE/day). FDA considers this level of intake
adequate to meet the vitamin A needs of formula-fed infants 0-12 months
of age, with a low risk of deficiency (Ref. 86).
[[Page 69063]]
Human milk composition data from multiple studies (Refs. 8, 94, 95)
support a plausible range of approximately 370 to 460 [mu]g retinol/L
in mature human milk, corresponding to approximately 57 to 71 [mu]g
RAE/100 kcal. The proposed minimum of 70 [mu]g RAE/100 kcal falls at
the upper end of this range, indicating that formula-fed infants
consuming formula at the proposed minimum would receive vitamin A at
concentrations consistent with mature human milk from well-nourished
populations. The proposed minimum also exceeds the LSRO recommendation
of 60 [mu]g RE/100 kcal and provides a buffer to account for
potentially lower vitamin A absorption from formula due to the absence
of BSSL (Ref. 86).
Lowering the minimum from 75 to 70 [mu]g RAE/100 kcal also responds
to manufacturing feasibility considerations. Manufacturers must account
for nutrient degradation over shelf life, lot-to-lot variability in raw
material potency, and inherent variation in blending and manufacturing
processes when formulating infant formulas. In conjunction with the
proposed maximum of 120 [mu]g RAE/100 kcal, a minimum of 75 [mu]g RAE/
100 kcal would create an allowable manufacturing range of only 45 [mu]g
RAE/100 kcal. Reducing the minimum to 70 [mu]g RAE/100 kcal widens this
range to 50 [mu]g RAE/100 kcal without compromising nutritional
adequacy, reducing the risk of unintentional noncompliance during
manufacturing (Ref. 86).
The proposed minimum of 70 [micro]g RAE/100 kcal aligns with the EU
minimum of 70 [micro]g RE/100 kcal (Ref. 38); exceeds the Codex
Alimentarius minimum for infant formula, the FSANZ minimum, the Health
Canada proposed minimum, and the LSRO recommendation (all 60 [micro]g
RE/100 kcal) (Refs. 1, 12, 39, 40); and falls modestly below the Codex
Alimentarius minimum for follow-on formula (75 [micro]g RE/100 kcal)
(Ref. 37). FDA's use of the NASEM AI as the primary reference value for
assessing minimum requirements is consistent with the higher U.S.
minimum relative to some international standards (Ref. 86).
FDA assesses that 70 [micro]g RAE/100 kcal is consistent with
available data on nutritional adequacy and appropriate as a minimum
specification. At this level, estimated intakes for infants 0-6 months
of age represent approximately 92 percent of the NASEM AI, within the
15 percent margin below the AI that has been used by other regulatory
bodies to indicate low risk of nutritional inadequacy (Ref. 100).
d. Decreasing the Maximum Specification From 225 to 120 [micro]g RAE/
100 kcal
FDA's evaluation of the maximum is guided by the NASEM UL of 600
[mu]g RAE/day for infants 0-12 months of age (Ref. 62), which is also
supported by EFSA (Ref. 89) and NHMRC/MoH (Ref. 53). The NASEM UL was
derived by applying an uncertainty factor of 10 to a LOAEL of 6,000
[micro]g/day, identified from case reports of hypervitaminosis A in
infants receiving supplemental preformed vitamin A.
At the current maximum of 225 [mu]g RAE/100 kcal, estimated vitamin
A intakes from infant formula substantially exceed the UL across all
intake scenarios evaluated. U.S. dietary intake data from multiple
national surveys consistently show that mean vitamin A intakes approach
or exceed the UL and that 21-39 percent of infants have intakes above
the UL (Refs. 81, 82, 84, 97). The current maximum also exceeds that of
all other international regulatory standards, none of which permit a
maximum above 180 [mu]g RE/100 kcal.
FDA initially considered a maximum of 180 [mu]g RAE/100 kcal,
consistent with the Codex standard. However, at typical intake volumes,
a maximum of 180 [mu]g RAE/100 kcal would still result in estimated
intakes from infant formula alone reaching 158 percent and 122 percent
of the UL for infants 0-6 and 7-12 months of age, respectively, and as
high as 251 percent and 238 percent of the UL among high consumers
(90th percentile of energy intake from infant formula) (Refs. 13, 14,
15, 16, 17, 18). EFSA found that regular consumption of infant formula
at the previously permitted maximum of 180 [mu]g RE/100 kcal would
result in intakes exceeding the UL (Ref. 7). In the interest of
maintaining an adequate safety margin, particularly for high consumers
of infant formula, FDA proposes a lower maximum of 120 [mu]g RAE/100
kcal.
At the proposed maximum of 120 [mu]g RAE/100 kcal, estimated
vitamin A intakes from infant formula at typical volumes represent 106
percent and 81 percent of the UL for infants 0-6 and 7-12 months of
age, respectively. Among high consumers (90th percentile of energy
intake) (Refs. 13, 14, 15, 16, 17, 18), estimated intakes from infant
formula alone reach 167 percent and 159 percent of the UL for the 0-6-
month and 7-12-month age groups, respectively. While intakes exceed the
UL under higher intake scenarios, the safety margin relative to the
LOAEL improves substantially from approximately 2.9- to 3.2-fold at the
current maximum to approximately 4.9- to 9.5-fold at the proposed
maximum.
FDA acknowledges that no available data suggest that routine intake
of infant formula at current vitamin A levels is associated with
adverse events, and that U.S. dietary intake studies did not assess
health outcomes associated with vitamin A intake levels (Refs. 81, 82,
84, 86, 97). Nevertheless, FDA considers it appropriate to limit
unnecessary exposure to preformed vitamin A above the UL, particularly
among high consumers.
The proposed maximum of 120 [micro]g RAE/100 kcal falls within the
range of international maximum specifications, which extend from 114
[micro]g RE/100 kcal (EU) to 180 [micro]g RE/100 kcal (Codex
Alimentarius, Health Canada, and FSANZ) (Refs. 12, 37, 39, 40) and is
below the LSRO recommendation of 150 [micro]g RE/100 kcal (Ref. 1). The
proposed maximum of 120 [micro]g RAE/100 kcal is higher than the
corresponding EU specification of 114 [micro]g RE/100 kcal. This range
is intended to provide manufacturers with sufficient operational
flexibility to account for manufacturing overages, nutrient losses
during processing, and shelf-life variability while ensuring
appropriate vitamin A intakes across the U.S. infant population. FDA
acknowledges that, despite a reduction of more than 46 percent from the
current maximum, estimated vitamin A intakes among high consumers of
infant formula may continue to exceed the UL at the proposed maximum.
The safety margin relative to the LOAEL ranges from approximately 4.9-
to 9.5-fold across intake scenarios evaluated (Ref. 86).
FDA acknowledges several important uncertainties in the evidence
base underlying the proposed specifications for vitamin A in infant
formula. The NASEM AI and UL were each derived from a limited number of
studies with few participants, and the UL was deliberately set
conservatively using a LOAEL rather than a NOAEL (Ref. 62). Human milk
retinol concentrations vary substantially across studies, reflecting
the influence of lactation stage, milk fat content, maternal vitamin A
status, and geographic differences in diet and supplementation
practices. The efficiency of vitamin A absorption from infant formula
relative to human milk has not been precisely quantified, and the
bioconversion efficiency of beta-carotene in infants remains unknown
(Refs. 62, 95). Finally, none of the available U.S. dietary intake
studies assessed health outcomes associated with vitamin A intake
levels, limiting the ability to assess health outcomes at current
intake levels. Given these
[[Page 69064]]
uncertainties, FDA has taken a conservative approach by only slightly
decreasing the current minimum to preserve the margin of nutritional
adequacy and implementing a large reduction in the maximum that is
supported by the available safety evidence and falls within the range
of current international maximum specifications (Ref. 86).
H. Sodium
The current requirements for sodium in infant formula are a minimum
level of 20 mg/100 kcal and a maximum level of 60 mg/100 kcal (Sec.
107.100). Based on our analysis of scientific information and data
since the 1998 comprehensive study of infant formula nutrients,
including infant formula sodium requirements in international
standards, we conclude that the required sodium levels in Sec. 107.100
remain appropriate.
1. Background
Sodium is an essential nutrient. It plays a critical role in
regulating extracellular fluid volume and blood pressure homeostasis,
and it is important for the absorption of amino acids, small peptides,
and monosaccharides (Refs. 76, 101, 102). Together with chloride and
potassium, sodium maintains osmotic and acid-base balance between
intracellular and extracellular compartments and is necessary for
transporting solutes across membranes and generating electrical signals
in the musculoskeletal and nervous systems (Refs. 101, 102, 103).
Sodium also interacts with calcium, as increasing sodium intake has
been shown to increase urinary calcium excretion, which may negatively
affect bone health (Refs. 76, 101, 102). Approximately 95 percent of
total body sodium is extracellular, and the body absorbs approximately
98 percent of dietary sodium consumed across a wide range of intakes
(Refs. 76, 101, 102). There is no sensitive or specific biomarker for
sodium status, as blood sodium concentrations are tightly controlled by
homeostatic mechanisms (Refs. 76, 101, 102).
a. Health Consequences of Sodium Deficiency
Hyponatremia, defined as a sodium concentration in the blood less
than or equal to 135 mmol/L, is rarely due to dietary sodium intake;
rather, it is typically due to disturbances in free water balance and
the hormonal regulation of that balance (Refs. 76, 101, 102). Low
dietary sodium intakes are rare in healthy populations because sodium
chloride and other sodium salts are ubiquitous in the food supply.
Sodium intakes of infants who participated in the 2002 FITS exceeded
the AIs (Ref. 43). There are also adaptive physiological mechanisms
that reduce sodium losses in urine, feces, and sweat at low intakes,
and the term-newborn kidney has sufficient renal absorption and
excretion capabilities to minimize obligatory sodium losses (Refs. 1,
76, 101, 102).
b. Health Consequences of Excess Sodium Intake
Hypernatremia, defined as a blood sodium concentration greater than
145 mmol/L, is typically a consequence of dehydration rather than
excessive sodium intake (Ref. 76). In adults, excessive sodium intake
has been linked to elevated blood pressure and increased risk of
cardiovascular disease (Refs. 76, 101, 102). It has been suggested that
sodium intake during infancy may influence future blood pressure and
taste preferences for sodium; however, the current evidence is
insufficient to establish an upper limit of intake for this age group,
and more research is needed (Refs. 76, 101, 102).
2. Nutrient Reference Values
a. NASEM
NASEM updated AIs for sodium in infants in its 2019 report, Dietary
Reference Intakes for Sodium and Potassium (Ref. 76). The AI for
infants 0-6 months of age was set at 110 mg/day, based on an estimated
mean human milk sodium concentration of 140 mg/L and an assumed average
consumption of 0.78 L/day. The AI for infants 7-12 months of age was
set at 370 mg/day, based on approximately 70 mg/day from human milk (at
110 mg/L and 0.6 L/day) plus an estimated 300 mg/day from complementary
foods. No UL was established for sodium in infants. In 2019, NASEM
expanded its DRI model toward establishing DRIs based on chronic
disease risk reduction intakes (CDRRs); however, NASEM was unable to
establish a CDRR for infants. The absence of a sodium UL reflects an
evolution in the DRI model's approach to characterizing risk rather
than a change in the evidence regarding risks associated with excessive
sodium intake (Refs. 76, 102).
b. EFSA
EFSA published a comprehensive scientific opinion on dietary
reference values for sodium in 2019 (Ref. 101). Because insufficient
data existed from which an AR could be derived, EFSA established an AI
of 200 mg/day for infants 7-11 months of age based on upward
extrapolation of the estimated sodium intake of exclusively breastfed
infants during the first 6 months of life (midpoint sodium
concentration of 150 mg/L and assumed milk transfer of 0.8 L/day = 120
mg/day), adjusted using the ratio of average energy requirements for
infants 3 and 9 months of age. EFSA did not establish an AI for infants
0-6 months of age due to insufficient data. No UL was established for
sodium in infants (Ref. 101).
c. D-A-CH
In 2017, D-A-CH established estimated values for sodium intake of
130 mg/day for infants 0 to under 4 months of age based on a mean
mature human milk sodium concentration of 170 mg/L and an assumed
average daily intake of 750 mL of human milk. For infants 4 months to
under 12 months of age, the estimated value of 200 mg/day was derived
from the 0-4-month value adjusted for differences in average body
weight, as complementary food intake data from Germany were
unavailable. No UL was established for sodium in infants (Ref. 28).
d. Comparison of International Recommendations
Table 12 shows the sodium AIs established by NASEM, EFSA, and D-A-
CH.
Table 12--Adequate Intakes and Tolerable Upper Intake Levels of Sodium
----------------------------------------------------------------------------------------------------------------
Age range Adequate intake Tolerable upper intake
Organization Year (months) (mg/day) level
----------------------------------------------------------------------------------------------------------------
NASEM........................... 2019 0-6 110 ND.
7-12 370 ND.
EFSA............................ 2019 7-11 200 ND.
[[Page 69065]]
D-A-CH.......................... 2017 0-4 130 ND.
4-12 200 ND.
----------------------------------------------------------------------------------------------------------------
All three expert bodies used human milk composition as the primary
basis for infant sodium reference values, and none established a UL for
sodium in infants (see table 12). The substantially higher NASEM AI for
infants 7-12 months (370 mg/day) compared to EFSA (200 mg/day) and D-A-
CH (200 mg/day) reflects a key methodological difference: NASEM
incorporated estimates of sodium intake from complementary foods, while
EFSA and D-A-CH applied body weight scaling or lacked complementary
food intake data. All expert bodies acknowledged wide variability in
reported human milk sodium concentrations across studies and
populations, which complicates the derivation of precise reference
values and underscores shared uncertainty in this area (Ref. 102).
3. Human Milk Composition
a. Sodium Concentration in Mature Human Milk
There is no clear correlation between maternal dietary sodium
intake and human milk sodium concentrations (Ref. 104). Direct
measurements of sodium concentrations in mature human milk across
individual study timepoints ranged from approximately 82 to 297 mg/L,
reflecting natural variability in human milk (Ref. 102).
b. Recent Data
The iHMNutD study, based on literature synthesis covering mature
milk from 21 to 180 days postpartum, included 12 studies with 924
participants with applicable sodium data (Ref. 8). The pooled weighted
mean sodium concentration was 14.73 <plus-minus> 6.99 mg/100 g, which
converts to approximately 152 <plus-minus> 72 mg/L. Eleven of the 12
studies overlap with sources reviewed by EFSA (Ref. 101) and NASEM
(Ref. 76) and are drawn from U.S. data sources. All studies with sodium
data except the Maternal-Infant Research on Environmental Chemicals
(MIREC) study were conducted before 2000, which was identified as a
data limitation (Ref. 8).
The MIREC Study (Ref. 105) provides additional recent data from a
large Canadian cohort. Samples were collected from 2007 through 2011,
from 3.5 to 10 weeks postpartum. The geometric mean sodium
concentration for the full sample set (n = 770) was 151 <plus-minus> 70
mg/L, and for the DRI variable subset (n = 660) was 153 <plus-minus> 71
mg/L. This study was included among the 12 studies evaluated in the
iHMNutD study (Refs. 8, 105).
The MILQ study (Ref. 36) provides the most comprehensive recent
data on human milk mineral composition. Median sodium concentrations
were 140 mg/L at 1-2 months of age, 111 mg/L at 3-4 months of age, and
97 mg/L at 5-6 months of age, with a pooled 1-6-month median of 111 mg/
L (IQR: 87-156 mg/L). Total daily median sodium intake from 1 to 6
months of age was 96.5 mg/day based on measured milk volumes (Ref. 36).
The pooled weighted mean of 152 mg/L reported by the iHMNutD study
(Ref. 8) is broadly consistent with values from the MIREC study (151-
153 mg/L) (Ref. 105) and converts to approximately 23 mg/100 kcal. The
MILQ study pooled median of 111 mg/L corresponds to approximately 17
mg/100 kcal. Together, these values suggest a central reference range
of roughly 17-23 mg/100 kcal as reflective of typical mature human milk
composition (Ref. 102).
4. International Regulatory Standards for Infant Formula
Sodium specifications for infant formula are generally aligned
among international regulatory bodies and expert organizations, and
most are closely aligned with Codex Alimentarius standards. The Codex
Alimentarius Commission specifies a minimum of 20 mg/100 kcal and a
maximum of 60 mg/100 kcal for both infant formula (0-6 months of age)
(Ref. 12) and follow-on formula (6-12 months of age) (Ref. 37). The EU,
based on recommendations from EFSA (Ref. 7), specifies a minimum of 25
mg/100 kcal and a maximum of 60 mg/100 kcal (Ref. 38). Other countries
that have adopted or proposed specifications aligned with Codex
Alimentarius include FSANZ (20-59 mg/100 kcal) (Ref. 39) and Health
Canada (20-60 mg/100 kcal) (Ref. 40). China specifies 30-59 mg/100 kcal
for infants 0-6 months of age (Ref. 41) but has different standards for
follow-on formula (6-12 months of age; see table 13) (Ref. 42).
In its 1998 comprehensive review, the LSRO Panel recommended a
minimum of 25 mg/100 kcal and a maximum of 50 mg/100 kcal (Ref. 1). The
LSRO Panel based the minimum on the 1989 RDA of 120 mg/day for infants
less than 6 months of age, which for a 5-kg infant consuming 100 kcal/
kg/day equates to 24 mg/100 kcal (rounded to 25 mg/100 kcal). The LSRO
Panel was reluctant to use the mean minus one standard deviation
approach typically applied to other nutrients due to high coefficients
of variation in reported human milk sodium values. The recommended
maximum of 50 mg/100 kcal was based on the 90th percentile of FDA
analyses of infant formulas available at that time (Ref. 1).
Table 13 shows the requirements and recommendations of these
international regulatory bodies and organizations.
Table 13--International Standards and/or Recommendations for Sodium in Infant Formula
----------------------------------------------------------------------------------------------------------------
Age range Minimum (mg/100 Maximum (mg/100
Organization (months) kcal) kcal) Reference
----------------------------------------------------------------------------------------------------------------
U.S. Current Standards.............. 0-12 20 60 21 CFR 107.100.
LSRO \1\............................ 0-12 25 50 LSRO, 1998.
Codex Alimentarius.................. 0-12 20 60 CXS 72-1981, CXS 156-1987.
EU.................................. 0-12 25 60 Commission Delegated
Regulation (EU) 2016/127.
Australia \2\....................... 0-12 20 59 FSANZ P1028.
Canada \3\.......................... 0-12 20 60 Health Canada, 2025.
[[Page 69066]]
China............................... 0-6 30 59 GB 10765-2021.
6-12 ND 84 GB 10766-2021.
----------------------------------------------------------------------------------------------------------------
\1\ Recommended ranges.
\2\ Values converted from per 100 kJ to per 100 kcal (1 kcal = 4.184 kJ).
\3\ Reflects proposed compositional requirements for infant formula.
5. Recent Scientific Evidence on Sodium Intake
Reported sodium intakes in U.S. infants 0-12 months of age
consistently met or exceeded the NASEM AIs across datasets reviewed,
including two iterations of FITS (FITS 2008 and FITS 2016) and one
cycle of NHANES (NHANES 2009-2012) (Refs. 81, 82, 84). For infants 0-
5.9 months of age, FITS 2016 reported a mean usual sodium intake of 214
mg/day (10th-90th percentile: 107-347 mg/day), and FITS 2008 reported a
mean of 175 mg/day for 0-5 months of age (10th-90th percentile: 138-240
mg/day), both exceeding the NASEM AI of 110 mg/day. For infants 6-11.9
months of age, mean usual sodium intakes were higher across all three
surveys: FITS 2016 reported a mean of 400 mg/day (10th-90th percentile:
207-634 mg/day), FITS 2008 reported 528 mg/day (10th-90th percentile:
165-1,104 mg/day), and NHANES 2009-2012 reported 497 mg/day (10th-90th
percentile: 163-946 mg/day), all exceeding the NASEM AI of 370 mg/day.
In FITS 2016, approximately 49 percent of older infants exceeded the
AI, and the wide 10th-to-90th percentile ranges observed across all
surveys, particularly for the 6-11-month age group, indicate
substantial variability in sodium exposure across the infant
population.
Several methodological considerations must be factored in when
interpreting these data. Human milk sodium content is relatively low
and fixed by imputed volume rather than directly measured, so there may
be limited precision when estimating sodium intakes in breastfed
infants. All three studies rely on proxy-reported 24-hour dietary
recalls, subject to recall bias. The statistical methods used to
estimate usual intake distributions differ slightly across studies,
though the approaches are designed to remove within-person variation
and are broadly comparable. Additionally, the AI for sodium in infants
is derived from estimated mean intakes from human milk in healthy,
exclusively breastfed infants rather than from experimental dose-
response data; consequently, exceeding the AI does not necessarily
indicate risk of adverse health effects. Taken together, the data
indicate that mean sodium intakes in U.S. infants meet or exceed the
NASEM AIs across both age subgroups.
6. Evidence Evaluation and Rationale
Based on our review of available scientific data, information, and
international standards, we conclude that the current minimum level of
20 mg/100 kcal and maximum level of 60 mg/100 kcal for sodium in Sec.
107.100 remain appropriate.
a. Maintaining the Minimum Specification of 20 mg/100 kcal
The current minimum specification of 20 mg/100 kcal is supported by
human milk composition data, intake-based reference value approaches,
and international regulatory standards. Recent North American data from
the MIREC study (Ref. 105) and the iHMNutD study (Ref. 8) converge on a
central estimate of approximately 23 mg/100 kcal, while the
multinational MILQ study (Ref. 36) suggests a somewhat lower value of
approximately 17 mg/100 kcal, together defining a central reference
range of approximately 17-23 mg/100 kcal for mature human milk sodium
content. The reaffirmed minimum of 20 mg/100 kcal falls within this
range. Applying the current NASEM AI of 110 mg/day using the same
intake-based approach used by the LSRO yields an estimate of 22 mg/100
kcal, consistent with the North American central estimate and further
supporting the current minimum (Refs. 1, 76, 102).
The current minimum requirement ensures that infant formula
provides sodium intakes that pose a low risk of inadequacy relative to
established AIs. For an infant 0-6 months of age consuming a typical
daily infant formula intake, formula at the minimum specification
provides 105 mg/day of sodium, which is 96 percent of the NASEM AI of
110 mg/day for infants 0-6 months of age. For an infant 0-4 months of
age, this consumption level provides 81 percent of the D-A-CH AI of 130
mg/day for that age subset. For a 6-12-month-old infant consuming a
typical daily intake of infant formula, the minimum specification
provides 81 mg/day from formula, which is 22 percent of the NASEM AI of
370 mg/day, 40 percent of the EFSA AI of 200 mg/day for 7-11-month-old
infants, and 40 percent of the D-A-CH AI of 200 mg/day for 4-12-month-
old infants. However, for infants 7-12 months of age, estimated sodium
intake from complementary foods of approximately 300 mg/day (Ref. 76)
would contribute substantially to total sodium intake, bringing the
total daily intake to approximately 381 mg/day, which is 103 percent of
the NASEM AI (Ref. 102).
The current minimum aligns with international standards. The U.S.
minimum of 20 mg/100 kcal is the same as Codex Alimentarius, FSANZ, and
Health Canada but lower than the EU minimum of 25 mg/100 kcal as well
as China's minimum of 30 mg/100 kcal. The current U.S. specification of
20 mg/100 kcal falls within this international consensus range, and no
compelling evidence from other jurisdictions suggests that changing the
minimum would provide any benefit (Ref. 102).
b. Maintaining the Maximum Specification of 60 mg/100 kcal
The current maximum provides a substantial margin above the central
estimates of sodium content of mature human milk (approximately 17-23
mg/100 kcal) (Refs. 8, 36, 105). The LSRO Panel's 1998 recommendation
of 50 mg/100 kcal as a maximum, although lower than the current
specification, was based on the 90th percentile of sodium content in
infant formulas available at that time, rather than on safety concerns,
as the LSRO Panel found no evidence that excessive sodium intake caused
adverse effects at these levels (Ref. 1). Finally, it is unclear if the
difference between 50 and 60 mg/100 kcal reflects any functional
significance, and the current maximum is aligned with international
standards (Ref. 102).
History of use and available intake data also support safety at the
current maximum. At typical daily infant formula intake volumes, the
current maximum would provide approximately 316 mg/day for an infant 0-
6-months of
[[Page 69067]]
age and 244 mg/day for an infant 6-12 months of age. Findings from the
2016 FITS reported mean sodium intakes of 214 mg/day (0-6 months of
age) and 400 mg/day (6-11 months of age) (Ref. 82), although these
estimates included intake from all dietary sources, including infant
formula and complementary foods (Ref. 102).
Further, no upper limit or CDRR has been established for infants,
and the current specification has not been associated with documented
adverse effects in contemporary populations since 1980 when the Infant
Formula Act was enacted. The evidence base for characterizing sodium
intake-response relationships in infants remains limited, and findings
derived from adult populations were extrapolated to children but not to
infants (Ref. 76). This indicates that the current maximum level is
sufficient to ensure nutritional adequacy in U.S. infants without
adverse effects. The specifications are well-positioned within
international regulatory consensus, and we find no compelling new
evidence demonstrating functional benefits of modification or
documented adverse effects at current levels (Ref. 102).
c. Consideration of the Evidence Base
We acknowledge several uncertainties in the evidence base that
supports maintaining the current specifications. There is variability
in reported mature human milk concentrations for sodium across studies
(82 to 297 mg/L), lack of a sensitive or specific biomarker of sodium
status and intake, and individual variability in infant requirements
(Ref. 102). Nevertheless, FDA concludes that the totality of available
evidence, including contemporary human milk composition data, alignment
with international standards, and the longstanding history of use
without documented safety concerns, supports maintaining the current
minimum and maximum sodium specifications.
I. Vitamin D (Proposed Sec. Sec. 107.10(a)(2), (b)(1), and 107.100(a))
The current requirements for vitamin D in infant formula are a
minimum level of 40 IU/100 kcal (1 [micro]g/100 kcal) and a maximum
level of 100 IU/100 kcal (2.5 [micro]g/100 kcal) (Sec. 107.100). Based
on our analysis of scientific information and data since the LSRO
Panel's 1998 comprehensive study of infant formula nutrients (Ref. 1),
including infant formula vitamin D requirements in international
standards, we propose to increase the required minimum to 2 [micro]g/
100 kcal (80 IU/100 kcal) and to increase the required maximum to 3
[micro]g/100 kcal (120 IU/100 kcal) in Sec. 107.100. We also propose
to change the primary unit of measure from IU to [m
[…truncated; see source link]Indexed from Federal Register on November 2, 2026.
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